The n e w e ng l a n d j o u r na l of m e dic i n e

Case Records of the Massachusetts General Hospital

Founded by Richard C. Cabot

Eric S. Rosenberg, M.D., Editor
Virginia M. Pierce, M.D., David M. Dudzinski, M.D., Meridale V. Baggett, M.D.,
Dennis C. Sgroi, M.D., Jo‑Anne O. Shepard, M.D., Associate Editors
Allison R. Bond, M.D., Case Records Editorial Fellow
Emily K. McDonald, Sally H. Ebeling, Production Editors

Case 6-2018: A 35-Year-Old Woman

with Headache, Subjective Fever, and Anemia
Steven J. Knuesel, M.D., J. Sawalla Guseh II, M.D., Rebecca Karp Leaf, M.D.,
Andrea L. Ciaranello, M.D., M.P.H., and George M. Eng, M.D., Ph.D.​​

Pr e sen tat ion of C a se

Dr. J. Sawalla Guseh II: A 35-year-old woman with a history of Crohn’s disease was From the Departments of Medicine (S.J.K.,
admitted to this hospital with headache, subjective fever, and anemia. J.S.G., R.K.L., A.L.C.) and Pathology
(G.M.E.), Massachusetts General Hospi‑
The patient had been in her usual state of health until 1 week before admission, tal, and the Departments of Medicine
when headache, fatigue, and myalgias developed. During the next 2 days, she felt (S.J.K., J.S.G., R.K.L., A.L.C.) and Pathol‑
generally unwell, and the headache did not diminish with the use of acetamino- ogy (G.M.E.), Harvard Medical School
— both in Boston.
phen. Five days before admission, she felt feverish, but her temperature (measured
at home) was 37.8°C. The frequency of bowel movements increased from a baseline N Engl J Med 2018;378:753-60.
DOI: 10.1056/NEJMcpc1712223
of one to three movements per day to five to eight per day; the color of the stool Copyright © 2018 Massachusetts Medical Society.
remained brown, but the consistency became looser, and the stool occasionally
contained small amounts of mucus and blood.
Two days before admission, the patient presented to her primary care physician
for evaluation. The hemoglobin level was reportedly 8 g per deciliter (reference
range, 12 to 16); 6 weeks earlier, the level had been 13 g per deciliter. A provi-
sional diagnosis of a flare of Crohn’s disease was made, and prednisone and intra-
venous fluids were administered. One day before admission, the hemoglobin level
was reportedly 7 g per deciliter, and the patient was asked by her gastroenterolo-
gist to stop taking prednisone and to present to the emergency department of this
hospital for evaluation.
In the emergency department, the patient reported ongoing headache, fatigue,
and myalgias but no dyspnea on exertion or palpitations. She had a history of
infertility, and 4 weeks before admission, she had completed one cycle of intra-
uterine insemination after the administration of follicle-stimulating hormone. She
did not become pregnant, and the last menstrual period began 2 weeks before
admission, with menstrual flow that was heavier and of longer duration than the
flow of previous menstrual cycles.
The patient had received a diagnosis of Crohn’s disease 9 years before admis-
sion. Two years later, cytomegalovirus colitis developed while she was receiving

n engl j med 378;8 nejm.org  February 22, 2018 753

The New England Journal of Medicine
Downloaded from nejm.org on February 21, 2018. For personal use only. No other uses without permission.
Copyright © 2018 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l
infliximab and azathioprine, and her treatment
was changed to infliximab monotherapy. Two
years before admission, she had evidence of
persistent inflammation on endoscopy, and her
treatment was then changed to vedolizumab.
Eight weeks before admission, the frequency of
the vedolizumab dose was increased after the
stool calprotectin level was found to be elevated.
The patient also had a history of primary
sclerosing cholangitis with normal hepatic syn-
thetic function, stable diffuse intrahepatic dis-
ease, and no evidence of a clear dominant
stricture on magnetic resonance cholangiopan-
creatography performed 3 months before admis-
sion. In addition to vedolizumab, medications
included cetirizine and a prenatal multivitamin
with iron. The patient did not smoke tobacco,
drank alcohol rarely, and did not use illicit
drugs. She lived in New England, worked as an
engineer, and was of Asian Indian descent. Her
3-year-old son attended day care regularly. Ten
days before admission, fever and an erythema-
tous facial rash had developed in the son; he was
not evaluated by a medical provider and recov-
ered after 2 days.
On examination, the temperature was 36.7°C,
the blood pressure 103/66 mm Hg, the pulse 96
beats per minute, the respiratory rate 18 breaths
per minute, and the oxygen saturation 100%
while the patient was breathing ambient air. She
was alert and oriented. The sclerae were anic-
teric, and the conjunctivae were pale. The oro-
pharynx appeared normal, and there was no
cervical lymphadenopathy. She did not have a
rash, petechiae, ecchymoses, spider angiomas,
or palmar erythema. Bowel sounds were present,
and the abdomen was soft, nondistended, and
nontender on palpation; there was no spleno-
megaly. The first and second heart sounds were
normal, without murmurs. The arms and legs
did not have edema. A rectal examination re-
vealed brown stool that tested positive for fecal
occult blood.
Blood levels of electrolytes, glucose, total pro-
tein, albumin, folate, vitamin B12, and fibrino-
gen were normal, as were results of kidney-
function and coagulation tests. The total
bilirubin level was 1.1 mg per deciliter (19 μmol
per liter; reference range, 0 to 1.0 mg per deci-
liter [0 to 17 μmol per liter]); it had increased
from a baseline level of 0.3 to 0.7 mg per deci-
liter (5 to 12 μmol per liter). Blood tests for
754 n engl j med 378;8 nejm.org  February 22, 2018
The New England Journal of Medicine
Downloaded from nejm.org on February 21, 2018. For personal use only. No other uses without permission.
Copyright © 2018 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
human immunodeficiency virus (HIV) type 1
p24 antigen and antibodies to HIV types 1 and
2 were negative. Urinalysis revealed a specific
gravity of 1.003 (reference range, 1.001 to 1.035)
and a pH of 6 (reference range, 5 to 9) and was
negative for glucose, blood, protein, bilirubin,
and urobilinogen. Other laboratory test results
are shown in Table 1.
Examination of a peripheral-blood smear re-
vealed sparse red cells, which were normal in
size and central pallor, with scattered sphero-
cytes; there were no schistocytes or reticulo-
cytes. White cells and platelets appeared normal,
except for the presence of a few atypical lympho-
cytes. One unit of packed red cells was trans-
fused, and the patient was admitted to this
hospital. Diagnostic tests were performed.
Differ en t i a l Di agnosis
Dr. Steven J. Knuesel: This 35-year-old woman pre-
sented with fever, malaise, headache, and nor-
mocytic anemia. Her symptoms were initially
attributed to a flare of Crohn’s disease, but the
rapidly progressive anemia was out of propor-
tion to the observed gastrointestinal blood loss.
The reticulocyte count was less than 0.5%, indi-
cating the complete absence of a bone marrow
response to the anemia (i.e., the absence of re-
ticulocyte production). Because anemia is the most
profound finding of this patient’s presentation,
I will focus my differential diagnosis on disease
processes that cause hypoproliferative anemia.
Nutritional Deficiencies
Deficiencies of folate, vitamin B12, and iron can
lead to hypoproliferative anemia. Because this
patient has a history of Crohn’s disease, she is at
risk for impaired absorption of these vitamins
and minerals in the small intestine. Chronic
gastrointestinal blood loss can also lead to iron
deficiency. However, the levels of folate, vitamin
B12, and iron were normal in this patient, and
the rapid decreases in her hemoglobin level and
hematocrit were more severe than the decreases
that would be expected with chronic blood loss,
especially in the absence of a clinically signifi-
cant bleeding event.
Systemic Diseases
Anemia of chronic disease, hypothyroidism, and
chronic kidney disease can affect the activity of
 Case Records of the Massachuset ts Gener al Hospital

erythrocyte precursor cells through aberrant or Table 1. Laboratory Data.*

absent hormonal signaling. However, this patient
had normal kidney function and no signs or Reference
Variable Range, Adults† On Admission
symptoms that would suggest hypothyroidism.
In addition, these processes typically cause a White-cell count (per mm3) 4500–11,000 9.7
reduced bone marrow response to anemia, as Differential count (%)
opposed to the complete lack of reticulocyte Neutrophils 40–70 32.8
production seen in this patient. Lymphocytes 22–44 51.2
Infiltrative processes involving the bone mar-
Monocytes 4–11 3.4
row that can lead to hypoproliferative anemia
include mycobacterial infection, granuloma- Eosinophils 0–8 12.6
tous diseases (e.g., sarcoidosis), and other disor- Platelet count (per mm3) 150,000– 345,000
400,000
ders, such as myelofibrosis, lysosomal storage
diseases, and cancer. This patient did not have Hematocrit (%) 36–46 18.1
any signs or symptoms of other organ involve- Hemoglobin (g/dl) 12–16 6.6
ment that would be suggestive of granulomatous Mean corpuscular volume (fl) 80–100 90.0
disease or cancer. She was receiving treatment Mean corpuscular hemoglobin (pg) 26–34 32.8
with vedolizumab, an anti-integrin antibody; Mean corpuscular hemoglobin level (g/dl) 31–37 36.5
however, vedolizumab does not cause clinically 3)
Red-cell count (per mm 4,000,000– 2,010,000
significant systemic immunosuppression, and the 5,200,000
risk of reactivation of latent tuberculosis is much Red-cell distribution width (%) 11.5–14.5 13.6
lower among patients receiving this drug than
Reticulocyte count (%) 0.5–2.5 <0.5
among those receiving anti–tumor necrosis factor
therapies or immunosuppressive agents.1 Finally, Fibrinogen (mg/dl) 150–400 329
I would expect infiltrative processes involving Alkaline phosphatase (U/liter) 30–100 101
the bone marrow to affect the platelet and Bilirubin (mg/dl)
white-cell counts, which were normal in this Total 0–1.0 1.1
patient. Overall, an infiltrative process involving Direct 0–0.4 <0.2
the bone marrow is unlikely to explain the ane-
Alanine aminotransferase (U/liter) 7–33 18
mia in this case.
Aspartate aminotransferase (U/liter) 9–32 36
Exposures Lactate dehydrogenase (U/liter) 98–192 408
This patient had no known exposure to radiation Ferritin (μg/liter) 10–200 1036
or to medications that are classically associated Iron (μg/dl) 30–160 226
with bone marrow toxicity, such as sulfonamides Iron-binding capacity (μg/dl) 230–404 232
or mycophenolate mofetil.2,3 Although azathio-
prine can cause anemia, her exposure to this * To convert the values for bilirubin to micromoles per liter, multiply by 17.1. To
convert the values for iron and iron-binding capacity to micromoles per liter,
medication had occurred in the distant past. multiply by 0.1791.
Her current medications (vedolizumab, cetirizine, † Reference values are affected by many variables, including the patient popula‑
and prenatal vitamins) are not associated with tion and the laboratory methods used. The ranges used at Massachusetts
General Hospital are for adults who are not pregnant and do not have medi‑
anemia. cal conditions that could affect the results. They may therefore not be appro‑
priate for all patients.
Pure Red-Cell Aplasia
Does this patient have pure red-cell aplasia?
Antibody-mediated pure red-cell aplasia can be related pure red-cell aplasia is most commonly
induced by pregnancy, viral hepatitis, HIV infec- seen in patients with advanced disease, and this
tion, leukemia, lymphoma, thymoma, and auto- patient is HIV-negative. Although pure red-cell
immune conditions. Although this patient had aplasia can be associated with autoimmune con-
undergone intrauterine insemination in an attempt ditions, it is far more common with rheumatoid
to become pregnant, she had a negative preg- arthritis and systemic lupus erythematosus than
nancy test. The presence of normal aminotrans- with inflammatory bowel disease.4 Finally, the
ferase levels makes viral hepatitis unlikely. HIV- sudden onset of this patient’s anemia suggests a

n engl j med 378;8 nejm.org  February 22, 2018 755

The New England Journal of Medicine
Downloaded from nejm.org on February 21, 2018. For personal use only. No other uses without permission.
Copyright © 2018 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

rapid process rather than a slowly developing lytic anemia. I will therefore now focus my dif-
autoimmune disease or cancer. ferential diagnosis on causes of hemolytic anemia
that could contribute to a transient aplastic
Parvovirus B19 Infection crisis in a patient with suspected parvovirus B19
Parvovirus B19 infection is an important consid- infection.
eration in this case, because this virus directly
infects erythrocytes and erythrocyte precursor Hemolytic Anemia
cells and causes hypoproliferative anemia. This A critical step in the evaluation of hemolytic
patient’s initial symptoms of fever, malaise, and anemia is to establish the site of red-cell de-
headache are typical of parvovirus B19 infection struction as either intravascular or extravascu-
in adults. In children, the classic manifestation lar. Intravascular hemolysis causes free hemo-
of parvovirus B19 infection is erythema infec- globin to be released into the plasma, where it
tiosum (fifth disease), which is characterized is bound by haptoglobin. When hemolysis oc-
by a “slapped cheek” rash. The rash is consid- curs at a rapid rate, the binding capacity of hap-
ered to be diagnostic of parvovirus B19 infec- toglobin in the blood may be overwhelmed,
tion in children, and serologic testing is typi- causing the level of free hemoglobin in the
cally not pursued.3,5,6 A rash that was highly plasma to rise. Free hemoglobin in the plasma
suggestive of erythema infectiosum had devel- may then be filtered into the urine, causing
oped in the patient’s son 10 days before her hemoglobinuria.10 In this patient, hemoglobin-
admission, providing a plausible history of ex- uria was not detected on urinalysis, which sug-
posure in this patient.7 I suspect that her fever, gests that the site of her hemolysis was most
malaise, and headache were due to parvovirus B19 likely extravascular. Extravascular hemolysis can
infection and that her hypoproliferative anemia be the result of abnormalities intrinsic to the red
was due to direct viral infection of the erythroid cells or extrinsic processes that hasten red-cell
precursor cells. destruction.
Can this patient’s anemia be attributed solely
to cessation of red-cell production due to parvo- Intrinsic Causes of Red-Cell Destruction
virus? Although acute parvovirus B19 infection Red-Cell Membranopathies
often causes temporary suppression of erythro- Red-cell membranopathies, such as hereditary
poiesis, it rarely leads to the severe decline in spherocytosis and hereditary elliptocytosis, are
hemoglobin level that was observed in this pa- inherited conditions in which hemolysis results
tient.8 Under normal conditions, red cells are from increased red-cell fragility. Although mild
expected to survive in vivo for 120 days, with a forms of these diseases can be detected later in
daily rate of red-cell destruction of 0.83%.9 Parvo- life, the diseases are typically diagnosed in child-
virus infection causes failure of the bone mar- hood; affected patients typically have a family
row to compensate for this normal red-cell loss, history of hemolytic anemia. In a patient with
thereby leading to a predictable decline in the either hereditary spherocytosis or hereditary ellip-
hemoglobin level. However, this patient presented tocytosis, I would expect examination of a periph-
with a hemoglobin level of 7 grams per deciliter, eral-blood smear to reveal more abundant
which is lower than the level that would be ex- ­abnormal cells rather than the scattered sphe-
pected if the anemia were attributed solely to rocytes that were reported in this case. Overall,
suppression of erythropoiesis due to parvovirus a red-cell membranopathy is unlikely in this
B19. The rapid progression of anemia suggests patient.
a second process, either loss of red cells or an
increased rate of red-cell destruction. In a pa- Glucose-6-Phosphate Dehydrogenase Deficiency
tient with parvovirus B19 infection, this rapid Could this patient have a glucose-6-phosphate
progression of anemia is called a transient dehydrogenase (G6PD) deficiency that is un-
aplastic crisis. This patient did not have a his- masked by an acute viral illness? Patients with
tory of substantial blood loss, and the elevated this condition have intracorpuscular injury dur-
blood levels of unconjugated bilirubin and lac- ing times of oxidative stress. As cytoskeletal ele-
tate dehydrogenase are consistent with hemo- ments are oxidized and the red-cell membrane is

756 n engl j med 378;8 nejm.org  February 22, 2018

The New England Journal of Medicine

Downloaded from nejm.org on February 21, 2018. For personal use only. No other uses without permission.
Copyright © 2018 Massachusetts Medical Society. All rights reserved.
 Case Records of the Massachuset ts Gener al Hospital
disrupted, the red cell becomes fragile and vul-
nerable to hemolytic mechanisms in the spleen
and liver. If this patient were to have a G6PD
deficiency,11 I would expect it to have been iden-
tified earlier in life, particularly given her his-
tory of Crohn’s disease and frequent contact
with the medical system.
Extrinsic Causes of Red-Cell Destruction
Malaria and babesiosis classically cause red-cell
destruction. Malaria is unlikely in this patient,
because she lives in the northeastern United
States and has not traveled recently. She lives in
an area in which Babesia microti is endemic, but
she has no known history of exposure to ticks
or of blood transfusions,12 and examination of a
peripheral-blood smear did not reveal any intra-
cellular parasites. Furthermore, she had no evi-
dence of splenomegaly on physical examination,
and therefore, conditions such as hypersplenism
and splenic sequestration of the red cells are
unlikely.
Autoimmune Hemolytic Anemia
Could this patient have an autoimmune hemo-
lytic anemia? Autoimmune hemolytic anemia is
classified as cold or warm, according to the
optimal temperature at which antibodies attach
to red cells. In cold autoimmune hemolytic ane-
mia, such as that seen in patients with Myco-
plasma pneumoniae infection, IgM autoantibodies
against erythrocyte surface antigens cause red-
cell destruction. The mechanism of the red-cell
destruction is either complement fixation and
the related formation of the membrane attack
complex or the engulfing of red cells by phago-
cytic cells in the liver or spleen. In patients with
cold autoimmune hemolytic anemia, spherocytes
are not commonly seen on examination of a
peripheral-blood smear.13
In warm autoimmune hemolytic anemia, IgG
autoantibodies against erythrocyte surface anti-
gens affix themselves to red-cell membranes,
usually at a temperature of 37°C. The Fc receptor
of macrophages in the spleen interacts with the
Fc fragment of the IgG molecule on the surface
of the red cell, resulting in phagocytosis. The
phagocytosis is often only partial, and the un-
consumed remainder of the red cell forms a
spherocyte. Given that spherocytes were noted
on examination of a peripheral-blood smear in
n engl j med 378;8 nejm.org  February 22, 2018
The New England Journal of Medicine
Downloaded from nejm.org on February 21, 2018. For personal use only. No other uses without permission.
Copyright © 2018 Massachusetts Medical Society. All rights reserved.
this patient, it is likely that she had warm auto-
immune hemolytic anemia.14
In summary, I suspect that this patient had a
transient aplastic crisis due to parvovirus B19
infection that was superimposed on preexisting
warm autoimmune hemolytic anemia. I would
recommend tests for IgM and IgG antibodies to
parvovirus B19, as well as a nucleic-acid test and
a direct antiglobulin (Coombs’) test.
Dr. Meridale Baggett (Medicine): Dr. Guseh, what
was your clinical impression when you evaluated
this patient?
Dr. Guseh: When I met this patient, I thought
several features of her presentation were notable.
Her son had had a self-limiting illness with fever
and rash that was consistent with erythema in-
fectiosum due to parvovirus B19 infection. Also,
reticulocytes were not detected in the peripheral
blood, which indicated a complete lack of erythro-
poiesis.
This patient’s presentation was consistent with
acquired pure red-cell aplasia, and we did not
have the benefit of knowing whether the aplasia
would be temporary or sustained. Among pa-
tients with parvovirus B19 infection, a transient
aplastic crisis typically occurs in those who are
immunocompetent, whereas chronic pure red-
cell aplasia typically occurs in those who are im-
munocompromised. Given this patient’s history
of autoimmunity, we considered the possibility
that she also had an autoimmune hemolytic
process. We noted that the degree of anemia was
out of proportion to the degree of hemolysis,
and therefore, we suspected that her illness was
most likely a transient aplastic crisis (or a chronic
pure red-cell aplasia, if sustained) due to parvo-
virus B19 infection that was superimposed on a
low-grade autoimmune hemolytic process.
Cl inic a l Di agnosis
Transient aplastic crisis due to parvovirus B19
infection and low-grade autoimmune hemolytic
anemia.
Dr . S te v en J. K nue sel’s
Di agnosis
Transient aplastic crisis due to parvovirus B19
infection that was superimposed on warm auto-
immune hemolytic anemia.
757
 The n e w e ng l a n d j o u r na l
Pathol o gic a l Discussion
Dr. George M. Eng: We performed enzyme immu-
noassays for IgM and IgG antibodies to parvovi-
rus B19. The tests were positive at the time of
admission (IgM level, 14.1 [reference range, <0.9];
IgG level, 1.4 [reference range, <0.9]). The IgM
antibody level decreased rapidly during the first
month and had become only slightly detectable
by the third month; the IgG antibody level had
an inverse trend, increasing during the first
month and reaching a plateau thereafter. These
findings are consistent with seroconversion.3
Furthermore, a qualitative polymerase-chain-
reaction (PCR) assay for parvovirus B19 was
positive at the time of admission and remained
positive throughout the patient’s course, further
confirming the diagnosis of parvovirus B19 in-
fection.
We performed additional tests to determine
whether this patient had underlying hemolytic
anemia. Two months before admission, the pa-
tient had undergone testing related to planned
fertility treatments. An antibody screening panel
(the first step in a screening process to detect
the presence of alloantibodies and autoanti-
bodies against red cells) was panreactive. A di-
rect antiglobulin test (performed with the use
of an anti-IgG reagent and the patient’s own red
cells) was positive, which confirmed the pres-
ence of an autoantibody. However, at that time,
the patient’s hemoglobin level was normal; there-
fore, these findings were thought to be most
compatible with a warm autoantibody to red
cells, leading to minimal (or no) hemolysis.
On admission, another antibody screening
panel was panreactive, with increased reactivity
as compared with the previous panel. A repeat
direct antiglobulin test was positive. Further test-
ing performed with autoadsorption (i.e., with
the use of the patient’s red cells to remove the
autoantibody and leave other potential diagnos-
tic antibodies in the serum) showed no evidence
of an underlying alloantibody.
Discussion of M a nagemen t
Dr. Rebecca Karp Leaf: The patient was known to
have had a positive direct antiglobulin test in the
past, without concurrent anemia. However, on
this admission, she had anemia and an elevated
758 n engl j med 378;8 nejm.org  February 22, 2018
The New England Journal of Medicine
Downloaded from nejm.org on February 21, 2018. For personal use only. No other uses without permission.
Copyright © 2018 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
lactate dehydrogenase level, and spherocytes were
noted on examination of a peripheral-blood smear.
Along with the positive direct antiglobulin test,
these findings are consistent with a diagnosis of
autoimmune hemolytic anemia.
We hypothesized that a clinically significant
autoimmune hemolytic anemia did not develop
in this patient until she was infected with par-
vovirus B19 and her aplastic marrow was unable
to compensate for the red-cell destruction in the
peripheral blood. Parvovirus B19, in addition to
causing such bone marrow suppression, may have
also directly exacerbated an underlying autoim-
mune hemolytic anemia through the induction
of antiviral antibodies that had self-antigen
recognition.15,16
While the patient was in the hospital, she
received a transfusion of additional units of
packed red cells, and her anemia transiently di-
minished. However, despite receiving supportive
care, the patient continued to have anemia and
marked fatigue. Although she had persistent
parvovirus B19 viremia, we considered treating
her with glucocorticoids, the standard of care
for most patients with warm autoimmune hemo-
lytic anemia. After consultation with the Infec-
tious Disease team, we initiated treatment with
prednisone. Four weeks after this treatment was
initiated, the patient’s hemoglobin level increased,
and the dose of prednisone was slowly tapered.
Folic acid was also administered daily to meet
the increased demands for erythropoiesis in the
context of hemolysis. After 10 weeks of predni-
sone therapy, the patient’s hemoglobin level,
lactate dehydrogenase level, and reticulocyte
count normalized. Her fatigue diminished, and
she had a consultation with the Perinatal Infec-
tious Disease service to discuss the possibility of
becoming pregnant.
Dr. Andrea L. Ciaranello: When I saw the patient
in the Perinatal Infectious Disease clinic, she
had one overarching question: When is it safe to
try to conceive? She was hoping to proceed with
intrauterine insemination and, if necessary, to
then try in vitro fertilization.
To address this question, we considered two
main issues. First, we considered the way in
which maternal parvovirus infection affects a
developing fetus and whether the timing of ma-
ternal infection is correlated with the risk of
transmission to the baby. Second, we considered
 Case Records of the Massachuset ts Gener al Hospital

the amount of time that parvovirus persists after
symptomatic infection, including the effect of
prednisone therapy on the duration of viremia,
and whether this is correlated with the risk of
transmission to the baby.
Maternal parvovirus infection during preg-
nancy may have several devastating consequences
for the developing fetus. Intrauterine fetal death
occurs at a very high rate (≥10%) in mothers
who are infected before 20 weeks of gestation
and occurs at a much lower rate (<1%) in moth-
ers who are infected at 20 weeks of gestation or
later. Anemia, high-output heart failure, and hy-
drops fetalis can occur in the fetus as a result of
destruction of fetal red-cell precursor cells and
myocardial cells. If these conditions develop, the
risk of intrauterine fetal death is high unless
intrauterine transfusion of red cells is possible.
Very limited data are available regarding fetal
outcomes associated with preconception infec-
tion. Routine antepartum screening does not
include a test for recent parvovirus infection.
However, it is likely that some women with
young children are infected between pregnan-
cies, which suggests that preconception viremia
probably does not cause substantial fetal mor-
bidity.17 In addition, in other infections, such as
cytomegalovirus infection, the risk of fetal in-
fection declines with each week that elapses
between maternal infection and conception.18
The duration of parvovirus B19 viremia in
immunocompetent patients has classically been
described as short. However, in patients with
severe immunosuppression — such as patients
who have recently undergone transplantation or
chemotherapy or those with advanced, untreated
HIV infection — prolonged viremia is often seen,
usually in the context of prolonged red-cell apla-
sia and anemia. In such immunosuppressed pa-
tients, the use of glucocorticoids can further
prolong both the viremia and the anemia.19,20
However, there are no data on the effect of glu-
cocorticoid use on viremia duration in immuno-
competent patients. Vedolizumab, which this
patient also received, is highly specific to the
gastrointestinal tract and therefore is less likely
to cause systemic immunosuppression than many
other agents.
In this patient, we monitored the results of
quantitative and qualitative PCR assays for parvo-
virus B19, as well as the results of tests for IgG
and IgM antibodies to parvovirus B19, for the 24
weeks after admission. At 24 weeks, the viral
load was undetectable on the quantitative PCR
assay (<100 copies per milliliter of plasma), but
the qualitative PCR assay remained positive. We
plan to continue to monitor the PCR assays, and
if they remain negative or low-level positive,
parvovirus B19 infection would not be a contra-
indication to proceeding with intrauterine in-
semination or in vitro fertilization.
Fina l Di agnosis
Anemia due to parvovirus B19 infection and
autoimmune hemolytic anemia.
This case was presented at the Medical Case Conference.
No potential conflict of interest relevant to this article was
reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.

References
1. Zerôncio M, Blake A, Rana-Khan Q,
Palo W, Bhayat F. Tuberculosis in patients
treated with vedolizumab: clinical trial
and post-marketing case series. J Crohns
Colitis 2017;​11:​Suppl 1:​S410-S411.
2. Laporte JR, Ibáñez L, Ballarín E, Pérez
E, Vidal X. Fatal aplastic anaemia asso­
ciated with nifedipine. Lancet 1998;​352:​
619-20.
3. Young NS, Brown KE. Parvovirus B19.
N Engl J Med 2004;​350:​586-97.
4. Means RT Jr. Pure red cell aplasia.
Blood 2016;​128:​2504-9.
5. Fifth disease (parvovirus B19). Wash-
ington, DC:​American Academy of Pedi-
atrics, 2011 (https:/​/​w ww​.healthychildren​
.org/​English/​health-issues/​conditions/​skin/​
Pages/​Fifth-Disease-Parvovirus-B19​.aspx).
6. Plummer FA, Hammond GW, Forward
K, et al. An erythema infectiosum–like ill-
ness caused by human parvovirus infec-
tion. N Engl J Med 1985;​313:​74-9.
7. Risks associated with human parvovi-
rus B19 infection. MMWR Morb Mortal
Wkly Rep 1989;​38:​81-88, 93-97.
8. Potter CG, Potter AC, Hatton CS, et al.
Variation of erythroid and myeloid pre-
cursors in the marrow and peripheral
blood of volunteer subjects infected with
human parvovirus (B19). J Clin Invest
1987;​79:​1486-92.
9. Allison AC. Turnovers of erythrocytes
and plasma proteins in mammals. Nature
1960;​188:​37-40.
10. Greer J, Arber DA, Glader B, et al, eds.
Wintrobe’s clinical hematology. 13th ed.
Philadelphia:​Lippincott Williams & Wil­
kins, 2014.
11. Gelehrter T, Collins FS, Ginsburg D.
Cytogenetics. In:​Gelehrter T, Collins, FS,
Ginsburg, D, eds. Principles of medical
genetics. Philadelphia:​Lippincott Williams
& Wilkins, 1998:​181.
12. Vannier E, Krause PJ. Human babesio-
sis. N Engl J Med 2012;​366:​2397-407.
13. Anderson DR, Kelton JG. Hemolysis
and thrombocytopenia. In:​Bowdler A, ed.
The complete spleen: structure, function,
and clinical disorders. 2nd ed. New York:​
Springer Science and Business Media,
2002:​193-213.
14. Dhaliwal G, Cornett PA, Tierney LM
Jr. Hemolytic anemia. Am Fam Physician
2004;​69:​2599-606.

n engl j med 378;8 nejm.org  February 22, 2018 759

The New England Journal of Medicine
Downloaded from nejm.org on February 21, 2018. For personal use only. No other uses without permission.
Copyright © 2018 Massachusetts Medical Society. All rights reserved.
 Case Records of the Massachuset ts Gener al Hospital

15. Bönsch C, Kempf C, Ros C. Interac-
tion of parvovirus B19 with human erythro-
cytes alters virus structure and cell mem-
brane integrity. J Virol 2008;​82:​11784-91.
16. Giovannetti G, Pauselli S, Barrella G,
et al. Severe warm autoimmune haemo-
lytic anaemia due to anti-Jk(a) autoanti-
body associated with parvovirus B19 in-
fection in a child. Blood Transfus 2013;​
11:​634-5.
17. Enders M, Weidner A, Zoellner I, Searle
K, Enders G. Fetal morbidity and mortal-
ity after acute human parvovirus B19 in-
fection in pregnancy: prospective evalua-
tion of 1018 cases. Prenat Diagn 2004;​24:​
513-8.
18. Manicklal S, Emery VC, Lazzarotto T,
Boppana SB, Gupta RK. The “silent” global
burden of congenital cytomegalovirus.
Clin Microbiol Rev 2013;​26:​86-102.
19. Chen MY, Hung CC, Fang CT, Hsieh
SM. Reconstituted immunity against per-
sistent parvovirus B19 infection in a pa-
tient with acquired immunodeficiency
syndrome after highly active antiretro­
viral therapy. Clin Infect Dis 2001;​ 32:​
1361-5.
20. Plentz A, Hahn J, Holler E, Jilg W,
Modrow S. Long-term parvovirus B19
viraemia associated with pure red cell
aplasia after allogeneic bone marrow trans-
plantation. J Clin Virol 2004;​31:​16-9.
Copyright © 2018 Massachusetts Medical Society.

lantern slides update

The Massachusetts General Hospital is no longer providing Lantern Slide
sets. If you have any questions please contact the Lantern Slides Service,
Department of Pathology, Massachusetts General Hospital, Boston, MA
02114 (telephone 617-726-2974) or email Pathphotoslides@partners.org.

760 n engl j med 378;8 nejm.org  February 22, 2018

The New England Journal of Medicine

Downloaded from nejm.org on February 21, 2018. For personal use only. No other uses without permission.
Copyright © 2018 Massachusetts Medical Society. All rights reserved.