The n e w e ng l a n d j o u r na l of
Case Records of the Massachusetts General Hospital
From the Departments of Medicine
(J.M.V., A.C.C., S.E.T.), Radiology (P.P.B.),
and Pathology (S.E.T.), Massachusetts
General Hospital, and the Departments
of Medicine (J.M.V., A.C.C., S.E.T.), Radi‑
ology (P.P.B.), and Pathology (S.E.T.),
Harvard Medical School — both in Boston.
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DOI: 10.1056/NEJMcpc2115846
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CME
at NEJM.org
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m e dic i n e
Founded by Richard C. Cabot
Eric S. Rosenberg, M.D., Editor
David M. Dudzinski, M.D., Meridale V. Baggett, M.D., Kathy M. Tran, M.D.,
Dennis C. Sgroi, M.D., Jo‑Anne O. Shepard, M.D., Associate Editors
Emily K. McDonald, Tara Corpuz, Production Editors
Case 9-2022: A 56-Year-Old Woman
with Fever, Myalgias, Diarrhea, and Cough
Jatin M. Vyas, M.D., Ph.D., Alison C. Castle, M.D., Patrick P. Bourgouin, M.D.,
and Sarah E. Turbett, M.D.​​
Pr e sen tat ion of C a se
Dr. Alison C. Castle: A 56-year-old woman was admitted to this hospital in the spring
of 2020, during the initial surge of the coronavirus disease 2019 (Covid-19) pan-
demic in Boston, because of fever, myalgias, diarrhea, and a dry cough.
Six weeks before this admission, the patient had contact with a person with
confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infec-
tion. At that time, she did not have any symptoms compatible with Covid-19 and
was not tested for SARS-CoV-2.
Four weeks before this admission, in accordance with statewide recommenda-
tions from the Department of Public Health, the patient began isolating at home
with her teenage son, working from home, and having groceries delivered. Two
weeks before this admission, she and her son left home for a few hours to eat
outdoors and spend time in a wooded area; they otherwise remained at home.
Six days before this admission, fever, chills, and myalgias developed. The next
day, watery diarrhea occurred. The patient’s temperature measured at home was
38.3°C; fever persisted despite the intermittent administration of acetaminophen.
Three days before this admission, a frontal headache developed, along with a dry
cough that was associated with a self-limited episode of chest pain. The patient’s
son had had no symptoms, except for a self-limited episode of diarrhea 2 weeks
before the patient’s symptoms developed. On the day of admission, the patient
continued to have fever, so she presented to the emergency department of this
hospital for evaluation.
In the emergency department, the patient reported ongoing myalgias, head-
ache, and cough. There was no nausea, vomiting, rash, shortness of breath, or
anosmia. She had no notable medical history and took no medications. She was
allergic to amoxicillin, with an unknown reaction. She did not smoke tobacco and
drank alcohol rarely; she did not use illicit drugs. The patient lived in an urban
area of New England and had traveled to Canada 6 months before this admission.
She had a pet cat; there was no other animal contact.
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 Case Records of the Massachuset ts Gener al Hospital

Table 1. Laboratory Data.*

Reference Range,
Variable Adults† Hospital Day 1 Hospital Day 2 Hospital Day 7
Hemoglobin (g/dl) 12.0–16.0 13.4 10.5 11.5
Hematocrit (%) 36.0–46.0 40.1 31.5 35.8
Mean corpuscular volume (fl) 80.0–100.0 95.2 94.9 97.0
Platelet count (per μl) 150,000–400,000 106,000 84,000 262,000
White-cell count (per μl) 4500–11,000 4490 3500 6250
Differential count (per μl)
Neutrophils 1800–7700 2990 2290 4430
Lymphocytes 1000–4800 950 620 1140
Monocytes 200–1200 470 500 630
Eosinophils 0–900 40 — —
Basophils 0–300 40 60 60
Sodium (mmol/liter) 134–140 138 137 137
Potassium (mmol/liter) 3.6–5.0 4.4 3.9 4.0
Chloride (mmol/liter) 98–108 97 103 100
Carbon dioxide (mmol/liter) 21–31 26 23 23
Anion gap (mmol/liter) 3–17 25 15 14
Glucose (mg/dl) 70–110 104 138 113
Calcium (mg/dl) 8.4–10.2 8.7 8.1 9.2
Phosphorus (mg/dl) 2.6–4.5 1.0 2.7 —
Urea nitrogen (mg/dl) 7–18 25 15 14
Creatinine (mg/dl) 0.42–1.09 0.86 0.85 1.01
Lactic acid (mmol/liter) 0.5–2.0 — — 0.7
Alanine aminotransferase (U/liter) 10–40 50 111 326
Aspartate aminotransferase (U/liter) 10–42 51 162 326
Alkaline phosphatase (U/liter) 32–92 109 98 137
Total bilirubin (mg/dl) 0.2–1.0 0.5 0.3 0.5
Albumin (g/dl) 3.8–5.0 3.6 3.1 3.5
Lactate dehydrogenase (U/liter) 110–210 276 309 —
High-sensitivity troponin T (ng/liter) 0–9 <6 — —
Creatine kinase (U/liter) 40–150 31 — —
Ferritin (μg/liter) 10–200 487 572 1358
d-dimer (ng/ml) <500 1306 1406 2222
C-reactive protein (mg/liter) <8 36.6 69.2 169.3
Erythrocyte sedimentation rate (mm/hr) 0–20 18 21 62

* To convert the values for glucose to millimoles per liter, multiply by 0.05551. To convert the values for calcium to milli­
moles per liter, multiply by 0.250. To convert the values for phosphorus to millimoles per liter, multiply by 0.3229. To
convert the values for urea nitrogen to millimoles per liter, multiply by 0.357. To convert the values for creatinine to
micromoles per liter, multiply by 88.4. To convert the values for lactic acid to milligrams per deciliter, divide by 0.1110.
To convert the values for bilirubin to micromoles per liter, multiply by 17.1.
† 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.

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

On examination, the patient appeared anxious,

A
but breathing was unlabored. The temperature
was 38.9°C, the blood pressure 121/64 mm Hg,
the heart rate 124 beats per minute, the respira-
tory rate 16 breaths per minute, and the oxygen
saturation 95% at rest and 98% during ambula-
tion, both while she was breathing ambient air.
The patient was alert and oriented to time, place,
and person. There were no focal neurologic
deficits. There was no meningism. The mucous
membranes were dry. The first and second heart
sounds were normal, without additional sounds
or murmurs. There were vesicular breath sounds.
The abdomen was soft and nontender, without B
hepatosplenomegaly. There was no rash. Labora-
tory test results are shown in Table 1.
Dr. Patrick P. Bourgouin: Chest radiography re-
vealed low lung volumes, without evidence of
pneumonia or pulmonary edema.
Dr. Castle: SARS-CoV-2 nucleic acid testing of a
nasopharyngeal specimen was negative, as was
testing for adenovirus, human metapneumovirus,
influenza virus types A and B, parainfluenza vi-
rus types 1 through 4, respiratory syncytial virus, * *
human rhinovirus and enterovirus, Bordetella per-
tussis, B. parapertussis, Chlamydia pneumoniae, and
Mycoplasma pneumoniae. Blood cultures were nega- Figure 1. CT of the Chest.
tive. Urinalysis was negative for leukocyte esterase An axial image in a lung window (Panel A) shows inter‑
and nitrites. The procalcitonin level was 0.36 ng lobular septal thickening (arrows) and mild ground‑glass
per milliliter (reference range, 0.00 to 0.08). Intra- opacities (arrowhead) in the lower lobes. An axial image
in a mediastinal window at the same level (Panel B)
venous fluids and acetaminophen were adminis- shows small bilateral pleural effusions (asterisks).
tered, and the heart rate decreased to 93 beats
per minute. The patient was admitted to this hos-
pital because of concerns that she had Covid-19. Dr. Castle: During the next 3 days, the patient
On the second hospital day, the patient had had ongoing myalgias, headache, and cough.
ongoing diarrhea, headache, and cough, along Fever persisted, and the oxygen saturation re-
with fatigue. The temperature was 40.2°C, the mained normal. Urine antigen testing for legion-
blood pressure 115/64 mm Hg, the heart rate 89 ella and Streptococcus pneumoniae antigens was
beats per minute, and the oxygen saturation negative, as was screening for human immuno-
96% while she was breathing ambient air. The deficiency virus (HIV) types 1 and 2 and nucleic
administration of intravenous fluids was contin- acid testing of a blood specimen for cytomega-
ued. SARS-CoV-2 nucleic acid testing of a second lovirus and Epstein–Barr virus. Blood cultures
nasopharyngeal specimen was negative. Labora- remained negative.
tory test results are shown in Table 1. On the On the seventh hospital day, diarrhea resolved,
third hospital day, the temperature was 38.7°C. but fever, myalgias, headache, and cough persist-
Dr. Bourgouin: Computed tomography (CT) of ed. The physical examination was unchanged, with
the chest, performed without the administration a normal oxygen saturation during ambulation.
of intravenous contrast material, revealed inter- Dr. Bourgouin: Chest radiography revealed no
lobular septal thickening, mild ground-glass evidence of pneumonia.
opacities at the lung bases, and small bilateral Dr. Castle: The procalcitonin level was 0.57 ng
pleural effusions (Fig. 1). per milliliter; other laboratory test results are

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 Case Records of the Massachuset ts Gener al Hospital

shown in Table 1. Levofloxacin was administered. system 1 to make quick, instinctual decisions. In
On the eighth hospital day, fever resolved but this system, speed is valued over accuracy, so we
headache and fatigue persisted. use heuristics to simplify information. System 1
A diagnostic test was performed. works best when timeliness is important and the
consequences for making an error are small. In
Differ en t i a l Di agnosis contrast, we rely on system 2 for slower, more
conscious efforts. In this system, accuracy is
Dr. Jatin M. Vyas: I participated in the care of this valued over speed, so we take the time to evalu-
patient, and I am aware of the final diagnosis. ate evidence and use algorithms. System 2 works
This 56-year-old woman presented with fever, best when timeliness is relatively less important
nonproductive cough, myalgias, hepatitis, throm- and the consequences for making an error are
bocytopenia, increased levels of inflammatory large.
markers in the blood, and ground-glass opaci- Which system is used by diagnosticians? Both.
ties on chest CT, with her presentation occurring When approaching real-world problems, making
during the first surge of the Covid-19 pandemic. quick, instinctual, gut-based decisions (with sys-
The most relevant question for the health care tem 1) can lead to the wrong answer, but me-
team was whether this patient had Covid-19. At thodically applying the scientific method to every
that time, we knew very little about SARS-CoV-2 situation (with system 2) can lead to delayed
infection, and we were using early viral diagnos- responses to routine problems. It is important
tic tests that had been authorized for emergency for clinicians to acknowledge which system is
use by the Food and Drug Administration but being used, to continually assess the outcome,
did not have an established track record to de- and to change decision-making strategies if the
termine performance in a wide spectrum of pa- outcome is not ideal.
tients. The pretest probability of Covid-19 in this
patient was increased by the history of known Cognitive Bias in Clinical Decision Making
exposure to SARS-CoV-2. In addition to recognizing the systems used for
decision making, clinicians must be aware of
Clinical Decision Making during a Pandemic cognitive bias in diagnostic medicine. Types of
The foundation of clinical decision making is cognitive bias include anchoring, ascertainment
built on a thorough history and physical exami- bias, availability bias, and premature closure.2
nation, followed by interpretation of the labora-
tory and imaging studies. These data support Anchoring and Problem Representation
the development of a differential diagnosis, which Problem representation has risen in popularity
guides the treating team in pursuing further as a framing device that is useful for conveying
studies to determine the correct diagnosis and critical information about a case to other team
ultimately leads to the development of a treat- members.3 Inherent to problem representation is
ment plan. the decision to highlight certain features of a
How is this traditional approach modulated case while choosing to minimize or exclude
during a pandemic, when a large number of pa- other data that are perceived to be less relevant.
tients present with the same illness? In other This introduces the potential for anchoring,
words, when the expected diagnosis during the which is the tendency to lock on to key features
pandemic is Covid-19, how and when do we of a patient’s presentation early in the diagnostic
consider alternative diagnoses? When the sheer process, without adjusting the differential diag-
volume of patients rises sharply, there is a ten- nosis on the basis of other available information.
dency to use mental shortcuts to arrive at a diag- In this case, anchoring on four key findings
nosis. This time-saving technique can be used to — fever, myalgias, cough, and ground-glass
provide care to a greater number of patients, but opacities on chest CT — could lead us to focus
there is a cost to this approach. on the diagnosis of Covid-19. However, we would
There are two independent cognitive systems not be considering other potentially important
for decision making: system 1 (fast thinking) and clues, such as elevated aminotransferase levels
system 2 (slow thinking).1 We tend to rely on and thrombocytopenia; any provisional diagno-

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

Premature Closure
Established Disease Premature closure refers to forming a conclu-
Atypical presentation
Typical presentation sion and stopping the diagnostic assessment too
early in the diagnostic process, in which case
alternative possibilities may not be explored and
the wrong diagnosis may be made. This type of
No. of cognitive bias can become more common when
Cases
time for clinical work is limited. One of the best
ways to avoid premature closure is by developing
a differential diagnosis. The most likely diagno-
New Disease sis can still be stated, but other relevant diagno-
ses are also listed. This strategy is particularly
useful when the patient’s illness deviates from
the course expected with a given diagnosis. The
Figure 2. Distribution of Typical and Atypical Presentations of Clinical Disease. following statement is an example of premature
closure: “After reviewing her chest CT, I think
she has Covid-19 pneumonia; we don’t need to
sis that is based only on the presence of fever, send any more tests.”
myalgias, cough, and ground-glass opacities does
not provide an adequate explanation for these Considering Covid-19 in This Patient
laboratory abnormalities. At the time of this This patient presented during the first surge of
patient’s presentation, the potential for anchor- the Covid-19 pandemic, but does she have a
ing was mitigated by our lack of familiarity with typical presentation of Covid-19? In clinical
the breadth of Covid-19 presentations. medicine, we rely on data from many cases to
establish what is “typical” and “atypical” (Fig. 2).
Ascertainment Bias As we gain more experience, with more cases
Ascertainment bias is thinking that is shaped by entering our mental database, we tend to see
previous expectations. Simply put, you see what many typical cases and can begin to identify
you want to see. In its most extreme form, this atypical ones. Eventually, we have seen enough
type of cognitive bias can lead to stereotyping. cases to recognize and manage both typical and
In this case, ascertainment bias could lead us to atypical presentations of any clinical disease.
think that the exposure to SARS-CoV-2 that had This is the principle underlying graduate medi-
occurred 6 weeks before presentation is a risk cal education. During internship, residency, and
factor and diagnostic clue, and therefore, to fellowship training, we are exposed to a high
conclude that the patient probably has Covid-19. number of cases so that we can master our un-
derstanding of typical cases and can recognize
Availability Bias atypical cases.
Availability bias occurs when the perceived like- How is Covid-19 different? During the early
lihood of a disease is based on the ease with days of the pandemic, health care workers
which the disease comes to mind. Thus, it can started to establish descriptions of both typical
lead to a quick diagnosis. Recent experience and atypical cases. The description of typical
with a disease may increase the chances that the cases came first, and important variations were
diagnosis will be made again. During the early described later. Our lack of knowledge about
days of the pandemic, when most patients who Covid-19 at the time of this patient’s presenta-
were admitted to the hospital had Covid-19, tion hindered the diagnostic process. At that
there was ample opportunity for this type of time, we had started to define the typical fea-
diagnostic error. Indeed, this type of cognitive tures of Covid-19 but did not have enough expe-
bias can lead to “tunnel vision,” with minimiza- rience or knowledge to define atypical features.
tion of other diagnostic possibilities. The follow- Although this patient presented with several
ing statement is an example of availability bias: findings suggestive of Covid-19, not all the fea-
“We have seen a lot of patients with Covid-19 tures of her illness were typical of this infection.
this week, so this patient probably has it, too.” Therefore, we needed to investigate whether this

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 Case Records of the Massachuset ts Gener al Hospital

patient had an atypical case of Covid-19. At this There are no diagnostic findings on physical
point in the diagnostic process, we could not examination that can be used to distinguish
rule out this possibility. these viral infections from one another, espe-
cially during early illness. Therefore, the diagno-
Additional Diagnostic Considerations ses must be established by means of laboratory
As we gained more information about the pa- testing.
tient’s clinical course, the team recognized that
our provisional diagnosis was probably the prod- Tickborne Infections
uct of system 1 thinking. In addition, anchoring, Although this patient’s clinical presentation is
ascertainment bias, availability bias, and prema- consistent with tickborne infection and she re-
ture closure were addressed. A review of her ported that she had spent time in a wooded area,
clinical course led us to develop a differential should we really consider this possibility in the
diagnosis. At this point, we considered addi- early spring in New England? Warmer days, in-
tional diagnoses, including bacterial, viral, and creased precipitation, and deviations from typi-
tickborne infections. cal seasonal weather are key effects of climate
change that increase the risk of tickborne dis-
Bacterial Infections eases.4 These factors influence the abundance of
Legionella pneumophila can cause pneumonia. Trans- ticks and their activity. The continued encroach-
mission of the pathogen typically occurs through ment of humans on previously uninhabited wood-
aerosolization of contaminated water or soil. In lands and green areas also increases the risk of
patients with legionellosis, clinical features in- tickborne infections. These observations show
clude gastrointestinal symptoms (nausea, vomit- the adverse effects of climate change on human
ing, and diarrhea). Elevated aminotransferase health.5
levels and hyponatremia are also commonly If this patient has a tickborne infection, can
observed. This patient had diarrhea and elevated we predict which one? Clinical clues and initial
aminotransferase levels, but she had a normal laboratory values can be helpful but are not di-
sodium level. When left untreated, legionellosis agnostic. Lyme disease is a possible cause of this
can progress to multifocal pneumonia, which patient’s illness, but hepatitis, thrombocytopenia,
was not seen in this patient. and the absence of a rash make this diagnosis
S. pneumoniae is the most common community- unlikely. It should be noted that a rash is ob-
acquired bacterial pathogen that causes pneu- served in 80% of patients with Lyme disease,6 so
monia. Patients typically present with cough, its absence does not rule out the disease. An-
shortness of breath, and subjective fever and other possibility is babesiosis, which is caused
chills. S. pneumoniae causes a neutrophilic exu- by the intraerythrocytic parasite Babesia microti.
date in the lung, which typically leads to the This infection typically results in profound ane-
presence of lobar infiltrates on chest radiography mia, which was not present in this patient.
and the detection of rales on physical examina- Anaplasmosis, which is caused by the bacte-
tion. An elevated white-cell count is seen in the rium Anaplasma phagocytophilum, typically leads
majority of patients. Leukopenia, which was to hepatitis, thrombocytopenia, and fever, all of
present in this patient, is typically associated which were features of this patient’s presenta-
with severe disease, which would not be consis- tion. Many symptoms that occur in patients with
tent with the other features of her presentation. anaplasmosis — such as fever, malaise, myalgias,
headache, and chills — can also occur in patients
Viral Infections with common viral illnesses, including influenza
When a patient presents with fever, hepatitis, and and Covid-19. Although no symptoms are spe-
thrombocytopenia, viral causes should be con- cific for anaplasmosis, the opportunity to have
sidered. In addition to investigating Covid-19, we been exposed to ticks is an important feature of
should include HIV, cytomegalovirus, Epstein– the patient history that should be investigated.
Barr virus, and adenovirus infection and acute Nearly 90% of cases of anaplasmosis occur in
viral hepatitis (hepatitis A, B, and E) on the dif- eight states: New York, Connecticut, Massachu-
ferential diagnosis. The clinical presentations of setts, New Hampshire, Vermont, Maine, Minne-
these viral diseases tend to be nonspecific. sota, and Wisconsin.7 The incubation period

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 The n e w e ng l a n d j o u r na l
ranges from 5 to 21 days. Leukopenia is present
in the majority of patients; the white-cell count
in this patient was near the low end of the nor-
mal range. No findings on chest CT are specific
for anaplasmosis. The CT findings observed in
this case (interlobular septal thickening, ground-
glass opacities, and pleural effusions) are non-
specific and can be seen with a wide array of
atypical infections, as well as noninfectious
causes. The main contribution of the imaging
findings in this case was to assist in ruling out
other possible explanations of the patient’s symp-
toms, such as typical bacterial pneumonia.
Human ehrlichiosis may mimic anaplasmosis,
but one third of patients with ehrlichiosis have a
maculopapular or petechial rash, which was not
present in this patient. Also, ehrlichiosis is less
likely to be associated with thrombocytopenia
than is human granulocytic anaplasmosis. On
the basis of the constellation of these findings,
I overcame my bias toward Covid-19 and consid-
ered tickborne infection, particularly anaplas-
mosis, to be the most likely diagnosis in this
patient. To establish this diagnosis, we per-
formed additional testing, including blood test-
ing for Lyme disease antibodies, an examination
of thick and thin blood smears for babesia, and
nucleic acid testing for A. phagocytophilum DNA.
Dr . Jat in M. V y a s’s Di agnosis
Tickborne infection most consistent with ana-
plasmosis.
Di agnos t ic Te s t ing
Dr. Sarah E. Turbett: The diagnostic test in this
case was the detection of A. phagocytophilum DNA
in the blood by means of real-time polymerase-
chain-reaction analysis and DNA hybridization.
Ehrlichia species that cause human ehrlichiosis,
a tickborne infection very similar to anaplasmo-
sis, were not detected in the same sample with
the use of the same method. An examination of
thick and thin blood smears was negative for
babesia parasites. Previous nucleic acid amplifi-
cation testing of two separately obtained naso-
pharyngeal specimens had revealed no detect-
able SARS-CoV-2 RNA.
Anaplasmosis is a zoonotic infection. The
pathogen is transmitted primarily through a bite
from the Ixodes scapularis or I. pacificus tick. The
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of m e dic i n e
geographic distribution of the infection follows
that of its vectors, with cases predominantly oc-
curring in the Northeast, Midwest, and Pacific
Northwest regions of the United States and
southern Canada.7 The incidence typically peaks
in the summer months, when ticks are most
active.7
In patients with anaplasmosis, the spectrum
of illness ranges from asymptomatic infection to
severe disease that requires intensive care.8,9 Most
patients present with fever, headache, and myal-
gias; cough has also been reported.8,10 Common
laboratory abnormalities include leukopenia,
thrombocytopenia, and elevated aminotransfer-
ase levels.8-10 The diagnosis is often made with
the use of nucleic acid amplification testing of
the blood, because this test has higher sensitiv-
ity and specificity than other methods during
acute infection.11,12 Serologic testing is also avail-
able but is most useful for confirming recent
infection during convalescence, since it has
lower sensitivity during early infection.9,11,12 Final-
ly, identification of morulae in neutrophils on
a peripheral-blood smear is also diagnostic of
anaplasmosis; however, the microscopist must
have the expertise to accurately differentiate these
structures from other intracytoplasmic elements
within cells.8,12 Given these technical requirements,
diagnosis through examination of a peripheral-
blood smear is not routinely performed in most
clinical laboratories.
Pathol o gic a l Di agnosis
Anaplasma phagocytophilum infection.
Discussion of M a nagemen t
Dr. Turbett: Doxycycline remains the first-line treat-
ment for anaplasmosis, with treatment courses
ranging from 7 to 10 days.10 Rifampin has also
been used successfully as alternative therapy
when tetracycline antibiotic agents are contrain-
dicated.10 Symptoms typically resolve within 24 to
48 hours after the initiation of antibiotic therapy;
chronic infection is not known to occur.8,10
With the emergence of Covid-19 in the Boston
area at the time of this patient’s presentation,
Covid-19 was appropriately high on the differen-
tial diagnosis for this patient, given her clinical
syndrome. Current guidelines from the Infectious
Diseases Society of America recommend SARS-
nejm.org March 24, 2022
 Case Records of the Massachuset ts Gener al Hospital

CoV-2 nucleic acid amplification testing of a nasopharyngeal specimens performed 24 hours

specimen from the upper respiratory tract in pa-
tients with symptoms compatible with Covid-19,
because this test has high sensitivity and speci-
ficity for the detection of SARS-CoV-2 RNA.13
Testing of a nasopharyngeal specimen has more
than 90% sensitivity in symptomatic patients who
are tested within 5 days after symptom onset;
there is a precipitous decrease in the sensitivity
when patients are tested later in the disease
course, as the viral burden in the upper respira-
tory tract declines.14
The likelihood of positive repeat SARS-CoV-2
nucleic acid amplification testing in patients with
an initial negative test has been reported to be
low (3%).15 However, given the infection control
and public health implications of a positive test,
it is recommended that repeat SARS-CoV-2 nu-
cleic acid amplification testing, preferably with
a specimen from the lower respiratory tract, be
performed 24 to 48 hours after the initial nega-
tive test when there is an intermediate or high
clinical suspicion for Covid-19.16 Although SARS-
CoV-2 nucleic acid amplification testing of a
specimen from the lower respiratory tract has
higher sensitivity than testing of a specimen
from the upper respiratory tract,17 repeat testing
is often performed with a specimen from the
upper respiratory tract for practical purposes:
many patients cannot expectorate sputum, the
personal protective equipment needed to obtain
more invasive samples has been limited through-
out the pandemic, and not all clinical laborato-
ries have a validated SARS-CoV-2 RNA assay for
specimens from the lower respiratory tract.16
In this case, the patient had two negative
SARS-CoV-2 nucleic acid amplification tests of
apart. Given the positive nucleic acid testing for
anaplasma, the high negative predictive value of
the two negative Covid-19 tests, and the features
of her presentation that did not fit with a typical
Covid-19 case (hepatitis and thrombocytopenia),
we could rule out Covid-19 as the diagnosis in
this case.
Fol l ow-up
Dr. Castle: The nucleic acid testing for A. phagocy-
tophilum DNA was positive on hospital day 11,
and empirical treatment with levofloxacin was
switched to first-line therapy with doxycycline.
That day, the patient had no fever and was dis-
charged home with a plan to complete a 10-day
course of doxycycline. Lyme disease testing for
arthropod coinfection would be an appropriate
part of the diagnostic workup in this case. How-
ever, doxycycline can treat both anaplasmosis
and Lyme disease that does not involve the cen-
tral nervous system. Therefore, the results of
additional serologic testing would not have
changed the treatment plan for this patient, so
such testing was not performed. After treat-
ment, the results of liver-function tests normal-
ized, and although the patient reported lingering
fatigue, this predominant symptom continued to
abate over the next few months.
Fina l Di agnosis
Anaplasmosis.
This case was presented at the Medicine Case Conference.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.

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