Nejmcpc 2100283

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Case Records of the Massachusetts General Hospital
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Eric S. Rosenberg, M.D., Editor
David M. Dudzinski, M.D., Meridale V. Baggett, M.D., Kathy M. Tran, M.D.,
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Emily K. McDonald, Tara Corpuz, Production Editors
Case 18-2021: An 81-Year-Old Man

with Cough, Fever, and Shortness of Breath
Kathryn A. Hibbert, M.D., Reece J. Goiffon, M.D., Ph.D.,
and Annemarie E. Fogerty, M.D.
Pr e sen tat ion of C a se
From the Departments of Medicine Dr. Matthew J. Emmett (Medicine): An 81-year-old man was admitted to this hospital
(K.A.H., A.E.F.) and Radiology (R.J.G.), with fever, cough, and shortness of breath during the pandemic of coronavirus
Massachusetts General Hospital, and
the Departments of Medicine (K.A.H., disease 2019 (Covid-19), the disease caused by severe acute respiratory syndrome
A.E.F.) and Radiology (R.J.G.), Harvard coronavirus 2 (SARS-CoV-2).
Medical School — both in Boston. The patient had been in his usual state of health until 3 days before this admis-
N Engl J Med 2021;384:2332-40. sion, when fever and cough developed. On the morning of admission, he noted an
DOI: 10.1056/NEJMcpc2100283 abrupt onset of shortness of breath at rest and dyspnea on exertion. There was also
Copyright © 2021 Massachusetts Medical Society.
substernal chest pain on the left side that worsened with deep breaths and when
he lay down. The patient’s son called emergency medical services, and the patient
was brought to the emergency department of this hospital for further evaluation.
On arrival at the emergency department, the patient described ongoing chest
pain and shortness of breath. The son reported that the patient had fallen at home
2 days before admission, but the patient did not remember falling and the son was
not able to provide details about the nature or circumstances of the fall. The pa-
tient reported no pain in his abdomen, arms, legs, or groin and no headache.
The patient had a history of hypertension. During a previous evaluation for
cough, he was reportedly told that he had a lung disease that had “caused the lung
tissue to harden.” Before the onset of his most recent symptoms, he had walked
outside on a daily basis without limitation from shortness of breath. He took an
unknown medication for hypertension. The patient did not smoke tobacco, use
illicit drugs, or drink alcohol. He lived in an apartment with his wife.
On examination, the temperature was 37.9°C, the blood pressure 157/95 mm
Hg, the pulse 112 beats per minute, the respiratory rate 30 breaths per minute,
and the oxygen saturation 91% while the patient was breathing ambient air. The
respiratory rate decreased to 28 breaths per minute and the oxygen saturation
improved to 96% with the administration of supplemental oxygen through a nasal
cannula at a rate of 4 liters per minute. The body-mass index (the weight in kilo-
grams divided by the square of the height in meters) was 22.8. Retractions were
noted in the supraclavicular areas. Inspiratory crackles could be heard at the lung
2332 n engl j med 384;24 nejm.org June 17, 2021
The New England Journal of Medicine

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Case Records of the Massachuset ts Gener al Hospital
bases. The heart sounds were regular, with tachy-

Table 1. Laboratory Data.*
cardia but no murmur. There was no tenderness
on palpation of the chest wall and no edema in Reference
the legs. Laboratory test results are shown in Range,
Variable Adults† On Admission
Table 1.
Dr. Reece J. Goiffon: A single-view portable an- Sodium (mmol/liter) 135–145 138
teroposterior radiograph of the chest showed Potassium (mmol/liter) 3.4–4.8 3.8
bilateral patchy airspace opacities that were Chloride (mmol/liter) 100–108 99
more extensive in the left lung than in the right Carbon dioxide (mmol/liter) 23.0–31.9 18
lung, with predominance in the peripheral lower Urea nitrogen (mg/dl) 8–25 17
lung zones and with relative sparing of the peri- Creatinine (mg/dl) 0.60–1.50 1.0
hilar regions (Fig. 1). These opacities were su- Glucose (mg/dl) 70–110 118
perimposed on mild apical and bibasilar bron- Lactic acid (mmol/liter) 0.5–2.0 3.5
chiectasis and bibasilar reticular opacities. A Alanine aminotransferase (U/liter) 10–55 70
radiograph of the pelvis showed no fracture. Aspartate aminotransferase (U/liter) 10–40 128
Dr. Emmett: An electrocardiogram showed sinus Alkaline phosphatase (U/liter) 45–115 128
tachycardia. Blood samples were obtained for Total bilirubin (mg/dl) 0.0–1.0 1.7
culture, and a nasopharyngeal swab was submit- Direct bilirubin (mg/dl) 0.0–0.4 0.5
ted to test for SARS-CoV-2 RNA. Azithromycin Albumin (g/dl) 3.3–5.0 3.5
and ceftriaxone were administered, and the pa- Hematocrit (%) 36–46 44.5
tient was admitted to the hospital. Hemoglobin (g/dl) 12–16 15
On arrival at the medical floor, the patient White-cell count (per μl) 4500–11,000 11,920
was in respiratory distress, with a respiratory Differential count (per μl)
rate of 40 breaths per minute and an oxygen Neutrophils 1800–7700 10,100
saturation of 86% while he was receiving supple- Lymphocytes 1000–4800 850
mental oxygen through a nasal cannula at a rate Monocytes 200–1200 600
of 4 liters per minute. The patient was restless Eosinophils 0–900 40
and appeared uncomfortable, moving around in Immature granulocytes 0–100 280
the bed and attempting to sit up; he reported Platelet count (per μl) 150,000–400,000 179,000
severe pleuritic chest pain. The oxygen flow rate Prothrombin time (sec) 11.5–14.5 14.7
was adjusted to 5 liters per minute, and mor-
Prothrombin-time international 0.9–1.1 1.2
phine was administered intravenously. A repeat normalized ratio
electrocardiogram showed sinus tachycardia. d-dimer (ng/ml) <500 >10,000
A diagnostic test was performed. Fibrinogen (mg/dl) 150–400 679
Ferritin (μg/liter) 20–300 1760
Differ en t i a l Di agnosis Lactate dehydrogenase (U/liter) 110–210 1340
C-reactive protein (mg/liter) <8 185
Dr. Kathryn A. Hibbert: This 81-year-old man with Erythrocyte sedimentation rate (mm/hr) 0–13 84
a history of hypertension and possible chronic Creatine kinase (U/liter) 60–400 1607
lung disease presents with fever, cough, acute N-terminal pro–B-type natriuretic peptide 0–1800 495
onset of shortness of breath, and focal pleuritic (pg/ml)
chest pain. His evaluation is notable for tachy- High-sensitivity troponin T (ng/liter) 0–14 62
pnea, tachycardia, hypoxemia, and signs of in-
creased work of breathing. Imaging studies * 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
show bilateral peripheral opacities. His clinical by 88.4. To convert the values for glucose to millimoles per liter, multiply by
trajectory is also a concern, given the progres- 0.05551. To convert the values for lactic acid to milligrams per deciliter, divide
sion of hypoxemia and respiratory distress with- by 0.1110. To convert the values for bilirubin to micromoles per liter, multiply
by 17.1.
in hours after presentation to the hospital. Taken † Reference values are affected by many variables, including the patient popu
together, these features indicate that this patient lation and the laboratory methods used. The ranges used at Massachusetts
presents with a rapidly worsening pneumonia General Hospital are for adults who are not pregnant and do not have medi‑
cal conditions that could affect the results. They may therefore not be appro‑
syndrome, which will be the starting point for priate for all patients.
building a differential diagnosis.
n engl j med 384;24 nejm.org June 17, 2021 2333

perihilar and radiate outward. In addition, this

patient did not report concomitant symptoms of
weight gain, leg swelling, abdominal discom-
fort, orthopnea, or paroxysmal nocturnal dys-
pnea that are classic features of heart failure.
His history of fever is also not consistent with
cardiogenic pulmonary edema.
Rapidly growing cancers such as lymphoma
can mimic infection with the presence of both
systemic symptoms and focal opacities. None-
theless, the tempo and acuteness of this pa-
tient’s disease course, which occurred over a
3-day period, would be atypical for cancer, espe-
cially given that he reported no subacute symp-
toms such as unintentional weight loss.
Vasculitis and diffuse alveolar hemorrhage
(inflammatory or bland) can mimic other alveo-
Figure 1. Chest Radiograph. lar filling processes such as edema and infec-
A portable anteroposterior chest radiograph shows bi‑ tious pneumonia, are not always accompanied
lateral patchy airspace opacities that are more extensive by hemoptysis, and can be accompanied by fever
in the left lung than in the right lung. The opacities are and other systemic symptoms. This patient has
mostly peripheral, with sparing of the perihilar region
(the reverse batwing sign). Basilar reticular opacities
elevations in inflammatory markers, including
are present, with mild basilar and apical bronchiectasis. the C-reactive protein level and the erythrocyte
sedimentation rate, but otherwise does not have
features in his history or presentation that would
Noninfectious Pneumonia Syndromes specifically suggest vasculitis or hemorrhage.
The causes of a pneumonia syndrome are not Although it is important to consider noninfec-
limited to infectious pneumonia and may in- tious causes of pneumonia, the absence of spe-
clude myriad other diseases, such as aspiration cific suggestive features in this patient reduces
pneumonitis, cardiogenic pulmonary edema, the likelihood of these conditions. These possi-
cancer, vasculitis (with or without hemorrhage), bilities should remain on the differential diag-
diffuse alveolar hemorrhage, and the broad group nosis if no other cause is identified.
of interstitial lung diseases.1 Some of these dis-
orders are particularly good mimics of an infec- Interstitial Lung Disease
tious process. However, this patient’s clinical The patient describes having a history of a dis-
history and imaging findings make many of ease that “caused the lung tissue to harden,” and
these causes of pneumonia syndrome unlikely. therefore interstitial lung disease deserves spe-
Aspiration pneumonitis is always important cial attention. There are many causes of intersti-
to consider in patients with radiographic opaci- tial lung disease, including diseases of unknown
ties and hypoxemia, particularly those who are cause (idiopathic)2 such as acute interstitial pneu-
elderly. However, in this case, no history is pro- monia and idiopathic pulmonary fibrosis, dis-
vided that would suggest dysphagia, clinically eases associated with specific exposures such as
significant gastroesophageal reflux disease, or hypersensitivity pneumonitis and drug-induced
an episode of emesis and aspiration. In addition, pneumonitis, and diseases associated with spe-
the peripheral distribution of radiographic den- cific diagnoses such as sarcoidosis. Among the
sities is not typical of aspiration, which frequent- interstitial lung diseases, those most likely to be
ly manifests as opacities in dependent areas of confused with acute infectious pneumonia in-
the lung. clude acute interstitial pneumonia (an idiopathic
Cardiogenic pulmonary edema is typically form of acute respiratory distress syndrome
characterized by dyspnea, hypoxemia, and bilat- [ARDS]), cryptogenic organizing pneumonia
eral opacities. However, the infiltrates associated (the idiopathic form of organizing pneumonia),
with cardiogenic pulmonary edema are usually and acute eosinophilic pneumonia. There are no

findings on imaging studies that would suggest the findings on the patient’s chest radiograph
a chronic fibrotic process, and the patient has — peripheral patchy opacities — SARS-CoV-2 is
no coexisting conditions such as rheumatologic the most likely infectious pathogen.6
disease that can be associated with nonspecific
interstitial pneumonitis. Acute interstitial pneu- Other Considerations
monia and cryptogenic organizing pneumonia In many ways, this patient’s history and presen-
are diagnoses that are typically made only after tation reflect what we now recognize as classic
infection has been ruled out, since their mani- features of Covid-19 — fever, cough, hypoxemia,
festations, and even their histologic patterns of patchy peripheral opacities, and common labora-
diffuse alveolar damage and organizing pneumo- tory abnormalities. However, the description of
nia, are commonly seen with infection. There- an acute worsening of shortness of breath and
fore, these two diagnoses should be considered the onset of focal pleuritic chest pain, although
only after an initial evaluation for infection has nonspecific, should arouse concern about acute
been performed. Acute eosinophilic pneumonia3 pulmonary embolism in any clinical context.
can be manifested by peripheral patchy opaci- If I am correct that this patient has pneumo-
ties, such as those that were seen on this pa- nia associated with Covid-19, the rapid progres-
tient’s chest radiograph, and the diagnosis re- sion of his hypoxemia suggests that ARDS may
quires the finding of eosinophil predominance have developed as a complication of the Covid-19–
on bronchoalveolar lavage. However, the demo- related pneumonia.7 The Berlin definition of
graphic features of patients with acute eosino- ARDS includes both a ratio of partial pressure of
philic pneumonia do not match those of this arterial oxygen (Pao2) to fraction of inspired
patient; although this type of pneumonia is oxygen (Fio2) of 300 mm Hg or less and a posi-
more commonly diagnosed in men than in tive end-expiratory pressure of at least 5 cm of
women, it is also most frequently diagnosed in water. However, the patient’s worsening clinical
patients 20 to 40 years of age. Therefore, inter- trajectory is troubling, and his ratio of Pao2 to
stitial lung disease does not seem to be the most Fio2 suggests that he would meet this hypoxemia
likely cause of this patient’s acute pneumonia threshold if an arterial blood gas measurement
syndrome. were obtained.8 Complicating this conclusion is
the development of a likely pulmonary embo-
Infectious Pneumonia lism, which would, in part, explain his hypox-
All that being said, the most likely diagnosis in emia. In fact, the mechanisms of hypoxemia for
this patient is community-acquired pneumonia.4 each of these pulmonary diseases are synergistic
The differential diagnosis of community-acquired and are probably worsening his hypoxemia be-
pneumonia is broad, and in many cases, a yond the independent effect of each disease.
pathogen may not be identified. However, em- The mechanisms of hypoxemia associated
pirical treatment should target the most common with ARDS include shunt (the perfusion of non-
pathogens, which include Streptococcus pneumoni- ventilated lung units) and low ventilation-to-
ae, and atypical pathogens such as Mycoplasma perfusion ratios in certain regions of the lungs
pneumoniae, legionella species, and Chlamydia pneu- whereby the degree of perfusion is out of pro-
moniae. It is also vital to keep in mind the epide- portion to the degree of ventilation; both of
miologic characteristics of respiratory viruses these mechanisms result in a reduction in oxy-
(e.g., seasonal influenza) in order to appropri- genated pulmonary capillary blood, as well as
ately consider viral causes of pneumonia. This systemic hypoxemia. The primary mechanism of
patient presented in Boston during the spring of hypoxemia in patients with clinically significant
2020, when the Covid-19 pandemic had a sub- pulmonary embolism is also a low ventilation-
stantial presence and the number of hospital- to-perfusion ratio. When a clot obstructs blood
ized patients was rapidly increasing.5 He also flow to one portion of the lung, the nonperfused
has laboratory findings that have been com- lung becomes so-called dead space (ventilation
monly reported in patients with Covid-19, in- without perfusion), and the cardiac output is
cluding lymphopenia and elevations in d-dimer, diverted to the remainder of the lung. Conse-
ferritin, and C-reactive protein levels and in the quently, the nonaffected lung has a net increase
erythrocyte sedimentation rate. Together with in perfusion (with the assumption that no clini-

Low ventilation-to-perfusion ratio

Oxygen Ventilation cannot be increased
Dead space
sufficiently because of fluid
Unit is ventilated
in the perfused unit
but not perfused
because of embolism
ALVEOLUS
Synergistic effects of
ALVEOLUS FLUID pulmonary embolism
and pneumonia
Pulmonary
or ARDS create a
embolism
state of hypoxemia
Pulmonary venous
Pulmonary artery Diversion of blood results
return to the left side
(oxygen-depleted in an increase in blood
of the heart
blood from the right flow to other regions
side of the heart)
Figure 2. Synergistic Effects of Pulmonary Embolism and Acute Respiratory Distress Syndrome.
Occlusion of the pulmonary vasculature with a clot results in lung units that are ventilated but not perfused — so‑called dead space.
Dead space decreases the efficiency of minute ventilation but does not itself cause hypoxemia. However, when part of the pulmonary
vascular tree is occluded and cardiac output is preserved, pulmonary arterial blood flow is diverted to the remaining lung units. To
maintain a normal ventilation‑to‑perfusion ratio and therefore oxygenation, ventilation to these lung units must increase proportionally.
If the patient is unable to sufficiently increase ventilation, particularly in the context of concomitant parenchymal disease such as pneu‑
monia or acute respiratory distress syndrome (ARDS), this regional increase in blood flow results in ventilation–perfusion mismatch
and hypoxemia.
cally significant right ventricular failure is pres- evolving ARDS limit his ability to augment effec-
ent). If a patient is able to augment local ventila- tive alveolar ventilation in the regions affected
tion to match this increase in perfusion, then by the clot, and the clot may have caused inef-
hypoxemia does not occur. However, if a patient fective perfusion in the regions of his lung that
is unable to augment ventilation sufficiently, are spared by Covid-19 (Fig. 2).
then hypoxemia develops. Hypoxemia may occur Is there a relationship between Covid-19 and
if the clot is large and if there is very high local pulmonary embolism? Microvascular dysfunc-
perfusion of the preserved lung, but it can also tion is a well-known feature of ARDS, and up to
occur when ventilation is impeded by a separate 30% of patients with ARDS have pulmonary
process. A complex cascade of pathophysiologi- emboli.9-11 These emboli are traditionally thought
cal processes, including the release of inflam- to be in situ vessel thromboses rather than true
matory mediators, that occurs in response to an emboli associated with peripheral deep venous
acute pulmonary embolism can affect ventila- thrombosis. Another consideration in this pa-
tion–perfusion mismatch by causing local bron- tient is whether his clot is more directly related
choconstriction, vasoconstriction, and surfactant to Covid-19 than to ARDS, although there is no
dysfunction. In this patient, the pneumonia and way to easily distinguish the two. The elegance

of a parsimonious diagnosis — one answer to Discussion of M a nagemen t

explain all of a patient’s ailments — is often
invoked along with the principle of Ockham’s Dr. Annemarie E. Fogerty: In the 19th century, Ru-
razor, which states that, “Plurality ought never dolf Virchow identified three factors that con-
be posed without necessity.”12 However, in clini- tributed to pathologic venous thrombosis: in-
cal medicine, patient presentations often do not creased blood coagulability, venous stasis, and
fit these maxims, and this is one clinical situa- vein damage. This patient had several features
tion in which a life-threatening diagnosis — related to Virchow’s triad. Although he did not
acute pulmonary embolism — must be ruled have a known genetic mutation associated with
out. Therefore, in addition to testing the pa- thrombosis, cancer, or previous venous throm-
tient’s nasopharyngeal specimen for SARS-CoV-2 boembolism, his illness involved infection and
RNA to establish the diagnosis of Covid-19, I inflammation, which are known hypercoagula-
would recommend obtaining a computed tomo- ble states. Venous stasis is another contributor
graphic (CT) pulmonary angiogram to identify in immobilized patients, particularly those in
pulmonary embolism. the intensive care unit (ICU). Endothelial injury
is most commonly attributed to surgery or
trauma, neither of which applied to this patient.
Dr . K athr y n A . Hibber t ’s
Di agnosis However, endothelial inflammation (i.e., endo-
theliitis) is considered to be a major factor con-
Pneumonia associated with severe acute respira- tributing to the risk of venous thromboembo-
tory syndrome coronavirus 2 (SARS-CoV-2) infec- lism in patients with Covid-19 and thus merits
tion and acute pulmonary embolism. special consideration.
The normal endothelium maintains an anti-
coagulant surface to permit smooth vascular
Di agnos t ic Te s t ing
blood flow. This is achieved through numerous
Dr. Emmett: The first diagnostic test was nucleic processes, including the antiplatelet functions of
acid testing of a nasopharyngeal swab for SARS- nitric oxide and prostaglandins; the anticoagu-
CoV-2 RNA; the specimen had been obtained lant properties of heparins, thrombomodulin,
while the patient was in the emergency depart- and the protein C receptor pathway; and the fi-
ment. Within a few hours after the specimen brinolytic activity of tissue plasminogen activa-
was submitted, the test showed a positive result tor. If the normal function of the endothelium is
for SARS-CoV-2 RNA, thus confirming the diag- interrupted, as can occur with SARS-CoV-2 in-
nosis of SARS-CoV-2 infection. fection, the anticoagulant properties can be
Dr. Goiffon: The second diagnostic test was thwarted, which can result in a procoagulant
dual-energy CT, which was performed after the state. Angiotensin-converting enzyme 2 (ACE2),
administration of intravenous contrast material which is abundantly expressed on the epithelia
that was timed to maximally opacify the pulmo- of the lung and small intestine and on the vas-
nary arteries (Fig. 3). The imaging revealed mul- cular endothelium, is the functional receptor of
tifocal ground-glass opacities and associated SARS-CoV-2.13 Thus, this patient was vulnerable
septal thickening in the periphery of both lungs to thrombogenesis on the basis of SARS-CoV-2
that were more extensive in the left lung than in infection leading to presumed endotheliitis.
the right lung. Some of the ground-glass opaci- Endothelial cell damage and direct invasion
ties abutted or surrounded smaller consolida- of SARS-CoV-2 within the endothelial cell mem-
tions. Iodine map images showed decreased brane have been shown to result in a distorted
perfusion that was disproportionate to the den- microvascular and endothelial architecture of
sity of the ground-glass opacities. Subocclusive the infected lung.14 Similar findings have been
filling defects were observed in the left main observed in the renal and small bowel endothe-
artery and segmental arteries of the left lower lium of patients with Covid-19.15 Endothelial in-
lobe, and an occlusive thrombus was noted in the flammation is reflected in the many laboratory
lingular arteries. A four-chamber image showed features that are now recognized as characteris-
that the ratio of the size of the right ventricle to tic of SARS-CoV-2 infection, which were seen
the size of the left ventricle was approximately 1.1. in this case: marked elevations in the levels of

A B
C D
E F G
RV
LV
Figure 3. CT of the Chest.

Dual‑energy CT was performed after the administration of intravenous contrast material according to a pulmonary
embolism protocol. Axial CT images at different levels (Panels A and B) with their corresponding dual‑energy iodine
maps (Panels C and D) show peripheral ground‑glass opacities (asterisks and arrowheads) with areas of consolida‑
tion (arrows). The ground‑glass opacities that appear least opaque have the greatest perfusion defect (asterisks),
disproportionate to that seen in other areas of abnormal lung. Axial and sagittal images (Panels E and F, respective‑
ly) show occlusive thrombosis (arrowheads) in the proximal lingular arteries and nonocclusive thrombosis (arrows)
of the basal segmental arteries of the left lower lobe, findings that correspond to the perfusion defects seen on the
iodine map images. A four‑chamber view of the heart without cardiac gating (Panel G) shows that the ratio of the
size of the right ventricle (RV) to the size of the left ventricle (LV) is approximately 1.1; additional nonocclusive
thrombi are also noted (arrows).
d-dimer, fibrinogen, C-reactive protein, and fer- not measured in this patient. The classic labora-
ritin. Interleukin-6 elevation is another feature tory profile of Covid-19 is contrary to the usual
of SARS-CoV-2 infection, although the level was profile of disseminated intravascular coagulation,

in which the fibrinogen level is low, the pro- bolism severity index is a tool for stratifying
thrombin time and activated partial-thrombo- patients according to a high or low risk of
plastin time are prolonged, and thrombocytope- death and includes blood pressure, heart rate,
nia predominates. This patient had the profile oxygen saturation, age, and a history of cancer,
more commonly associated with Covid-19, which lung disease, or heart failure. Additional con-
is that of marked elevation of inflammatory siderations in the scoring system include respi-
markers, with a relatively preserved prothrombin ratory rate, sex, mental status, and body tem-
time, activated partial-thromboplastin time, and perature. The Pulmonary Embolism Response
platelet count. Team Consortium defines a pulmonary embo-
A d-dimer elevation alone (even when mark- lism as massive when the systolic blood pressure
edly elevated) is not sufficient to confirm a di- is less than 90 mm Hg or there is a need for
agnosis of venous thromboembolism, even in vasopressor support; a pulmonary embolism is
SARS-CoV-2–infected patients, since the d-dimer defined as submassive when the pulmonary em-
level can be elevated in many physiologic and bolism severity index score indicates high risk or
pathophysiological states. In patients with there is evidence of right ventricular dysfunction
Covid-19, an elevated d-dimer level has been as- (as observed on imaging or suggested by an ele-
sociated with numerous poor outcomes, includ- vated troponin or N-terminal pro–B-type natri-
ing ICU admission, the need for mechanical uretic peptide level). A massive or submassive
ventilation, thrombosis, bleeding, and death.16-18 pulmonary embolism is preferentially managed
Circulating d-dimers are generated after clot with mechanical intervention.20 In this case, the
formation and subsequent lysis. Initially, the patient’s condition was hemodynamically stable;
production of fibrinogen is enhanced by inter- thus, he was assessed as having a lower-risk
leukin-6, and fibrinogen is converted to a fibrin pulmonary embolism, for which anticoagulation
clot in the presence of thrombin. As plasmin alone was initiated.
breaks down the fibrin clots, D domains from In patients with pulmonary embolism, achiev-
adjacent fibrin monomers are released into the ing therapeutic anticoagulation early is associ-
circulation and can be quantified with the use of ated with decreased mortality21 and therefore is
the d-dimer assay. Thus, an elevated d-dimer critical to achieve expeditiously. However, the
level can occur in venous thromboembolism but use of dose-adjusted unfractionated heparin of-
also in small-vessel microthrombosis, endothe- ten fails to achieve a therapeutic effect on the
lial inflammation, cancer, advanced age, preg- activated partial-thromboplastin time within 48
nancy, and liver and renal failure. Because there hours after initiation.22 Low-molecular-weight
is no threshold of d-dimer level that distinguish- heparin at a weight-based dose is more biologi-
es thrombosis from endothelial damage alone in cally predictable and is associated with a lower
a SARS-CoV-2–infected patient, a high clinical risk of additional thrombus formation and
suspicion of venous thromboembolism is indi- bleeding, as well as smaller thrombi, than dose-
cated. For example, in a patient with worsening adjusted intravenous unfractionated heparin.23
respiratory status or hypotension that is out of The use of up-front direct oral anticoagulant
proportion to findings on chest radiography, ap- agents (factor II and X inhibitors) is also appro-
propriate diagnostic imaging is warranted, as priate for patients with lower-risk pulmonary
was the case in this patient. embolism. In this case, low-molecular-weight
Once thrombosis in the pulmonary artery is heparin was chosen to ensure rapid anticoagula-
identified, risk stratification is necessary to de- tion within the therapeutic range, to minimize
termine the appropriate treatment strategy — staff exposure to twice-daily injections, and to
specifically, the need for mechanical interven- avoid drug interactions.
tion as opposed to anticoagulation alone.19 This Because this patient received a diagnosis of
assessment is based primarily on the associated venous thromboembolism during his hospital-
hemodynamic effect. Options for mechanical ization, the venous thromboembolism is classi-
intervention can vary depending on local exper- fied as provoked. In cases of provoked venous
tise and institutional experience and can include thromboembolism, a finite course of anticoagu-
thrombolysis (systemic [at a full or reduced lation is usually advised, whereas longer-term
dose] or catheter-directed) or thrombectomy anticoagulation is appropriate in cases of unpro-
(catheter-based or surgical). The pulmonary em- voked thromboses.

Fol l ow-up mouth. At this point, with the assistance of the

palliative care service, the patient and family
Dr. Emmett: The patient was admitted to the ICU, decided to transition the goals of care to com-
where he remained for 3 days. His oxygenation fort measures only. He received dedicated care
was monitored closely, and the pulmonary em- for intensive end-of-life care support. Ultimately,
bolism was initially treated with enoxaparin. Dur- he died peacefully on the 16th hospital day.
ing this time, he was able to maintain appropriate
oxygenation while he was receiving supplemen- Fina l Di agnosis
tal oxygen through a nasal cannula at a rate of
6 liters per minute. After 3 days, he was trans- Pneumonia associated with severe acute respira-
ferred to the general medical floor. He began tory syndrome coronavirus 2 (SARS-CoV-2) in-
having clinically significant episodes of pleuritic fection and acute pulmonary embolism.
chest pain and aspiration events that were associ-
This case was presented at the Medicine Case Conference.
ated with periods of hypoxemia. He also began Disclosure forms provided by the authors are available with
to have substantial bleeding from the nose and the full text of this article at NEJM.org.
References
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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

Case Records of the Massachusetts General Hospital

Founded by Richard C. Cabot

Case 18-2021: An 81-Year-Old Man

Pr e sen tat ion of C a se

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The New England Journal of Medicine

bases. The heart sounds were regular, with tachy-

n engl j med 384;24 nejm.org June 17, 2021 2333

perihilar and radiate outward. In addition, this

2334 n engl j med 384;24 nejm.org June 17, 2021

The New England Journal of Medicine

n engl j med 384;24 nejm.org June 17, 2021 2335

Low ventilation-to-perfusion ratio

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The New England Journal of Medicine

of a parsimonious diagnosis — one answer to Discussion of M a nagemen t

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Figure 3. CT of the Chest.

2338 n engl j med 384;24 nejm.org June 17, 2021

The New England Journal of Medicine

n engl j med 384;24 nejm.org June 17, 2021 2339

Fol l ow-up mouth. At this point, with the assistance of the

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The New England Journal of Medicine

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