Open Forum Infectious Diseases

BRIEF REPORT

High-Dose Intravenous including existing and new generation of antivirals, steroids,

and traditional Chinese medicine, the optimal strategy for se-
Immunoglobulin as a Therapeutic vere COVID-19 remains unclear.
Option for Deteriorating Patients With The clinical spectrum of SARS-CoV-2 infection is quite wide
and includes asymptomatic infection and mild type, with only
Coronavirus Disease 2019 upper respiratory tract illness, common type with pulmonary
Wei Cao,1 Xiaosheng Liu,2 Tao Bai,3 Hongwei Fan,1 Ke Hong,3 Hui Song,3 Yang Han,1 infiltrations, severe type with respiratory distress, and critically
Ling Lin,1 Lianguo Ruan,3,a and Taisheng Li1,a
1
ill patients needing intubation or intensive care [2]. Clinical fea-
Department of Infectious Diseases, Peking Union Medical College Hospital, Chinese Academy
of Medical Sciences, Beijing, China, 2Tsinghua-Peking Center for Life Sciences, School of tures of those with pneumonia include fever and cough, and

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Medicine, Tsinghua University, Beijing, China, and 3Department of Infectious Diseases, Jin in many cases a sudden and accelerating respiratory distress
Yin-tan Hospital, Wuhan, China
originated from interstitial pneumonia. In those who rapidly
The outbreak of coronavirus disease 2019 (COVID-19) has progressed to critical conditions, reduced peripheral lympho-
spread rapidly in China. Until now, no definite effective treat- cyte counts and elevated inflammatory factors were observed,
ment has been identified. We reported on 3 patients with severe indicating an overwhelming immune response [3, 4]. Previous
COVID-19 who received high-dose intravenous immuno- experiences with SARS showed that the main pathogenesis of
globulin (IVIg) with satisfactory recovery. Based on these ob- organ dysfunction lay in the overall cytokine dysregulation.
servations, randomized studies of high-dose IVIg should be Similarly, the point when status deterioration starts in patients
considered in deteriorating patients infected with COVID-19. with COVID-19 should be a critical window of opportunity for
Keywords. coronavirus disease 2019; high-dose intrave-
intervention. Here we report on 3 patients with COVID-19 who
nous immunoglobulin; immunomodulation; SARS-CoV-2.
received high-dose intravenous immunoglobulin (IVIg) at the
time of initiation of respiratory distress, with satisfactory clin-
The outbreak of pneumonia of unknown cause that first oc- ical and radiographic recovery.
curred in Wuhan, China, in December 2019, has recently been
assessed by the World Health Organization (WHO) as a pan- CASE PRESENTATION
demic. The pneumonia is caused by a novel coronavirus, severe Patient 1
acute respiratory syndrome coronavirus 2 (SARS-CoV-2, pre- On January 22, 2020, a 56-year-old man was admitted to Jin Yin-
viously known as 2019-nCoV), and the disease it caused was tan Hospital, Wuhan, China. Patient had had a sore throat since
later designated coronavirus disease 2019 (COVID-19) by the January 19 and reported fever for 2 days before admission, with
WHO. As of March 12, 2020, a total of 80 981 cases had been the highest temperature at 38.2ºC. He was given oseltamivir and
reported in China, including 3173 reported deaths. Meanwhile, azithromycin by a local clinic to empirically cover community-
the number of confirmed patients continues to grow outside of acquired respiratory pathogens, without any improvement. On
China, and 45 309 cases have already been reported [1]. The rel- January 21, he came to the Emergency Department of Jin Yin-
atively high infectivity, rapid progression of lung involvement, tan Hospital, and a computed tomography (CT) scan was done
and lack of definite effective treatment make it urgent to develop showing scattered interstitial patches and pleural thickening on
efficient measures of management based on the pathogenesis the right side (Figure 1A). Oropharyngeal swab was positive
of COVID-19. Although many empirical therapeutic options for SARS-CoV-2 by real-time reverse transcription polymerase
have been introduced on several operational recommendations, chain reaction (rRT-PCR) assay. He was previously generally
healthy and denied any exposure or direct contact with the
Huanan seafood market.
Received 19 February 2020; editorial decision 17 March 2020; accepted 19 March 2020.
a
Equal contribution On admission, he was afebrile, with blood pressure
Correspondence: Taisheng Li, MD, PhD, Department of Infectious Diseases, Peking Union 125/80 mmHg, pulse 86 beats per minute, respiratory rate 20
Medical College Hospital, Chinese Academy of Medical Sciences, 1# Shuai Fu Yuan, Beijing,
China, 100730 ([email protected]).
breaths per minute, and oxygen saturation 96% when breathing
Open Forum Infectious Diseases® ambient air. Both lungs were clear on auscultation, and the re-
© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases mainder of the examination was unremarkable. Laboratory
Society of America. This is an Open Access article distributed under the terms of the Creative
Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/
results reflected a significant lymphocytopenia with a lympho-
by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any cyte count of 0.48 (1.1–3.2) ×109/L. His inflammatory markers
medium, provided the original work is not altered or transformed in any way, and that the
were elevated, with an erythrocyte sedimentation rate (ESR) 49
work is properly cited. For commercial re-use, please contact [email protected]
DOI: 10.1093/ofid/ofaa102 (0–15) mm/h and high-sensitive C-reactive protein (hsCRP)

BRIEF REPORT • ofid • 1

 Discharge
A
Intravenous immunoglobin
Illness day 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Hospital day 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

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Discharge
B
Intravenous immunoglobin

Illness day 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Hospital day 1 2 3 4 5 6 7 8

Discharge
C
Intravenous immunoglobin

Illness day 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 22
Hospital day 1 2 3 4 5 6 7 8 9 10 11 12 13 17

Figure 1. Chest computed tomography scan of patient 1 (A), patient 2 (B), and patient 3 (C) before and after high-dose intravenous immunoglobulin with days of illness.

2 • ofid • BRIEF REPORT

of 57.8 (0–5) mg/L. Liver function and renal function were The patient was diagnosed with COVID-19, severe type.
within the normal range (Table 1). Detection of antigens was IVIg was administered immediately at a dose of 25 g/d for
negative for influenza A and B, as well as for H7 subtype avian 5 days (body weight 63 kg). The patient became afebrile on
influenza virus. the second day of IVIg treatment, with a gradual improvement
The patient was diagnosed with COVID-19, common type. of breathing difficulty. CT scan was repeated on February 3,
Supportive care and empirical moxifloxacin were given, with showing prominent absorption compared with the scan from
close monitoring of clinical status. He had intermittent fever, January 30 (Figure 1B). The nasal PCR testing turned nega-
but his vital signs remained largely stable until January 26, tive for SARS-CoV-2 on February 3, and he was discharged
when cough and shortness of breath developed. His oxygen sat- on February 5.
uration decreased to 91% when breathing ambient air, and his
hsCRP further elevated to 106.2 mg/L. A CT scan on January 29 PATIENT 3
showed progressing infiltrations bilaterally compared with the A 35-year-old woman was admitted to Jin Yin-tan Hospital on
scan from January 21 (Figure 1A).

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January 24, 2020. She reported malaise and low-grade fever
The diagnosis was modified to COVID-19, severe type. High- (maximal 37.3ºC) with mild coughing since January 19. A CT
dose IVIg was started on January 28 (hospital day 7) at 25 g/d for scan from local hospital showed mild ground-glass opacities.
5 days (body weight 66 kg). Moxifloxacin was continued until Her nasopharyngeal swab was positive for SARS-CoV-2, and
February 2. On the same day after IVIg infusion, the patient be- oral lopinavir/ritonavir was prescribed with close monitoring.
came afebrile. No adverse event was reported. Over the next few The patient developed high-degree fever around 39ºC on
days, his clinical status gradually improved. The supplemental January 22 but had no obvious shortness of breath and got ad-
oxygen was discontinued, and his oxygen saturation level re- mitted on January 24. She was previously generally healthy, but
turned to 97%–98% on February 3 when breathing ambient air. reported close contact with her colleague who had been diag-
Test results on February 5 showed recovered lymphocyte count nosed with COVID-19 a few days before.
to 1.6 ×109/L. The ESR decreased to 31 mm/h, and hsCRP re- On admission, she was afebrile, with blood pressure
turned to normal range. The CT scan showed partial resolution 105/68 mmHg, pulse 91 beats per minute, respiratory rate 20
of previous lesions (Figure 1A). Two consecutive oropharyngeal breaths per minute, and oxygen saturation 98% when breathing
swabs on February 2 and 3 were both negative for 2019-nCoV. ambient air. Her lungs were clear to auscultation. Laboratory
The patient was discharged on February 5. studies revealed mild lymphocytopenia with a lymphocyte
count of 0.85 ×109/L and slightly elevated hsCRP at 41.4 mg/L
PATIENT 2
(Table 1). IgM tests for respiratory pathogens were negative for
A 34-year-old man presented with fever and dry cough for influenza A and B, parainfluenza, RSV, adenovirus, mumps
10 days and was admitted on January 29, 2020, to Jin Yin-tan virus, and microvirus B19. A chest CT scan on January 24
Hospital. The patient reported fever up to 38.5ºC with dry showed multiple ground-glass opacities and infiltrations bilat-
cough. On January 28, he began to feel short of breath and came erally that were more advanced than those on the scan from
to a local hospital. An oropharyngeal swab was confirmed pos- January 20 (Figure 1C).
itive for SARS-CoV-2, and the patient was transferred to Jin Lopinavir/ritonavir was continued to complete the 2-week
Yin-tan Hospital the next day. He had a 2-year history of hyper- course. The patient’s temperature was between 37.5ºC and
tension that was well controlled by valsartan and felodipine and 38.5ºC. On January 29, she developed shortness of breath,
denied any exposure or direct contact with the seafood market. and her oxygen saturation decreased to 92% when breathing
Physical examination showed a body temperature of 37.5°C, ambient air. Prominent deterioration was also noticed on a
blood pressure 138/90 mmHg, pulse 86 beats per minute, res- chest CT, accompanied by further reduction of lymphocyte
piratory rate 26 breaths per minute, and oxygen saturation was counts to 0.6 ×109/L and elevation of hsCRP to 69.5 mg/L
90% when breathing ambient air. Laboratory results on admis- (Figure 1C).
sion reflected mild thrombocytopenia at 97 (120–350) ×109/L Her clinical diagnosis grading was modified from common
and moderately elevated inflammation markers including to severe type, and IVIg was administered beginning from
ESR 58 mm/h and hsCRP 82 mg/L. The level of creatine ki- January 29 at 25 g/d for 5 days (body weight 56 kg). Meanwhile,
nase was elevated at 1081 (50–310) U/L, and myoglobin was methylprednisolone 40 mg/d was given for 3 days. Fever sub-
mildly increased to 153.8 (0–146.9) ng/mL (Table 1). IgM tests sided after the first day of enhanced treatment. Her symptoms
for respiratory pathogens were negative for influenza A and B, improved significantly 2 days later, when her oxygen satura-
parainfluenza, respiratory syncytial virus (RSV), adenovirus, tion returned to 98% when breathing ambient air. Negative
mumps virus, and microvirus B19. A CT scan on January 30 PCR testing for SARS-CoV-2 was confirmed on February 2 and
indicated bilateral infiltrations and opacities that were more 3. Chest CT scan revealed radiographic resolution (Figure 1C).
prominent on the right side (Figure 1B). She was discharged on February 9.

BRIEF REPORT • ofid • 3

 Table 1. Laboratory Tests of the 3 Patients Before and After Infusion of High-Dose Intravenous Immunoglobulin

Patient 1a Patient 2b Patient 3c

Reference Illness Day 4 Illness Day 9 Illness Day 18 Illness Day 12 Illness Day 16 Illness Day 6 Illness Day 11 Illness Day 14

Measure Range Hospital Day 1 Hospital Day 6 Hospital Day 15 Hospital Day 2 Hospital Day 6 Hospital Day 1 Hospital Day 6 Hospital Day 9

4 • ofid • BRIEF REPORT

WBC, 109/L 3.5–9.5 4.22 6.61 8.74 4.74 3.91 3.06d 3.39d 4.4
RBC, 1012/L 4.3–5.8 4.4 4.26d 4.02d 5.21 4.92 4.25 4.34 3.83
Hb, g/L 130–175 144 139 128d 147 139 127 126 114
9
PLT, 10 /L 120–350 147 210 241 97d — 153 274 287
NEUT#, 109/L 1.8–6.3 3.4 5.82 6.51e 3.11 2.27 1.86 2.46 3.42
LYM#, 109/L 1.1–3.2 0.48d 0.58d 1.63 1.2 1.04d 0.85d 0.60d 0.85d
ESR, mm/h 0–15 49e — 31e 58.8e — 40e 41.5e
e e e e e e
hsCRP, mg/L 0–5 57.8 106.2 4.3 82.0 25.1 41.1 69.5 6.6e
e
Mb, ng/mL 0–146.9 96.3 36.5 — 153.8 — 16.6 — —
hsTnI, pg/mL 0–28 1.1 1.3 — 3.6 — 0 — —
SF, ng/mL 21.8–274.66 459.57e — 563.02e 806.99e 632.55e 85.91 — 232.62e
PCT, ng/mL <0.05 — <0.05 <0.05 <0.05 0.05 <0.05 <0.05 <0.05
TBIL, μmol/L 0–26 15.5 15.4 6.5 15 — 8.4 — 5.9
ALT, U/L 9–50 20 14 60e 52e — 15 — 20
AST, U/L 14–40 36 34 40 54e — 25 — 11d
ALB, g/L 40–55 39.3d 34.2d 39.6d 32.4d — 33.4d — 33.0d
ALP, U/L 45–125 47 47 46 60 — 47 — 26d
e
γ-GT, U/L 10–60 17 19 29 87 — 15 — 33
CRE, μmol/L 57–97 88.8 69.2 63 72.7 — 51.6 — 47
UA, μmol/L 208–428 191d 99d 195d 472e — 201 — 131d
CK, U/L 50–310 267 81 51 1081e — 46 — 32d
e e e e
LDH, U/L 120–250 308 315 296 651 — 163 — 222
D-dimer, μg/mL 0–1.5 0.37 — — 0.43 — — — 1.55e
PT, sec 10.5–13.5 10.6 — 10.2d 11.3 — — — —
PTA, % 0.8–1.2 129.7e — 117.4 95.5 — — — —
FIB, g/L 2–4 4.1e — 3.7 4.4e — — — —

Abbreviations: γ-GT, γ -glutamyltransferase; ALB, albumin; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartase aminotransferase; CK, creatinekinase; CRE, creatinine; ESR, erythrocyte sedimentation rate; FIB, fibrinogen; Hb, hemo-
globin; hsCRP, hypersensitive C-reactive protein; hsTn, hypersensitive troponin; IVIg, intravenous immunoglobulin; LDH, lactate dehydrogenase; LYM#, absolute lymphocyte count; Mb, myoglobin; NEUT#, absolute neutrophil count; hsTn, hypersensitive
troponin; PLT, platelet count; PT, prothrombin time; PTA, prothrombin activity; RBC, red blood cell count; SF, serum ferritin; TBIL, total bilirubin; UA, urine acid; WBC, white blood cell count.
a
IVIg was initiated on hospital day 7.
b
IVIg was initiated on hospital day 2.
c
IVIg was initiated on hospital day 6.
d
The value in the patient was below normal.
e
The value in the patient was above normal.

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DISCUSSION As a result, high-dose IVIg at 0.3–0.5 g per kg weight per
Although confirmed cases of COVID-19 have rapidly accumu- day for five days was used in our patients as a potent and safe
lated during the past 2 months, our understanding of the clinical immune modulator. The dose of IVIg was determined based
spectrum and pathophysiological changes of this infection still on well-established practice in immune modulation therapy
remains very limited. Nevertheless, no definite treatment has for other diseases, including neuromuscular disorders, auto-
been identified, which makes clinical management extremely immune thrombocytopenic purpura, etc. [6, 7], with a con-
difficult. Here we report a case series of patients with COVID- sideration of potential cardiac or renal impairment in severe
19, all of whom were successfully treated by high-dose IVIg at COVID-19 patients. None of the 3 patients reported any adverse
the early stage of clinical deterioration. Based on these observa- events. All patients were clinically improved shortly after the ad-
tions, a high dose of IVIg administered at the appropriate point ministration, with their temperature back to normal in 1–2 days
could successfully block the progression of the disease cascade and breathing difficulties alleviating in 3–5 days. Confounding
and improve the outcome of COVID-19. factors did exist, including the use of different antivirals in 2
of the 3 patients at various time points and a short course of

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The natural history of SARS-CoV-2 infection does not re-
semble that of any of the previously known coronaviruses. To date, steroids in patient 3. Moreover, in patient 2, valsartan, an angi-
we have noticed quite a wide clinical spectrum of SARS-CoV-2 otensin receptor 1 blocker (AT1R), had been used for treating
infection, including asymptomatic infection, mild upper respira- hypertension. As angiotensin-converting enzyme 2 (ACE2) has
tory tract illness, and pulmonary infiltrations. A large proportion been identified as the major receptor-binding domain of SARS-
of reported symptomatic cases, including our patients and many CoV-2 [8, 9], there has been a hypothesis that higher expres-
others, followed a similar track of progression. The infection often sion of ACE2 after being chronically medicated with AT1R may
started with mild or moderate unspecific symptoms, including protect SARS-CoV-2-infected patients against acute lung injury
but not limited to low-grade fever, sore throat, coughing, fatigue, rather than putting them at higher risk, though this currently
and malaise, similar to the symptoms of a common cold. The in- remains unproven [10]. Nevertheless, from the timeline and
itial symptoms would abate or persist for around 3–7 days, when patterns of disease course in these 3 patients, it is most probable
high-grade fever developed and respiratory distress became quite that high-dose IVIg played the leading role in their recovery.
prominent. Some of these patients would also have gastrointes- IVIg is a blood product containing polyclonal immunoglob-
tinal symptoms during this period. However, if we look at the CT ulin G isolated and pooled from healthy donors, and it has been
series shown here, which were quite typical of most COVID-19 used for over 30 years. As a complex preparation, it contains a
patients, we would have a very strong impression that most of large number of bioactive moieties, and the entirety of its ef-
the lesions started from the periphery, especially the subpleural fects is not yet fully understood. IVIg of higher dose has been
region when acute respiratory distress syndrome (ARDS) devel- a choice of immunomodulatory therapy for autoimmune or in-
oped [5]. These features indicated a hematogenous or lymphatic flammatory disease and for prophylaxis and treatment of severe
distribution or spreading of pathogenic factors rather than direct infections, especially in immunocompromised patients [11, 12].
inspiration. Several theories have been proposed to explain its potential
Based on these observations, we deduced that symptomatic immunomodulatory mechanisms, including Fc-mediated and
COVID-19 mainly consists of 3 phases, including a starting phase, Fab-mediated approaches [13, 14]. In previous studies of SARS
spanning the acquisition of the virus and subsequent viremia; and in and Middle East respiratory syndrome (MERS), IVIg therapy has
many but not all patients an accelerating phase, when virus-induced exhibited various clinical benefits with good tolerance [15–17].
secondary damage of targeting organs and tissue occurs, including Considering its efficacy in improving passive immunity and
the lungs, the heart, the gastrointestinal tract, and even an overall in- modulating immune inflammation and the overall safety
flammatory storm. The third phase is the final recovery phase. This profile, high-dose IVIg could be considered a promising op-
was demonstrated by not only the clinical features but also the lab- tion at the early stage of clinical deterioration of patents with
oratory dynamics, including progressive lymphocytopenia and ele- COVID-19.
vated inflammation markers at the time of acceleration. Therefore, Our report is limited by the small numbers of patients we in-
strategies against COVID-19 should also be specified according to cluded, and more evidence is needed to confirm the conclusions.
the course of infection. The best timing of antivirals, if any are used, However, this report provides an important therapeutic clue to
may lie in the phase before acceleration. When clinical deterioration the current situation of rapid disease spreading. The timing of
begins, the first few days of deterioration may present a critical point IVIg administration is critical in practice. Patients might not
when potent suppression of the inflammatory cascade could save receive much benefit when systemic damage has already taken
the patients from fatal immune-mediated injuries, as shown here. place. Currently, a randomized controlled trial evaluating the
Moreover, from the experiences of our patients, if the acceleration efficiency of high-dose IVIg therapy in severe COVID-19 has
of the disease could be stopped, it seemed to work well even if no been initiated (NCT 04261426), which will provide more evi-
effective antiviral drugs were given. dence for IVIg use in treating such patients.

BRIEF REPORT • ofid • 5

Acknowledgments 6. Patwa HS, Chaudhry V, Katzberg H, et al. Evidence-based guideline: intrave-
nous immunoglobulin in the treatment of neuromuscular disorders: report of
We are grateful to the patients for their consent to publish this case series.
the Therapeutics and Technology Assessment Subcommittee of the American
We thank all the nurses and clinical staff who provided care for these pa-
Academy of Neurology. Neurology 2012; 78:1009–15.
tients and who are providing continuous care to other patients in China. 7. Godeau B, Caulier MT, Decuypere L, et al. Intravenous immunoglobulin for
Author contributions. T.L. and W.C. designed the use of IVIg in these pa- adults with autoimmune thrombocytopenic purpura: results of a randomized
tients. W.C. and X.L. drafted the manuscript. L.R., T.B., K.H., and H.S. took trial comparing 0.5 and 1 g/kg b.w. Br J Haematol 1999; 107:716–9.
clinical care of these 3 patients and collected all the data and imaging 8. Lu R, Zhao X, Li J, et al. Genomic characterisation and epidemiology of 2019
studies. H.F., Y.H., and L.L. reviewed the literature and critically revised the novel coronavirus: implications for virus origins and receptor binding. Lancet.
manuscript. All authors reviewed the manuscript, provided feedback, and 2020; 395:565–74.
approved the manuscript in its final form. 9. Wan Y, Shang J, Graham R, Baric RS, Li F. Receptor recognition by novel corona-
virus from Wuhan: an analysis based on decade-long structural studies of SARS.
Potential conflicts of interest. All authors: no reported conflicts of in-
J Virol. In press.
terest. All authors have submitted the ICMJE Form for Disclosure of
10. Gurwitz D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics.
Potential Conflicts of Interest. Conflicts that the editors consider relevant to Drug Dev Res. In press.
the content of the manuscript have been disclosed. 11. Galeotti C, Kaveri SV, Bayry J. IVIG-mediated effector functions in autoimmune
and inflammatory diseases. Int Immunol 2017; 29:491–8.
12. De Ranieri D, Fenny NS. Intravenous immunoglobulin in the treatment of pri-

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6 • ofid • BRIEF REPORT