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Haoli Jin, MD, PhD, James C. Reed, MD, MHS, Sean T.H. Liu, MD, PhD, Hsi-en Ho,
MD, Joao Pedro Lopes, MD, Nicole B. Ramsey, MD, PhD, Omar Waqar, MD, Farah
Rahman, DO, Judith A. Aberg, MD, Nicole Bouvier, MD, Charlotte Cunningham-
Rundles, MD, PhD, The Mount Sinai Health System Convalescent Plasma Team
PII: S2213-2198(20)30945-4
DOI: https://doi.org/10.1016/j.jaip.2020.08.059
Reference: JAIP 3108
Please cite this article as: Jin H, Reed JC, Liu STH, Ho He, Lopes JP, Ramsey NB, Waqar O, Rahman
F, Aberg JA, Bouvier N, Cunningham-Rundles C, The Mount Sinai Health System Convalescent Plasma
Team, Three patients with X-linked agammaglobulinemia hospitalized for COVID-19 improved with
convalescent plasma, The Journal of Allergy and Clinical Immunology: In Practice (2020), doi: https://
doi.org/10.1016/j.jaip.2020.08.059.
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition
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© 2020 Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology
1 Three patients with X-linked agammaglobulinemia hospitalized for COVID-19
2 improved with convalescent plasma
3
4 Haoli Jin, MD, PhD1, 4, James C. Reed, MD, MHS2, 4, Sean T.H. Liu, MD, PhD3, 4, Hsi-en
5 Ho1, MD, Joao Pedro Lopes, MD1, Nicole B. Ramsey, MD, PhD1, Omar Waqar, MD1,
6 Farah Rahman, DO3, Judith A. Aberg, MD3, Nicole Bouvier, MD3, 10, Charlotte
7 Cunningham-Rundles, MD, PhD1, * and The Mount Sinai Health System Convalescent
8 Plasma Team.
9
10 Affiliations:
11 1. Icahn School of Medicine at Mount Sinai, Division of Allergy and Clinical
12 Immunology, Departments of Medicine and Pediatrics, New York, New York
13 2. Mount Sinai Kravis Children’s Hospital, Pediatric Physician-Scientist Residency
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14 Program, New York, NY
15 3. Icahn School of Medicine at Mount Sinai, Division of Infectious Diseases, Department
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16 of Medicine, New York, New York
17 4. Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New
18
19
York, New York
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5. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York,
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20 New York
21 6. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New
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22 York
23 7. Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New
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24 York
25 8. Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New
26 York
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29 10. Icahn School of Medicine at Mount Sinai, Department of Microbiology, New York,
30 New York
31
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32 Contributed equally to this article
*
33 Corresponding Author
34
35 Address correspondence to:
36 Charlotte Cunningham-Rundles, MD, PhD
37 Departments of Medicine and Pediatrics
38 The David S. Gottesman Professor
39 The Immunology Institute
40 Icahn School of Medicine at Mount Sinai
41 1425 Madison Avenue
42 New York, NY 10029
43 Phone: 212 659 9268
44 Fax: 212 987 5593
45 E-mail Charlotte.Cunningham-Rundles@mssm.edu
46
47 Conflict of Interest: None of the authors including all Convalescent Plasma Team
48 members have any conflict of interest.
49
50 Clinical Implications:
51 We describe three XLA patients with COVID-19 who failed supportive treatment but
52 recovered after receiving convalescent plasma.
53
54 The Coronavirus Disease 2019 (COVID-19) pandemic has presented a global challenge.
55 The pathogenesis of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2)
56 infection is complex and effective therapy is currently lacking. Convalescent plasma
57 transfusion is safe and under investigation for effectiveness.1-6
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58
59 We report three hospitalized patients (Supplementary Table E1 and Figure E1) with X-
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60 linked agammaglobulinemia (XLA) who experienced protracted courses with minimal
61 improvement on supportive therapies, but demonstrated clinical improvement soon after
62
63
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transfusion with unmixed ABO-compatible donor convalescent plasma containing anti-
spike protein titer of ≥1:320 from the New York Blood Center.
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64
65 Case 1 is a 10 year-old male with a history of hereditary spherocytosis and XLA
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69 middle and lower lobe infiltrates. On presentation, he was febrile, tachycardic, and
70 tachypnic, and had scleral icterus, pallor, 2/6 systolic murmur, and splenomegaly. Two
71 nasopharyngeal SARS-CoV-2 real time reverse transcription-polymerase chain reaction
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72 (RT-PCR) tests were negative. Respiratory PCR panel and bacterial blood cultures were
73 negative. He had leukopenia and thrombocytopenia, atypical lymphocytosis, hemolytic
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102 elevated CRP, d-dimer, and inflammatory cytokines (Table 1). Nasopharyngeal
103 respiratory panel and SARS-CoV-2 RT-PCR swab, however, oropharyngeal SARS-CoV-
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104 2 swab was positive. Patient 2 was started on subcutaneous heparin and oral
105 azithromycin. Patient 2 received two units of 200 mL convalescent plasma on day 16.
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107
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His temperature rose to 38.1ºC after infusion, but he defervesced within hours. Chest
pain resolved and he tolerated room air. His inflammatory markers decreased, and he
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108 was discharged on day 19.
109
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110 Case 3 is 40 year-old man with XLA receiving IVIG every three weeks with a history of
111 chronic sinusitis. He had seven weeks of fatigue, recurrent fevers and chills, cough,
112 dyspnea, and 15-lb weight loss, with oxygen saturation of 90% requiring 2-3 liters of
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113 oxygen at home. He completed a 12-day course of azithromycin with little improvement.
114 He tested positive for COVID-19 by nasopharyngeal swab as an outpatient. With
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115 continued cough, dyspnea and oxygen dependence, he was admitted on day 42. His
116 oxygen saturation was 95% with otherwise normal vital signs and physical exam
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117 findings. Lab results showed an elevated CRP, IL-6, IL-8 and ferritin (Table 1). Chest CT
118 scan showed irregular peripheral ground glass opacities seen predominantly in the lower
119 lobes (Figure 1). Two units of 200 ml convalescent plasma were infused on day 44 of
120 illness. He was discharged the following day, tolerating room air. His d-dimer,
121 fibrinogen, CRP, and ferritin were decreased. The patient’s SARS-CoV-2 antibody titer
122 was undetectable prior to transfusion and increased to 1:160, 12-hours after infusion.
123
124 Patients with congenital immune defects are presumed to be at risk for more severe
125 courses in the setting of COVID-19 infection, but data on these subjects is limited. Two
126 recent articles described four agammagloblulinemia patients with COVID-19, one of who
127 had an autosomal recessive form of agammagloblulinemia. He was asymptomatic. The
128 XLA patients endured mild short courses.7,8 The positive outcome of these cases led to a
129 hypothesis that humoral immunity might not be essential to overcome COVID-19.
130
131 Our patients displayed strong pro-inflammatory responses in the absence of B cell
132 signaling, but have impaired abilities to control COVID-19, leading to prolonged courses.
133 This highlights the importance of antibody in viral removal. The rapid response to
134 convalescent plasma in these patients is somewhat unusual and the mechanism remains
135 unclear. Whether B cells, as antigen presenting cells, are important in T cell activation in
136 COVID-19 is unknown. We acknowledge the presence of multiple factors and different
137 therapies in the treatment course of our patients. While antivirals, such as remdesivir,
138 may aid in limiting viral replication, convalescent plasma may help neutralize virus and
139 bridge the gap from adaptive immunity and shorten the duration of illness, even in the
140 later stages of COVID-19. We report 3 cases, but it raises possibilities regarding the role
141 of B-cells and antibodies in XLA patients with COVID-19. Future investigations would
142 be needed to draw more definitive conclusions.
143
144 Financial Disclosure: Dr. Cunningham-Rundles has received consulting fees from CSL
145 Behring, Momenta, Atara, Pharming, and UBC; served on boards for CSL Behring and
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146 Takeda Pharmaceutical Company Limited, and serves on the Scientific Advisory Board
147 of the Immune Deficiency Foundation. She acknowledges support from the National
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148 Institutes of Health, AI 101093, AI-086037, AI-48693, and the David S Gottesman
149 Immunology Chair.
150
151
Contributors’ Statement: -p
All authors conceptualized and drafted the initial manuscript, reviewed and revised the
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152 manuscript.
153
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154 All authors approved the final manuscript as submitted and agree to be accountable for all
155 aspects of the work.
156
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157 Acknowledgements:
158 The authors thank all front-line providers and consultants at Kravis Children’s Hospital
159 and Mount Sinai Hospital, Dr. Jeffery Gumprecht for assistance with the case
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162 Rahman, Dr. Zoe Shtasel Gottlieb, Dr. Karen Wilson and Dr. Prantik Saha for ensuring
163 transfusion on the floor.
164
165 * The Mount Sinai Health System Convalescent Plasma Team*.
166 Sean T. H. Liu, M.D., Ph.D., Hung-Mo Lin, Sc.D., Alexandra Abrams-downey, M.D.,
167 Krystal P. Cascetta, M.D., Aaron E. Glatt, M.D., Sanjana C. Koshy, M.D., Erna Kojic,
168 M.D., Dana S. Mazo, M.D., David Perlman, M.D., Steven Rudolph, M.D., Jason
169 Steinberg, M.D., Thomas Schneider, M.D., Ian Baine, M.D., Ph.D., Ania Wajnberg,
170 M.D., Jeffrey P. Gumprecht, M.D., Farah Rahman, D.O., Denise Rodriguez, A.A.S.,
171 Charles Sanky, B.A., Amy Dupper, M.A., M.P.H., Deena R. Altman, M.D., Florian
172 Krammer, Ph.D., Damodara Rao Mendu, Ph.D., Adolfo Firpo-Betancourt, M.D., Carlos
173 Cordon-Cardo, M.D., Ph.D., Jeffrey S. Jhang, M.D., Suzanne A. Arinsberg, D.O., David
174 L. Reich, M.D., Judith A. Aberg, M.D., Nicole M. Bouvier, M.D.
175
176 The authors would like to thank Dr. Sacha Gnjatic and Ms. Diane M Del Valle for their
177 providing the cytokine reference range of patients at age of 10-40 with COVID-19
178 between March and June 2020 in Mount Sinai Health System.
179
180 References:
181 1. Bloch EM, Shoham S, Casadevall A, Sachais BS, Shaz B, Winters JL, et al. Deployment of
182 convalescent plasma for the prevention and treatment of COVID-19. J Clin Invest.
183 2020;130(6):2757-65.
184 2. Joyner MJ, Wright RS, Fairweather D, Senefeld JW, Bruno KA, Klassen SA, et al. Early
185 safety indicators of COVID-19 convalescent plasma in 5,000 patients. J Clin Invest. 2020.
186 3. Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, et al. Treatment of 5 Critically Ill Patients
187 With COVID-19 With Convalescent Plasma. JAMA. 2020.
188 4. Duan K, Liu B, Li C, Zhang H, Yu T, Qu J, et al. Effectiveness of convalescent plasma
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189 therapy in severe COVID-19 patients. Proc Natl Acad Sci U S A. 2020;117(17):9490-6.
190 5. Ye M, Fu D, Ren Y, Wang F, Wang D, Zhang F, et al. Treatment with convalescent plasma
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191 for COVID-19 patients in Wuhan, China. J Med Virol. 2020.
192
193
194
6. -p
Liu STH, Lin H-M, Baine I, Wajnberg A, Gumprecht JP, Rahman F, et al. Convalescent
plasma treatment of severe COVID-19: A matched control study. Medrxiv preprint. 2020.
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195 7. Quinti I, Lougaris V, Milito C, Cinetto F, Pecoraro A, Mezzaroma I, et al. A possible role
196 for B cells in COVID-19? Lesson from patients with agammaglobulinemia. J Allergy Clin Immunol.
197 2020.
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198 8. Soresina A, Moratto D, Chiarini M, Paolillo C, Baresi G, Foca E, et al. Two X-linked
199 agammaglobulinemia patients develop pneumonia as COVID-19 manifestation but recover.
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203
204 Figure 1: CT Chest images for Patient 1 (A), 2 (B) and 3 (C), respectively, showing
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Normal Peds Admit Peak Discharge Normal Adults Admit Peak Discharge Admit Peak Discharge
Inflammatory
Markers
CRP 0.0-5.0 mg/L - 22.4 6.7# 0.0-5.0 mg/L 64 64 18.4 15.2 16.4 13.4
ESR 0-10 mm/hr - 35 - 0-15 mm/hr 89 89 - - - -
LDH 150-260 U/L - 530 - 100-220 U/L 214 289$ 210 183 183 -
642#
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Ferritin 20-200 ng/mL - 642 30-400 ng/mL 123 185 166 967 967 775
IL-1β‡ 0-5.0 pg/mL - <0.3 - 0-5.0 pg/mL 8.6 8.6 <0.3 <0.3 0.5 0.5
IL-6 ‡ 0-5.0 pg/mL - 11.1 - 0-5.0 pg/mL 20.5 20.5 3.8 14.1 15.1 15.1
IL-8 ‡ 0-5.0 pg/mL - 12.7 - 0-5.0 pg/mL 27.3 27.3 21.4 6.7 8.5 8.5
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TNF-α‡ 0-22.0 pg/mL - 19.8 - 0-22.0 pg/mL 18.0 18.1 18.1 15.3 15.3 13.7
Coagulation
Studies
INR
D-Dimer
Normal Peds
0.8-1.2
0.00-0.50 µg/mL
Admit
-
-
Peak
1.3
1.23
Discharge
-
0.30*
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Normal Adults
0.8-1.2
0.00-0.50
Admit
1.1
0.67
Peak
1.1
1.04
Discharge
1.0
0.28
Admit
0.9
0.45
Peak
1.0
0.45
Discharge
1.0
-
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µg/mL
Immune Normal Peds Admit Peak Discharge Normal Adults Admit Peak Discharge Admit Peak Discharge
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Regulation
δ
IgG 698-1,560 mg/dL 560 - -- 700-1,600 821 - - 1057 - -
Quantitative mg/dL
Absolute B Cell 432-3,345 / mm3 13α - 25-335 / mm3 1α - - 3α - -
Count
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221
222 Pediatric ranges are given for patient 1 and adult ranges for patients 2 and 3.‡ Abbreviations are
223 WBC (White Blood Cell Count), HGB (Hemoglobin), PLTS (Platelets), Lymph% (Lymphocyte
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224 Percentage), CRP (C-Reactive Protein), ESR (Erythrocyte Sedimentation Rate), LDH (Lactate
225 Dehydrogenase), IL (Interleukin), and INR (international normalized ratio). *These values are
from * = 1 day prior to discharge and # = 3 days prior to discharge. $A value of more than 10
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226
227 times this is the recorded peak however it does fit with the remainder of the patient’s clinical
228 data. α, = at diagnosis. δ = before IVIG, later increased to 1,021 on readmission. Bolded
229 numbers are abnormal lab values. ‡ For COVID-19 patients aged 10-40 years at our institution, the first to third quartile ranges are
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230 0.1-0.7 pg/mL for IL-1β, 9.9-70.8 pg/mL for IL-6, 13.3-44.3 pg/mL for IL-8, and 11.6-28.0 pg/mL for TNF-α.
231
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B
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C
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