Journal Pre-proof

Three patients with X-linked agammaglobulinemia hospitalized for COVID-19

improved with convalescent plasma

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

To appear in: The Journal of Allergy and Clinical Immunology: In Practice

Received Date: 22 June 2020

Revised Date: 23 July 2020
Accepted Date: 24 August 2020

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.

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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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27 9. Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount

28 Sinai, New York, New 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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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
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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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66 receiving subcutaneous immunoglobulin every other week with two pneumonia

67 hospitalizations in the prior year. He was admitted for 10 days of fever, cough, bilateral
68 chest pain, and lack of improvement on oral antibiotics. A chest X-ray suggested right
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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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74 anemia, and elevated inflammatory markers (Table 1).

75
76 In the first two weeks of hospitalization, he received a red blood cell transfusion, broad-
77 spectrum antibiotics, oxygen supplementation and albuterol treatments, and a dose of
78 scheduled intravenous immunoglobulin (IVIG). However, his condition failed to improve
79 with further increases in CRP and ESR. On day 16, he experienced episodes of oxygen
80 desaturation to 89%, dyspnea, increased oxygen demand, and fatigue. Chest CT scan on
81 day 17 showed multiple peripherally distributed and predominant lower lobe ground-
82 glass opacities bilaterally with total atelectasis of the right middle lobe (Figure 1). He was
83 placed on enoxaparin. Bronchoalveolar lavage on day 19 was RT-PCR positive for
84 SARS-CoV-2. Soon after diagnosis, the patient was started on a 10-day course of
85 remdesivir, and two units of 200 mL of convalescent plasma were infused on days 22 and
86 23. One day later, patient was afebrile for the first time in 3 weeks and had improved
87 energy. He was weaned off oxygen support and discharged on day 29. The patient’s
88 SARS-CoV-2 antibody titer before convalescent plasma was undetectable; 3 days after
89 infusion, the antibody titer was 1:80.
 90
91 Case 2 is 24-year-old male with XLA receiving IVIG every three weeks with a history of
92 chronic sinusitis, bronchiectasis, recurrent Clostridium difficile colitis, and Helicobacter
93 skin infections, was initially admitted for 5 days of febrile illness with chills, cough and
94 myalgia. Left lower lobe consolidation was noted on chest X-ray. Two nasopharyngeal
95 and one rectal SARS-CoV-2 RT-PCR swabs were negative. He was discharged on day 8
96 after receiving broad-spectrum antibiotics and his scheduled dose of IVIG. Patient was
97 re-admitted on day 13 of illness due to fatigue, cough, shortness of breath, left sided chest
98 pain, diarrhea, myalgia, and headaches. Chest X-ray showed worsening pneumonia, and
99 he was tachycardic, with an oxygen saturation of 93% on room air. Chest CTA scan
100 showed diffuse multifocal ground-glass and patchy airspace opacities throughout the
101 lungs (Figure 1). Initial laboratory studies showed leukopenia, reduced hemoglobin,

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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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160 management, Ms. Denise Rodriguez for assistance in obtaining Emergency

161 Investigational New Drug approval from FDA, and Dr. Christine Quake, Dr. Nazifa
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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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200 Pediatr Allergy Immunol. 2020.

201 9. Del Valle DM, Kim-Schulze S, Huang HH, Beckmann ND, Nirenberg S, Wang B, et al. An
202 inflammatory cytokine signature predicts COVID-19 severity and survival. Nat Med. 2020.
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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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205 diffuse bilateral ground-glass opacities.

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218 Table 1: Laboratory Values
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220
Patient1 Patient2 Patient 3
CBC Normal Peds Admit Peak Discharge Normal Adults Admit Peak Discharge Admit Peak Discharge
WBC 4.5-11.4 x103/µL 3.2 14.3 14.3* 4.5-11.0 4.2 9.2 4.4 6.4 6.4 5.3
x103/µL
*
HGB 10.6-14.4 g/dL 6.6 10.2 10.0 13.9-16.3 g/dL 10.8 10.9 10.8 12.6 12.6 11.3
PLTS 150-450x10 3/µL 134 193 175* 150- 260 391 333 248 248 187
450x103/µL
Lymph % 12.2-48.4% 31.7 34 23.0* 12.2-48.4% 28.8 61.4 54.6 17.0 29.3 24.7

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 -
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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.

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