Convalescent Plasma in a Patient with Protracted COVID-19 and Secondary Hypogammaglobulinemia Due to Chronic Lymphocytic Leukemia: Buying Time to Develop Immunity?

Round 1

Reviewer 1 Report

Overall this reported case will be very beneficial for both scientists and clinical practitioners working with patients suffering from leukemia infected with SARS-CoV-2. 

Introduction:

Now during COVID-19 pandemic, anyone who reads this article will understand the context. However, I suggest that in the introduction you should include definitions and brief information about what COVID-19 and CLL are and how they manifest.

Case report

I propose to supplement the case report with the doses and route of administration of drugs administered to the patient (remdesivir, dexamethasone, cefuroxime, ceftazidime, voriconazole).

Figures: Figures are made in a legible way, they add value to the work, very well show the change of the patient's condition during hospitalization, taking into account the treatment.

Discussion

The standard of care for a patient with COVID-19 may differ slightly depending on the treatment center. I would suggest extending the discussion in line 196 including your centre's standard of care for COVID-19 patients.

Line 269: vaccinated “for” COVID-19 should be changed into vaccinated “against” COVID-19 (for->against)

References: References are selected adequately.

Author Response

THank you for your constructive feedback

Now during COVID-19 pandemic, anyone who reads this article will understand the context. However, I suggest that in the introduction you should include definitions and brief information about what COVID-19 and CLL are and how they manifest.
We added two sentences with brief information about covid19 and CLL. line 32-24 and line 40-42

Case report

I propose to supplement the case report with the doses and route of administration of drugs administered to the patient (remdesivir, dexamethasone, cefuroxime, ceftazidime, voriconazole).
We added the doses of the drugs

Figures: Figures are made in a legible way, they add value to the work, very well show the change of the patient's condition during hospitalization, taking into account the treatment.

Discussion

The standard of care for a patient with COVID-19 may differ slightly depending on the treatment center. I would suggest extending the discussion in line 196 including your centre's standard of care for COVID-19 patients.
This part in the article is concentrated on the influence of glucocorticosteroids. Dexamethason was/is part of standard of care for covid-19 patients. 

Line 269: vaccinated “for” COVID-19 should be changed into vaccinated “against” COVID-19 (for->against)
We changed this in the text

Reviewer 2 Report

In their case report Hanssen et al. present a protracted case of COVID-19 infection in a CLL patient under ibrutinib therapy. This is an interesting study due to additional data concerning immunological resposne measurements. I would recommending accepting this paper for publication with some improvements:

1) please indicate comorbidities of this patient upon COVID-19 infection;

2) did immunoglobulin supplementation before COVID-19 infection had any clinical effect? What was the duration of this treatment;

3) what was the ibrutinib dose at COVID-19 onset and CLL advancement? Please define the response to ibrutinib;

4) please indicate the dosing of dexamethasone and remdisivir and their treatment duration. Was remdesivir retreatment taken into account?

5) Were antigen test performed in addition to RT-PCR?

6) I recommend standarizing the X axis in Figure 2, so that in all diagrams the x axis has the same refrerence values and dimensions. It will enable better data presentation.

7) What were the antibody titers of particular CCPs were measured?

Author Response

Thank you for your constructive feedback

1) please indicate comorbidities of this patient upon COVID-19 infection;
These are mentioned in description of the case, there are no extra comorbidities not mentioned

2) did immunoglobulin supplementation before COVID-19 infection had any clinical effect? What was the duration of this treatment;
This is also mentioned in the article. lines 69 -74

3) what was the ibrutinib dose at COVID-19 onset and CLL advancement? Please define the response to ibrutinib;
we added the dose of and response to ibrutinib. line 66-69

4) please indicate the dosing of dexamethasone and remdisivir and their treatment duration. Was remdesivir retreatment taken into account?
We added dosing and duration of treatment. Remdesivir was not considered for retreatment.

5) Were antigen test performed in addition to RT-PCR?
No this was not performed. That is not common clinical practice in our hospital.

6) I recommend standarizing the X axis in Figure 2, so that in all diagrams the x axis has the same refrerence values and dimensions. It will enable better data presentation.
The reference values and dimensions on the x axis of figure 2 have the same reference values and dimensions. Figure 2C goes from day 20 till 100, and 2B and 2C go grom 20 till 80 but with the same values

7) What were the antibody titers of particular CCPs were measured?
This is mentioned in line 111-112

Reviewer 3 Report

The authors present and interesting case of a patient with CLL who developed severe respiratory distress due to COVID-19 and recovered after treatment with steroids, remdesivir, bacterial antibiotics and multiple infusions of convalescent plasma. The investigators performed multiple immunologic assessments on the patient.

The paper is well written and provides interesting data.

What was the patient’s CBC results prior to the development of COVID and at the time of diagnosis of COVID? How low did his lymphocytes go during his hospital course?

Line 149: The decreases in T cell response could have also been due to the multiple rounds of steroids administered.

Author Response

Thanks for you suggestions, this is our reply

What was the patient’s CBC results prior to the development of COVID and at the time of diagnosis of COVID? How low did his lymphocytes go during his hospital course?
We added the requested CBC results and development of the lymphocytes. Lines 75, 81 and 136

Line 149: The decreases in T cell response could have also been due to the multiple rounds of steroids administered.  
We agree with this, we also state this (indirectly) in the discussion. line 216/217

Reviewer 4 Report

This very well-written about convalescent plasma in a patient with CLL has some minor comments.  First, in the title I am nos sure if the final word (cellular immunity) should be included. Perhaps is better: ... buying time to developed immunity.   

1. It could be improved by including to comment 2-3 additional references on poor response to SARS-CoV-2 vaccination of patients with CLL, mainly those with active disease or are being treated with BTK or BCL2 inhibitors. Herishanu Y et al. Efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with chronic lymphocytic leukemia. Blood 2021. Parry H et al. Antibody responses after first and second Covid-19 vaccination in patients with chronic lymphocytic leukaemia. Blood Cancer J 2021.
2. Some mention to other clinical trials with hyperimmune plasma can be done. Avendaño-Sola C et al . A multicenter randomized open-label clinical trial for convalescent plasma in patients hospitalized with COVID-19 pneumonia. J Clin Invest 2021, in press.
3. Although it can be inferred from their reading in the text, in Figure 2C the curves of the anti-S and anti-NC antibodies are not sufficiently clear. It is suggested that a legend be incorporated into the graph, as shown in Figure 3.
4. It is suggested that it be clarified whether hypogammaglobulinemia was already present at the time of CLL relapse or was found under ibrutinib treatment.
5. In lines 228 and 288, is said '...CCP in combination with oxygen therapy merely bought time...'  The reference to oxygen treatment, in the sense that it is associated with the immune response, may be confusing for some readers.
6. Finally, Aspergillus fumigatus and Pseudomonas aeruginosa identification in repeated cultures of sputum could be a contamination.  Was a seriation of galactomannan test be performed? Was any lesion suggestive of Aspergillus infection observed on imaging probes?

Author Response

Thanks for your suggestions:

First, in the title I am nos sure if the final word (cellular immunity) should be included. Perhaps is better: ... buying time to developed immunity.   
-We changed the title according to this suggestion

1. It could be improved by including to comment 2-3 additional references on poor response to SARS-CoV-2 vaccination of patients with CLL, mainly those with active disease or are being treated with BTK or BCL2 inhibitors. Herishanu Y et al. Efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with chronic lymphocytic leukemia. Blood 2021. Parry H et al. Antibody responses after first and second Covid-19 vaccination in patients with chronic lymphocytic leukaemia. Blood Cancer J 2021.
2. Some mention to other clinical trials with hyperimmune plasma can be done. Avendaño-Sola C et al . A multicenter randomized open-label clinical trial for convalescent plasma in patients hospitalized with COVID-19 pneumonia. J Clin Invest 2021, in press.
   We added the 2 references. line 289-290
3. Although it can be inferred from their reading in the text, in Figure 2C the curves of the anti-S and anti-NC antibodies are not sufficiently clear. It is suggested that a legend be incorporated into the graph, as shown in Figure 3. 
   We added a small legend in the figure to make more readable
4. It is suggested that it be clarified whether hypogammaglobulinemia was already present at the time of CLL relapse or was found under ibrutinib treatment.
   we added this information. line 71
   
5. In lines 228 and 288, is said '...CCP in combination with oxygen therapy merely bought time...'  The reference to oxygen treatment, in the sense that it is associated with the immune response, may be confusing for some readers. 
   We feel that this a correct sentence and left it unchanged
   
6. Finally, Aspergillus fumigatus and Pseudomonas aeruginosa identification in repeated cultures of sputum could be a contamination.  Was a seriation of galactomannan test be performed? Was any lesion suggestive of Aspergillus infection observed on imaging probes?
   A serum galactomannan was done (not in sputum), added in line 125/126
   There was a suggestive lesion with a cavity, added in 118