Challenges in Diagnosis and Clinical Management of COVID-19 in Patient with B-Cell Chronic Lymphocytic Leukemia (CLL): Report of One Case

Round 1

Reviewer 1 Report

The results in the Table are not easy to understand. Legends could be improved.

In the Conclusion, it is assumed that the problem of the tests was the time of analysis of the samples from the moment of the acquisition. Therefore, it seems that the real problem of false COVID-19 negative test should be related to the poor procedure of the laboratory, and not that the test by itself is not enough sensitive, or the CLL condition affect the results. The narrative could be improved.

Author Response

1) The results in the Table are not easy to understand. Legends could be improved.

A.: We provide to add a legend of the table 1, in order to better clarify its content

2) In the Conclusion, it is assumed that the problem of the tests was the time of analysis of the samples from the moment of the acquisition. Therefore, it seems that the real problem of false COVID-19 negative test should be related to the poor procedure of the laboratory, and not that the test by itself is not enough sensitive, or the CLL condition affect the results. The narrative could be improved.

A.: As we mentioned on the abstract, “the recognition of the Covid-19 was delayed because of its atypical clinical presentation and technical problems related to the methods”. However, we agree with the referee 1 about the observation that a lack of sensitivity in the diagnostic RT-PCR should be remarked. According to this, we improved the report adding the following sentences in the discussion: ”Although such repeated negative results may be related to this specific patient, they could reflect a lack of sensitivity in the panels used for RT-PCR REFS (as confirmed by Niu A et al, Blood 2020 and reviewed by Mihaila R, Oncology Letters 2021). However, as suggested by Niu A et al (Blood 2020), since patients with hematological diseases have a high risk of developing a severe form of COVID-19 and are also more susceptible to false negative RT-PCR test, the diagnostic and therapeutic management of this selected population should be more aggressively performed.”

Reviewer 2 Report

The authors discuss the pros and cons of the COVID-19 tests available. A more detailed explanation whether corticosteroid usage is a potential cause of false negative results will improve the perspective. It is possible that the patient's history of prednisone usage controlled the viral load leading to negative test result. However, even the reduced load was sufficient to cause serious disease due to underlying CLL. This does raise a point about susceptibility of patients with underlying conditions that require regular steroid usage changing the susceptibility of the patient to infect/disease as well as diagnosis.

Author Response

The authors discuss the pros and cons of the COVID-19 tests available. A more detailed explanation whether corticosteroid usage is a potential cause of false negative results will improve the perspective. It is possible that the patient's history of prednisone usage controlled the viral load leading to negative test result. However, even the reduced load was sufficient to cause serious disease due to underlying CLL. This does raise a point about susceptibility of patients with underlying conditions that require regular steroid usage changing the susceptibility of the patient to infect/disease as well as diagnosis.

A.: We agree with the referee 2 that the regular steroid usage for managing CLL may limit the overreaction of the immune system (frequently observed during COVID-19), also leading to a possible reduction in specific SARS-CoV-2 immunoglobulin production (ESMO Open. 2022 Jan 28: 100403. doi: 10.1016/j.esmoop.2022.100403). However, we were able to detect specific SARS-CoV-2 antibodies despite steroid administration. Whether the literature regarding the role of corticosteroids in the management of COVID-19 patients remains controversial, it should not affect the sensitivity of RT-PCR tests, that repeatedly gave false negative results in our patient. Future studies that will further investigate these findings are needed.

Reviewer 3 Report

Vincenzo vistco et al described an 84-year-old man with CLL who suffered from COVID-19 infection. They described the patient had lymphocytosis and the diagnosis of COVID-19 was delayed because of conflict result of different test panels. The following are some critiques:

1. The repeated negative results might not be related to this specific patient but only reflected the poor sensitivity of the panels used. If this was really related to this patient, can the authors explain this phenomenon?
2. The lymphocytosis might merely be a response to his COVID-19 infection.
3. The authors described an interesting case but the mechanistic aspects were not adequately discussed.

Author Response

1) The repeated negative results might not be related to this specific patient but only reflected the poor sensitivity of the panels used. If this was really related to this patient, can the authors explain this phenomenon?

A.: We don’t really know if those repeated negative results can be related to this specific patient, but also they may reflect a lack of sensitivity in the panels used for RT-PCR in CCL patients affected by SARS-COV-2 (as previously suggested).

2) The lymphocytosis might merely be a response to his COVID-19 infection.

A.: We agree. In fact, according to this, we modified the text of the discussion adding the following part: ”We should consider that lymphopenia is commonly present in patients with COVID-19. However, an opposite behavior of lymphocytes -in patients affected by CLL- could be remarked. In fact, although occasionally found, a marked lymphocytosis in COVID-19 patients has been previously described, especially in those affected also by CLL (Safarpour D, Srinivasan K, Farooqui M, Roth C, Ghouse M. A Case of COVID-19-Induced Lymphocytosis in a Patient With Treatment-Naive CLL: Should It Be treated? Clin Lymphoma Myeloma Leuk. 2021 Jan;21(1):69-72. doi: 10.1016/j.clml.2020.09.005. Epub 2020 Sep 18. PMID: 33039356; PMCID: PMC7499147). This peak of lymphocytosis might partially mask the occurrence of COVID-19, (as previously suggested^4,5) which is the case of our patient. However, we cannot exclude that the lymphocytosis may be related to the immune response to the viral infection”.

 3) The authors described an interesting case but the mechanistic aspects were not adequately discussed.

A.: We are not able to give insight on the mechanisms at the basis of the observed lymphocytosis in our COVID-19 patient. In patients affected by CLL, lymphocytosis is caused by clonal expansion of lymphocytes in blood, marrow and second lymphoid tissue. It is not clear how SARS-CoV-2 virus may interfere with this effect. It has been reported that lymphocytosis may affect negatively the course of the disease, possibly because of an excessive activation of the immune response and, on the contrary, immunodeficiency, typically observed in most COVID-19 patients, may exert a protective role from severe disease (Scarfò L, Chatzikonstantinou T, Rigolin GM, Quaresmini G, Motta M, Vitale C, Garcia‐Marco JA, Hernandez‐Rivas JÁ, Mirás F, Baile M, et al: COVID‐19 severity and mortality in patients with chronic lymphocytic leukemia: A joint study by ERIC, the European research initiative on CLL, and CLL Campus. Leukemia 34: 2354‐2363, 2020).

We also modified the conclusion of the report, suggesting that “All the possible attempts should be made to obtain the correct identification of the disease, using the most accurate methods, to avoid misdiagnosis and delay in identifying the infection thus preventing the spreading of the virus”. 

We are now confident on the fact that those adjustments can be able to improve the narrative of the case report and to suggest possible strategies to the correct identification of COVID-19 infection in patients affect by CLL.

Round 2

Reviewer 3 Report

The authors addressed my concern well.