Our patient had a strong systemic inflammatory reaction and a severe inflammatory response locally in the airways. Previous studies have reported a mild clinical course of COVID-19 in individuals with XLA [
1]. The BTK is also expressed by macrophages and other myeloid cells [
8]. Pharmacological BTK-inhibition has been reported to attenuate hyperinflammation in COVID-19, and dysfunctional BTK has been suggested an explanation for mild disease in some patients with XLA [
9]. However, the lack of BTK in XLA does not affect ex vivo function of monocytes and polymorphonuclear cells, a finding in line with the strong inflammatory response seen in our patient [
8]. It can be hypothesized that the absent humoral response protected our patient from the immunopathology driven by SARS-CoV-2 specific antibodies, resulting in multi-organ failure, despite protracted hyperinflammation [
8]. Instead, low avidity T-cells may also have contributed to the inflammatory process [
10]. After CC-plasma therapy, there was a dramatic shift in the clinical status of the patient, in line with previous reports on XLA-patients with less severe hyperinflammation [
4,
5]. Our case adds evidence to the importance of antibodies in the immunological process of SARS-CoV-2 clearance. Studies performed during 2021 have confirmed the benefit of treatment with SARS-CoV-2 mAbs in COVID-19, particularly in seronegative individuals [
11,
12]. Passive administration of SARS-CoV-2 specific IgG opsonize viral particles and may thereby improve viral clearance by affecting natural killer cell cytotoxicity and modulating T-cell interactions with antigen presenting cells and thereby resulting in a more efficient anti-viral T-cell response. Negative nasopharyngeal SARS-CoV-2 PCR day 49, and improvement of the T-cell phenotype day 56, with decreasing expression of the checkpoint PD-1, may also reflect effects of the CC-plasma therapy. By 100 days post-infection, the patient’s T cell phenotypes were considered fully recovered, after comparison with samples collected prior to the COVID-19 pandemic. The presence of CMV-virus specific T-cells at this time point, may also indicate functional recovery of the T-cell compartment. CC-plasma therapy is considered safe but does not affect the clinical status in immunocompetent hospitalized patients with COVID-19 [
13]. In COVID-19, administration of CC-plasma against SARS-CoV-2 within 72 h after onset of symptoms, reduces severe disease in elderly [
14]. Presence of a SARS-CoV-2 specific T-cell response indicates ability to control the infection, still antibody therapy with SARS-CoV-2 specific mAbs, or in low to middle income countries with CC-plasma therapy, should be considered to promote viral clearance in patients with antibody deficiencies [
11].
Limitations of this case report include the lack of extended immune phenotyping of T-cells and assessment of SARS-CoV-2 specific T-cell responses prior to day 34. In addition, the presence of viremia was never investigated. Bacteria were isolated in the sputum cultures and a bacterial infection may have contributed to the clinical symptoms. The treatment with broad spectrum antibiotics may also have affected the clinical process. There was no access to test for SARS-CoV-2 neutralizing antibodies in the CC-plasma given. However, only plasma with high anti-spike protein titers was used for treatment. The fact that the patient did not receive any anti-viral drugs or anti-inflammatory treatments can be considered strengths of this case, CC-plasma was the only specific treatment given. Also, the long follow up period as well as the access to T-cell phenotype and chest images, prior to COVID-19 diagnosis, can be included in the strengths.
The patient was overwhelmed by the fast recovery of COVID-19 after the initial CC-plasma transfusions. The patient had a relevant fear of re-infection that was alleviated by regular CC-plasma therapy. Plasma-transfusions continued until we found out about his strong specific T-cell response. It was stressful for the patient when the decision to discontinue the prophylactic CC-plasma therapy was made. However, after careful information that his T-cell response reflected protection against COVID-19 he accepted the decision.
We suggest evaluation of specific SARS-CoV-2T-cell responses in patients with severe COVID-19 and primary or acquired antibody deficiencies (XLA, CVID and patients on B-cell depletion therapy). Albeit clinical studies are needed, the presence of specific T-cell responses indicate protective immunity and may reduce the need for pre-exposure prophylaxis [
15] and prophylactic therapy with SARS-CoV-2 mAbs, or CC-plasma, in individuals with antibody deficiencies.