A possible role for B cells in COVID-19? Lesson from patients with agammaglobulinemia.

To the Editor:

An epidemic of coronavirus SARS-CoV-2 has become the focus of scientific attention. The high infectivity of SARS-CoV-2 and rapid rise in the number of patients affected reflects the lack of preexisting immunity as reported by the World Health Organization (https://www.who.int/emergencies/diseases/novel-coronavirus-2019). The clinical presentation of coronavirus disease 2019 (COVID-19) is variable, ranging from lack of symptoms to severe respiratory distress and multiorgan failure requiring intensive care unit admission and mechanical ventilation. Treatment of COVID-19 requires in-depth knowledge of the immune-mediated mechanisms of the disease. To date, we have identified 7 patients with primary antibody deficiencies (PADs) and COVID-19 infection: 5 had common variable immune deficiencies (CVIDs) and 2 had agammaglobulinemia (1 with X-linked agammaglobulinemia and 1 with autosomal recessive agammaglobulinemia). All of the patients with PADs had defective antibody production. Patients with agammaglobulinemia lack B lymphocytes, whereas patients with CVID have dysfunctional B lymphocytes. In patients with agammaglobulinemia, the COVID-19 course was characterized by mild symptoms, short duration, and no need for treatment with an immune-modulating drug blocking IL-6, and it had a favorable outcome. In contrast, patients with CVIDs presented with a severe form of the disease requiring treatment with multiple drugs, including antiretroviral agents and IL-6–blocking drugs, as well as mechanical ventilation (Table I ). The strikingly different clinical course of COVID-19 in patients with agammaglobulinemia compared with that in patients with CVIDs cannot be explained by the levels of serum immunoglobulins, which were similarly low in all patients with PADs at diagnosis and were maintained at adequate and comparable levels in all patients by immunoglobulin substitutive therapy (see Table E1 in this article’s Online Repository at www.jacionline.org). A detailed COVID-19 clinical history, laboratory data, type and dosage of administered treatment, and disease timing are provided for each patient in Case Reports in this article’s Online Repository (at www.jacionline.org). The lung high-resolution computed tomography (HRCT) of a patient with CVID at hospital admission for COVID-19 showed extensive ground glass opacities associated with areas of alveolar consolidation in the upper and lower lobes, with the alveolar component predominating over the interstitial component. (Fig 1 , A). On treatment, the lung HRCT showed a reduction in the extent of ground glass opacities and areas of alveolar consolidation. (Fig 1, B). In contrast, the lung HRCT of a patient with agammaglobulinemia performed at the time of COVID-19 was unchanged from lung HRCT performed 1 year earlier and showed bronchiectasis and sequelae of a right lung pneumonectomy done when the patient was 18 years old (Fig 1, C and D). All patients with PADs are equally vulnerable to most bacterial infections because antibodies are important in blocking infectivity and preventing diseases. In addition, antibodies have a role in the immune response to viral infections. Patients with agammaglobulinemia are susceptible to a limited number of viral infections only—mainly norovirus and enteroviruses such as polioviruses, with an increased incidence of postvaccination poliomyelitis due to the oral attenuated Sabin vaccine. CVIDs patients are susceptible to rhinoviruses, noroviruses, and herpesviruses that in turn play a role in driving an underlying inflammatory condition. Because only patients with agammaglobulinemia had a mild course of COVID-19, we speculate on a possible role of B lymphocytes in the SARS-CoV-2–induced inflammation. We have already shown that children appear to better contain SARS-CoV-2 in the early phase of infection, possibly because their B cells are able to generate natural antibodies in a timely manner on encounter with novel pathogens when compared with B cells from adults. The role of inflammation in aggravating the clinical picture of subjects with COVID-19 has already been described. Treatment with drugs such as IL-6 inhibitors aimed at reducing the cytokine storm syndrome and lung inflammation associated with a profound increase in level of cytokines such as IL-6 and increased level of ferritin have already been carried out, initially on an individual basis and currently within clinical trials. Of note, our patients with CVID who required IL-6–blocking treatment (3 of 5) presented with increased serum ferritin levels (see the Online Repository). It has been demonstrated that B cells produce IL-6 to drive germinal center formation. In patients unable to carry on the physiologic immune response, IL-6 produced by B cells may increase the level of inflammation. Lack of B-cell–derived IL-6 abrogates spontaneous autoimmune germinal center formation in a mouse model, resulting in protection from systemic autoimmunity. Thus, it appears that cytokine storm syndrome may play a significant role in the respiratory failure in COVID-19 infection. The role of B cells in determining lung inflammatory disorders is also demonstrated by the observation that granulomatous-lymphocytic interstitial lung disease, which occurs in 10% of patients with CVID, can be treated with B-cell–depleting drugs. COVID-19 treatments might contemplate the possibility of dampening the inflammatory functions of B cells and blocking cytokine production by monocytes and dendritic cells. Our data represent the first description of COVID-19 in patients affected with primary antibody defects, offer useful insights to the putative mechanisms underlying the immunologic response to the infection, and suggest possible clues to novel therapeutic targets.

Table I

Summary of data for the 7 patients with PAD and COVID-19

Patient No.	PAD	Age (y)	Sex	COVID-19
				Clinical symptoms	Days	Treatment	ICU	Outcome
1	ARA	56	M	No symptoms	0	Hydroxychloroquine, azithromycin, darunavir/cobicistat	No	Recovery
2	XLA	34	M	High fever	3	Hydroxychloroquine, ceftriaxone, lopinavir/ritonavir	No	Recovery
3	CVID	59	F	High fever, dyspnea	20	Hydroxychloroquine, azithromycin, tocilizumab	Yes	Death
4	CVID	32	F	High fever, dyspnea	16	Hydroxychloroquine, darunavir/ritonavir, tocilizumab	No	Recovery
5	CVID	57	M	High fever, dyspnea	25	Hydroxychloroquine, lopinavir/ritonavir, remdesivir methylprednisolone.	Yes	Recovery
6	CVID	52	M	High fever, dyspnea	21	Hydroxychloroquine, azithromycin, lopinavir/ritonavir,	No	Recovery
7	CVID	41	M	High fever, dyspnea	19	Hydroxychloroquine, piperacillin/tazobactam, lopinavir/ritonavir, tocilizumab, remdesivir	Yes	Recovery

ARA, Autosomal recessive agammaglobulinemia; F, female; ICU, intensive care unit; M, male; XLA, X-linked agammaglobulinemia.

Table E1

Summary of immunologic data of the 7 patients with PAD collected 1 to 6 months before COVID-19 infection

Patient No.	Date of last investigation	IgG level (mg/dL)	IgA level (mg/dL)	IgM level (mg/dL)	Lymphocyte count (mm3)	CD19 cell count (mm3)	CD3 cell count (mm3)	CD4 cell count (mm3)	CD8 cell count (mm3)	NK cell count (mm3)
1	January 2020	750	0	0	1300	0	1247	460	739	25
2	November 2019	800	0	0	1700	0	1600	900	700	28
3	January 2020	897	30	33	1600	400	1030	672	338	46
4	January 2020	500	0	153	2050	200	1800	950	850	30
5	October 2019	550	40	44	3400	96	3200	2767	1658	21
6	December 2019	662	11	8	890	55	750	274	258	85
7	September 2019	700	10	30	1800	278	1500	800	700	15

NK, Natural killer.

Fig. 1

Lung HRCT in a patient with CVID at admission, showing extensive ground glass opacities associated with areas of alveolar consolidation in the lower lobes, where the alveolar component predominates over the interstitial component (A [left, mid-upper; right: lower), and after treatment, showing reduction in extent of ground glass opacities and areas of alveolar consolidation (B [left, mid-upper; right, lower]). Lung HRCT in a patient with agammaglobulinemia. Axial sections showing bronchiectasis and sequelae of right lung pneumonectomy (in March 2020 [C] and January 2019 [D]).