Inverse Association Between Chronic Hepatitis B Infection and Coronavirus Disease 2019 (COVID-19): Immune Exhaustion or Coincidence?

To the Editor—We read with great interest the report by Zhao et al, regarding a case of delayed immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a patient with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfection [1]. The authors stipulate that previous HIV and HCV infection could confer immune dysfunction providing a differential immune response during coronavirus disease 2019 (COVID-19) development.

This report, as most initial reports, originated in China, which has an intermediate-high prevalence of chronic hepatitis B (HBV) infection [2]. We evaluated all peer-reviewed articles, written in the English language, reporting cases of COVID-19 infection and specifically defining rates of HBV infection and hospital admission, since 1 December 2019 until 25 March 2020 and found a surprisingly low prevalence of chronic HBV in COVID-19 cases admitted to the hospital. Indeed, Of the 2054 cases that were reported with this information, only 28 patients (1.36%) were reported positive for HBV. Several of these studies reported 0% incidence of HBV among individuals infected with COVID-19. We matched the HBV rates in COVID-19 subjects to age-specific rates of HBV reported in the respective geographic areas of origin (Table 1). The median age of COVID-19 infected individuals in the evaluated studies ranged between 47 and 51 years, corresponding to HBV rates ranging from 7% to 11%, whereas the HBV rates of those with COVID-19 remained between 0% and 1.3%. It is unclear whether this is a simple epidemiological “misconnection” or if being chronically infected with HBV impacts the chances of clinically significant infection with SARS-CoV-2 leading to fewer hospital admissions, in a similar fashion as that reported by Zhao et al to HIV and HCV. In this regard, research has documented that chronic HBV infection leads to a reduced or absent virus-specific T-cell reactivity (although HBV-specific T cells). This phenomenon, known as “immune exhaustion,” is manifested by an impaired ability of T-lymphocytes to produce appropriate cytokines secondary to years of continuous, yet inefficient, immune reaction to the virus [3]. Immune exhaustion is also frequently observed in chronic HCV infection [4]. In this setting, it is plausible that the exhaustion of T lymphocytes may affect their ability to respond to other viruses and reduce the degree of “cytokine storm” that has been noticed in COVID-19 patients, thus culminating in a less severe disease. Similar patterns of immune cointeraction with consequences in clinical presentation and prognosis have been reported in individuals infected with HBV and schistosomiasis [5]. Further research is needed to elucidate if this epidemiological outlier is a consequence of immune dysregulation or just coincidence. If it is indeed the former, it could provide important insights in to the immunopathology of COVID-19 and open potentially unique venues for prevention and treatment.

Table 1.

Rates of Hepatitis B Infection Among Patients With Coronavirus Disease 2019 and the General Population by Region and Age Group

Study	Region Studied	No. of Patients	Age Group of COVID-19 Patients, y, median (IQR)	No. of Patients With HBV	Hepatitis B Rate, %
					COVID-19 Patients	Region	Similar Age Group in Region
Zhao et al [6]	Anhui, China	19	48 (27–56)	1	5.26	7.44	7.5–9a
Guan et al [7]	China	1099	47 (35–58)	23	2.1	6.89	~5.5–7a
Chen et al [8]	Wuhan, China	99	55.5 (36–64)	0	0	6.89b	~5.5–7b
Xu et al [9]c	Wuhan, China	62	41 (32–52)	2	3.22	6.89b	~5.5–7b
Chen et al [10]	Shanghai, China	249	51 (36–64)	2	0.8	7.2	8.3–8.7a
Young et al [11]c	Singapore	18	47 (31–71)	0	0	3.6	~4.1a
Pan et al (in press)	Hubei, China	204	52.9 (SD, 16)	0	0	9.2	11.1a

Abbreviations: COVID-19, coronavirus disease 2019; HBV, hepatitis B virus; SD, standard deviation.

aLi et al. [12]; Wang et al. [13]; Ji et al. [14]; Ang et al. [15]; She et al. [16].

bNo data specific to the Wuhan area were noted and so general rates in China were used here.

cPersonal communication from the authors.