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. 2020 Jun 5;72(1):180–182. doi: 10.1093/cid/ciaa592

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

Chimaobi M Anugwom 1,2, Elizabeth S Aby 1,2, Jose D Debes 1,2,3,
PMCID: PMC7314123  PMID: 32502247

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.

Notes

Acknowledgments. The authors thank Drs Lanjuan Li (Wuhan, China) and Barnaby Young (Singapore) for providing information from their manuscripts regarding hepatitis B virus.

Financial support. This work was supported by the Robert Wood Johnson Foundation’s Harold Amos Medical Faculty Development Program (to J. D. D.); and the National Cancer Institute of the National Institutes of Health (grant number R21 CA215883-01A1 to J. D. D.).

Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.

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