Logo American Journal of Case Reports

Call: 1.631.629.4328
Mon-Fri 10 am - 2 pm EST

Contact Us

Logo American Journal of Case Reports Logo American Journal of Case Reports Logo American Journal of Case Reports

20 February 2022: Articles  Japan

Relapsing Infectious Mononucleosis-Like Symptoms Associated with Liver Insufficiency in a Chronic Hepatitis B Patient with Common Variable Immunodeficiency

Unusual clinical course, Challenging differential diagnosis, Unusual or unexpected effect of treatment

Akira Sato1ABCDEF*, Fumiaki Sano2CD, Hideaki Takahashi1B, Nobuyuki Matsumoto1B

DOI: 10.12659/AJCR.934003

Am J Case Rep 2022; 23:e934003

0 Comments

Abstract

BACKGROUND: Common variable immunodeficiency (CVID) is a rare disease. Infectious mononucleosis-like symptoms due to Epstein-Barr virus reactivation in adulthood are also rare. Here, we aimed to report a case of Epstein-Barr virus reactivation presenting with relapsing infectious mononucleosis-like symptoms with liver failure in common variable immunodeficiency with chronic hepatitis B virus infection.

CASE REPORT: A 36-year-old Japanese woman with chronic hepatitis B virus infection developed relapsing fever, lymphadenopathy with marked splenomegaly, and ascites 6 months after treatment with propagermanium, a nonspecific immune modulator, and subsequent treatment with entecavir and pegylated interferon sequential therapy. Although the hepatitis B virus load was controlled, Epstein-Barr virus deoxyribose nucleic acid was detected in her serum. Seven months later, her symptoms improved following corticosteroid treatment. Prior to sequential therapy, she developed pneumonia 4 times in 2 months and exhibited consistent hypoimmunoglobulinemia before corticosteroid treatment. Further examinations showed low amounts of switched memory B cells, and absence or barely detectable levels of isohemagglutinins. Subsequently, she was diagnosed with common variable immunodeficiency.

CONCLUSIONS: Epstein-Barr virus reactivation with relapsing infectious mononucleosis-like symptoms can occur following immune modulation therapy in patients with common variable immunodeficiency, and this can affect the patient’s primary disease. Therefore, immunoglobulin screening along with the consideration of CVID in all patients is required before immune modulation therapy is planned.

Keywords: Common Variable Immunodeficiency, Epstein-Barr Virus Infections, Hepatitis B, Proxigermanium

Background

Epstein-Barr virus (EBV) infection is extremely common worldwide, and approximately 90% of adults are infected before 30 years of age [1]. Following primary infection, EBV persists for the remainder of an individual’s life. It can reactivate under physical and psychological stress and in individuals with a variety of autoimmune diseases and cancers [2]. Moreover, reactivation sometimes results in severe or fatal outcomes [3].

Common variable immunodeficiency (CVID) is a primary immunodeficiency disease characterized by hypogammaglobulinemia, recurrent infections, and various complications, with a prevalence of 0.001–3.374 per 100 000 population, and the prevalence tends to be higher in countries with a high Human Development Index [4]. It is very rare for patients with CVID to present with relapsing infectious mononucleosis (IM)-like symptoms.

Propagermanium (PG) is an organic germanium that is used to treat chronic hepatitis B in Japan owing to its immune modulatory effects; it can reduce levels of hepatitis B e (HBe) antigen, hepatitis B virus (HBV) deoxyribose nucleic acid (DNA) polymerase, and alanine aminotransferase (ALT), as well as increase the HBe antibody titer [5]. In recent years, attempts have been made to use PG for the treatment of various diseases owing to its multiple effects, including anti-inflammatory, antitumor, and antiviral effects [6–8].

Here, we report a case of relapsing IM-like symptoms associated with liver insufficiency due to the reactivation of EBV after PG treatment in a patient with chronic HBV infection accompanied by CVID.

Case Report

A 36-year-old Japanese woman was diagnosed with chronic HBV infection through a medical examination and was followed up for 5 years. Her prior medical history revealed only a diagnosis of mild sinusitis when she was 24 years old. One year ago, her HBe antigens converted to HBe antibodies. However, her HBV DNA levels fluctuated between 4.0 and 8.1 log copies/mL, and her ALT levels fluctuated as well. Recent abdominal ultrasonography revealed chronic hepatitis with marked splenomegaly (Figure 1). Upper gastrointestinal endoscopy revealed no signs of portal hypertension. She was started on 30 mg of PG for the disease in February 2010. Laboratory data prior to PG administration are shown in Table 1. One month after the commencement of PG therapy, the patient developed pneumonia (positivity for Streptococcus pneumoniae urinary antigen), and she recovered following a course of oral antibiotics. However, pneumonia developed 3 more times within the following 2 months, and PG was discontinued 8 weeks after commencement. The level of ALT increased to 170 IU/L at week 8 of the PG treatment, but returned to the same lower abnormal level as before initiation and remained at a similar level. During this treatment, in May, she became aware of bilateral cervical lymphadenopathy, and she was followed up by an otolaryngologist. At this time, splenomegaly was also observed on breast computed tomography (CT), and a liver biopsy showed grade 2 activity and stage 3 fibrosis according to the Scheuer system [9]. We commenced sequential therapy with entecavir and pegylated interferon α (pegIFN α) in June. During the 6 months she received entecavir, the patient developed fever above 38°C several times, which subsided within a few days of taking loxoprofen. In October, weekly administration of pegIFN α was initiated. Subsequently, she developed fever again and took loxoprofen 1–3 times daily. The fever disappeared after 5 months with completion of pegIFN α therapy. However, her fever returned, and she reported having cervical lymphadenopathy without pain 2 weeks later. She consulted with an otolaryngologist and was referred to a hematologist. A few bilateral lymphadenopathies were observed in the cervical lymph nodes (2–4 cm in diameter) and in the axillary and inguinal regions (1–2 cm in diameter). Histological findings of a cervical lymph node biopsy specimen were compatible with vascular transformation of the lymph node sinuses. The patient continued to take loxoprofen as needed. Although her fever and lymph-adenopathies subsided temporarily, fever reoccurred starting in October 2011. In December, the patient visited our department reporting feeling a sense of abdominal fullness, marked swelling of the bilateral cervical lymph nodes, and frequent fever above 39°C. Abdominal CT revealed massive ascites and striking splenomegaly (Figure 2). Although her serum HBV DNA level had decreased to 2.1 log copies/mL following pegIFN α treatment, it increased to ≥9.0 log copies/mL after 4 months (September) and persisted at this level. However, the increase in her serum ALT level was modest. Her serum albumin level decreased to 3.4 g/dL, and an ascites examination through flow cytometry showed no abnormal cell populations. We again commenced the administration of entecavir, diuretics, and branched-chain amino acid granules. Gradually, her HBV DNA level decreased to 3.4 log copies/mL, and her serum albumin level recovered to 4.0 g/dL; further, her ascites was unremarkable by March 2012. However, splenomegaly and occasional fever with lymphadenopathy persisted. A second biopsy of the cervical lymph nodes showed no significant changes compared with the first biopsy. In May, the patient developed a fever of 38–40°C, which persisted for 2 weeks along with marked cervical and axillary lymphadenopathies. Ascites reappeared coincident with a decrease in the serum albumin level to 3.1 g/dL and in prothrombin activity to 58%. The HBV DNA load decreased to 2.8 log/mL, ALT levels remained normal for 5 months, and the increase in C-reactive protein levels was modest (3.48 mg/dL). However, the soluble interleukin 2-receptor (sIL-2R) levels were extremely high (29 800 IU/mL), and a serum EBV DNA load of 1300 copies/mL was detected. Anti-EBV capsid antigen immunoglobulin (Ig)M or anti-EBV nuclear antigen antibodies were not detected (Table 2). We commenced daily treatment with 30 mg of prednisolone (PSL). Five days after PSL administration, her fever disappeared, and her lymphadenopathy subsided. Ascites was not observed physically, and normalization of serum albumin levels occurred after 3 weeks. Therefore, the dose of PSL was reduced to 25 mg. Two weeks later, it was further reduced to 20 mg. Thereafter, the dose of PSL was reduced by 2.5 mg every 3–8 weeks to ensure that there was no tendency for symptoms and sIL2-R to relapse. Although the decrease in splenomegaly was very modest, her other symptoms improved remarkably, and her sIL-2R level decreased to 1700 IU/mL at 14 weeks after the start of the PSL treatment. Five months after PSL administration, EBV DNA levels decreased to < 100 copies/mL. The dose of PSL was reduced to 7.5 mg daily. However, her fever started occurring repeatedly 2 months later. The dose of PSL was increased to 30 mg daily in March 2013. Although her fever resolved and the dose of PSL was reduced as before, it appeared again 8 weeks after reducing the dose of PSL to 12.5 mg daily. The dose was then increased to 20 mg daily and was reduced very slowly (1 mg every 3–4 months). At this time, it was found that the patient’s Ig levels remained consistently low, which started prior to PSL administration. The IgG level was 421 mg/dL, the IgA level was 17 mg/dL, and a low IgM level of 17 mg/dL was observed after PSL administration (Table 3). We tried 5.0 g of intravenous immunoglobulin (IVIG) once when the dose of PSL was reduced to 13 mg, and 2 months later, the sIL-2R, which had been mildly abnormal and had stopped decreasing, normalized. Subsequently, the dose of PSL was further reduced to 10 mg daily and was maintained for more than 3 years. In 2015, her Ig levels were still low (Table 3), and we found that isohemagglutinins were absent or barely detectable (Table 4), and she had few switched memory B cells (Table 5). Because she did not have antibodies to human immunodeficiency virus, she was diagnosed with CVID.

Discussion

Our patient presented with 2 unique clinical manifestations. The first was relapsing IM-like symptoms due to EBV reactivation. The second was CVID that became apparent after the commencement of PG treatment.

EBV infection is one of the most common infections in humans, and approximately 90% of humans acquire EBV infection by young adulthood [1]. Following infection, EBV remains latent in infected B cells in healthy individuals; however, it occasionally reactivates and sometimes causes severe illness. Even when EBV reactivation is asymptomatic, it influences the severity of a patient’s primary disease [12]. Our patient presented with relapsing IM-like symptoms with positivity for serum EBV DNA, which was suspected to be a result of chronic active EBV infection [13].

However, 2 examinations of lymph node biopsy specimens only revealed the vascular transformation of the lymph node sinuses, posing a clinical diagnostic challenge. The consistently low Ig levels seen prior to PSL administration led to the suspicion of CVID, and subsequent findings of decreased switched memory B cells and lack of isohemagglutinins were consistent with this diagnosis [14]; further, this condition was thought to be an important cause of the atypical IM-like symptoms in this case.

CVID is a primary immunodeficiency characterized by reduced serum levels of IgG, IgA, and sometimes IgM, with reduced or absent specific antibody production [14]. The prevalence of CVID in Japan is estimated to be 0.25 per 100 000 population [15]. The clinical features of CVID vary and can include acute and chronic infections, inflammatory diseases, autoimmune diseases, and increased incidence of cancer and lymphoma. There are several known atypical forms of EBV infection in patients with primary immune deficiencies [16]; however, to the best of our knowledge, reactivation of EBV in patients with CVID has not yet been reported.

The hallmark of CVID is the loss of B-cell function, but CVID is a heterogenous disease, and some patients may have additional hidden abnormalities in T cells or natural killer (NK) cells [17], which play an important role in EBV latency [18].

PG was formerly used in Japan for the treatment of chronic hepatitis B and had ameliorating effects on biochemical and virological markers. The mechanism underlying these effects is thought to be immunomodulation, including activation of cytotoxic T cells and NK cells [5]. Furthermore, PGs have also been reported to stimulate and proliferate B-cell lines [19].

In this case, we thought it was highly likely that CVID, which had been asymptomatic until then, stimulated the immune system including NK cells, T cells, and B cells via PG, which destabilized the latent state of EBV and reactivated EBV, leading to the onset and recurrence of IM-like symptoms.

With regard to chronic HBV, although the HBV DNA level was increased, exacerbation of hepatitis did not occur after discontinuation of PG. However, liver insufficiency occurred in association with relapsing IM-like symptoms, suggesting the influence of EBV reactivation. Recently, Goh et al reported that EBV reactivation in sepsis caused by pneumonia is associated with increased morbidity [12]. Additionally, Hu et al reported that EBV infection is associated with a high Child-Pugh score in patients with liver cirrhosis and that it has an influence on the liver function of patients with HBV-related acute-on-chronic liver failure [20,21]. These studies also suggest the influence of EBV reactivation on liver insufficiency.

Since PG has various immunomodulatory effects, the use of PG in patients with CVID with a latent EBV infection may lead to immune imbalance and reactivation of EBV. As PG can be used for the treatment of various diseases in the future, we recommend screening for CVID by testing immunoglobulin levels prior to PG administration.

Conclusions

We present a case of relapsing IM-like symptoms due to EBV reactivation associated with liver insufficiency after PG treatment in a patient with chronic hepatitis B, and CVID was diagnosed during the subsequent clinical course. EBV reactivation can occur in patients with CVID after immune modulation therapy, and it can affect the patient’s primary disease; therefore, immunoglobulin levels should be checked along with the consideration of CVID before administering this therapy.

References:

1.. Dunmire SK, Hogquist KA, Balfour HH, Infectious mononucleosis: Curr Top Microbiol Immunol, 2015; 390(Pt 1); 211-40

2.. Kerr JR, Epstein-Barr virus (EBV) reactivation and therapeutic inhibitors: J Clin Pathol, 2019; 72; 651-58

3.. Takahashi T, Maruyama Y, Saitoh M, Fatal Epstein-Barr virus reactivation in an acquired aplastic anemia patient treated with rabbit antithymocyte globulin and cyclosporine: Case Rep Hematol, 2015; 2015; 926874

4.. Weifenbach N, Schneckenburger AAC, Lötters S, Global distribution of Common Variable Immunodeficiency (CVID) in the light of the UNDP Human Development Index (HDI): A Preliminary perspective of a rare disease: J Immunol Res, 2020; 2020; 8416124

5.. Hirayama C, Suzuki H, Ito M, Oda T, Propagermanium: A nonspecific immune modulator for chronic hepatitis B: J Gastroenterol, 2003; 38; 525-32

6.. Mulder P, van den Hoek AM, Kleemann R, The CCR2 inhibitor propagermanium attenuates diet-induced insulin resistance, adipose tissue inflammation and non-alcoholic steatohepatitis: PLoS One, 2017; 12; e0169740

7.. Kikuchi S, Noguchi K, Wakai K, Propagermanium induces NK cell maturation and tends to prolong overall survival of patients with refractory cancer: Anticancer Res, 2019; 39; 4687-98

8.. Ishiwata Y, Suzuki E, Yokochi S, Studies on the antiviral activity of propagermanium with immunostimulating action: Arzneimittelforschung, 1994; 44; 357-61

9.. Theise ND, Liver biopsy assessment in chronic viral hepatitis: A personal, practical approach: Mod Pathol, 2007; 20(Suppl. 1); S3-14

10.. Blanco E, Pérez-Andrés M, Arriba-Méndez S, Age-associated distribution of normal B-cell and plasma cell subsets in peripheral blood: J Allergy Clin Immunol, 2018; 141; 2208-19

11.. Kucybała I, Ciuk S, Tęczar J, Spleen enlargement assessment using computed tomography: Which coefficient correlates the strongest with the real volume of the spleen?: Abdom Radiol, 2018; 43; 2455-61

12.. Goh C, Burnham KL, Ansari A, Epstein-Barr virus reactivation in sepsis due to community acquired pneumonia is associated with increased morbidity and an immunosuppressed host transcriptomic endotype: Sci Rep, 2020; 10; 9838

13.. Accessed 25 Nov. 2021. Available from: URL: https://rarediseases.info.nih.gov/diseases/9534/chronic-active-epstein-barr-virus-infection#ref_8879

14.. Seidel MG, Kindle G, Gathmann B, The European Society for Immunodeficiencies (ESID) Registry working definitions for the clinical diagnosis of inborn errors of immunity: J Allergy Clin Immunol Pract, 2019; 7; 1763-70

15.. Ishimura M, Takada H, Doi T, Nationwide survey of patients with primary immunodeficiency diseases in Japan: J Clin Immunol, 2011; 31; 968-76

16.. Dropulic LK, Cohen JI, Severe viral infections and primary immunodeficiencies: Clin Infect Dis, 2011; 53; 897-909

17.. Yazdani R, Habibi S, Sharifi L, Common Variable Immunodeficiency: Epidemiology, pathogenesis, clinical manifestations, diagnosis, classification, and management: J Investig Allergol Clin Immunol, 2020; 30; 14-34

18.. Tangye SG, Palendira U, Edwards ES, Human immunity against EBV-lessons from the clinic: J Exp Med, 2017; 214; 269-83

19.. Cho JM, Chae J, Jeong SR, Immune activation of Bio-Germanium in a randomized, double-blind, placebo-controlled clinical trial with 130 human subjects: Therapeutic opportunities from new insights: PLoS One, 2020; 15; e0240358

20.. Hu J, Zhang X, Yu G, Epstein-Barr virus infection is associated with a higher Child-Pugh score and may predict poor prognoses for patients with liver cirrhosis: BMC Gastroenterol, 2019; 19; 94

21.. Hu J, Zhao H, Lou D, Human cytomegalovirus and Epstein-Barr virus infections, risk factors, and their influence on the liver function of patients with acute-on-chronic liver failure: BMC Infect Dis, 2018; 18; 577

SARS-CoV-2/COVID-19

29 June 2022 : Case report  USA

A Clinical Case of COVID-19 Vaccine-Associated Guillain-Barré Syndrome

Am J Case Rep In Press; DOI: 10.12659/AJCR.936896  

16 June 2022 : Case report  Ecuador

Multidrug-Resistant Klebsiella pneumoniae in a Patient with SARS-Cov-2 Pneumonia in an Intensive Care Unit ...

Am J Case Rep In Press; DOI: 10.12659/AJCR.936498  

13 June 2022 : Case report  Japan

Stenotrophomonas maltophilia Infection Associated with COVID-19: A Case Series and Literature Review

Am J Case Rep In Press; DOI: 10.12659/AJCR.936889  

13 June 2022 : Case report  Saudi Arabia

Atlantoaxial Subluxation Secondary to SARS-CoV-2 Infection: A Rare Orthopedic Complication from COVID-19

Am J Case Rep In Press; DOI: 10.12659/AJCR.936128  

In Press

30 Jun 2022 : Case report  China (mainland)

Septic Shock Induced by Acute Pyelonephritis Resulting from Kidney Stones Treated by Double-J Ureteral Sten...

Am J Case Rep In Press; DOI: 10.12659/AJCR.936967  

30 Jun 2022 : Case report  USA

A Clinical Case of COVID-19 Vaccine-Associated Guillain-Barré Syndrome

Am J Case Rep In Press; DOI: 10.12659/AJCR.936896  

29 Jun 2022 : Case report  Kuwait

A Challenging Case of Jejunal Dieulafoy’s Lesion: A Rare Cause of Refractory Lower-Gastrointestinal Bleeding

Am J Case Rep In Press; DOI: 10.12659/AJCR.936313  

29 Jun 2022 : Case report  USA

A Rare Case of Synchronous Intraductal Papillary Mucinous Neoplasm-Associated Pancreatic Adenocarcinoma and...

Am J Case Rep In Press; DOI: 10.12659/AJCR.935242  

Most Viewed Current Articles

23 Feb 2022 : Case report  USA

Penile Necrosis Associated with Local Intravenous Injection of Cocaine

DOI :10.12659/AJCR.935250

Am J Case Rep 2022; 23:e935250

17 Feb 2022 : Case report  Oman

Myocarditis, Pulmonary Hemorrhage, and Extensive Myositis with Rhabdomyolysis 12 Days After First Dose of P...

DOI :10.12659/AJCR.934399

Am J Case Rep 2022; 23:e934399

06 Dec 2021 : Case report  Brazil

Lipedema Can Be Treated Non-Surgically: A Report of 5 Cases

DOI :10.12659/AJCR.934406

Am J Case Rep 2021; 22:e934406

09 Feb 2022 : Case report  Saudi Arabia

Extensive Cerebral Venous Sinus Thrombosis (CVST) After the First Dose of Pfizer-BioNTech BNT162b2 mRNA COV...

DOI :10.12659/AJCR.934744

Am J Case Rep 2022; 23:e934744

Your Privacy

We use cookies to ensure the functionality of our website, to personalize content and advertising, to provide social media features, and to analyze our traffic. If you allow us to do so, we also inform our social media, advertising and analysis partners about your use of our website, You can decise for yourself which categories you you want to deny or allow. Please note that based on your settings not all functionalities of the site are available. View our privacy policy.

American Journal of Case Reports eISSN: 1941-5923
American Journal of Case Reports eISSN: 1941-5923