Uncommon pulmonary manifestation of hepatitis B virus: a case report of secondary organizing pneumonia

Abstract

Background

Hepatitis B virus (HBV) primarily affects the liver, but increasingly, it is recognized for its potential extrahepatic manifestations. This case highlights the importance of considering viral infections in the differential diagnosis of pulmonary nodules.

Case presentation

A 63-year-old man presented with a new mixed ground-glass nodule in the left lower lobe during a routine check-up. He had a history of liver resection for hepatocellular carcinoma, with results negative for hepatitis B virus surface antigen. The HBV viral load in the patient’s serum was below the detection limit of quantitative PCR (qPCR). Immunohistological analysis of lung biopsy samples indicated chronic inflammation. However, after a course of intravenous antibiotics, the nodule increased in size, prompting further investigation. Therefore, lung biopsy tissue was subjected to metagenomic next-generation sequencing (mNGS), and HBV DNA was detected. The patient was diagnosed with secondary organizing pneumonia associated with HBV. Then he was treated with prednisone acetate and had remission.

Conclusion

This case underscores the potential for HBV to manifest as pulmonary complications, such as secondary organizing pneumonia. Therefore, in the stage of infectious diseases in patients with a history of hepatocellular carcinoma, HBV needs to be the focus of monitoring, so as to clarify the cause of diagnosis and treatment as soon as possible.

Clinical trial

Not applicable.

Background

Hepatitis B virus (HBV) is a hepatotropic virus that can induce significant liver pathologies, including acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). Globally, an estimated 254 million individuals are affected by chronic HBV infection, leading to nearly one million fatalities each year [1]. However, recent evidence suggests that HBV may also play a role in extrahepatic manifestations, including renal diseases, systemic manifestations, as well as hematological, rheumatological, neurological, and dermatological conditions [2,3,4,5]. These factors significantly influence both the survival duration and quality of life of patients.

Organizing pneumonia is an interstitial lung disease primarily characterized by imaging findings such as pulmonary nodules, consolidations, or ground-glass opacities on computed tomography [6]. Based on its etiology, organizing pneumonia can be categorized into cryptogenic organizing pneumonia (COP) and secondary organizing pneumonia (SOP) [7, 8]. COP has no identifiable cause, while SOP arises from known factors, which include infections, medications, certain autoimmune diseases, and organ transplants. Various pathogens, including bacteria, fungi, viruses, and parasites, can induce organizing pneumonia [7, 9,10,11]. HBV is rarely reported to be an infectious cause of organizing pneumonia.

This case report presents a rare instance of SOP linked to HBV infection in the lung, highlighting its potential pulmonary implications, which are often overlooked in clinical practice.

Case presentation

A 63-year-old man was admitted to the hospital following the discovery of a new mixed ground-glass nodule in the left lower lobe, measuring 13.1 mm×10.9 mm, during a routine check-up on October 27, 2023 (Fig. 1A). He was treated with intravenous levofloxacin and sodium chloride for 7 days, but a follow-up enhanced chest CT scan on November 11, 2023, revealed an increase in the size of the nodule to 22 mm×18 mm (Fig. 1B).

Fig. 1

Chest computed tomography images at different time-points. (A) A new mixed ground-glass nodule was found in the left upper lobe (13.1 mm×10.9 mm) on October 27, 2023. (B) On November 11, 2023, after 7 days of treatment with levofloxacin and sodium chloride injection, the nodule increased in size (22 mm×18 mm). (C) On December 15, 2023, after one month of oral prednisone acetate, the nodule decreased (17 mm×16 mm), and the ground-glass appearance significantly lightened. (D) The pulmonary nodule had disappeared on March 29, 2024

The patient had a medical history of left hemihepatectomy for hepatocellular carcinoma two years prior and a tension-free repair for an abdominal wall incisional hernia eight months ago. He reported no history of smoking or alcohol consumption, infectious diseases, or family histories of genetic conditions. His relevant comorbidities included hypertension and diabetes. He denied experiencing any respiratory symptoms such as cough, sputum production, fever, chills, shortness of breath, or hemoptysis.

On examination, the patient’s vital signs were stable, with a temperature of 37.1℃, blood pressure of 122/74 mm Hg, heart rate of 90 beats/min, respiratory rate of 19 breaths/min, and oxygen saturation of 97% on room air. There were no abnormal physical findings, including palpable lymphadenopathy. Laboratory tests demonstrated elevated levels of hypersensitive C-reactive protein (10.9 mg/L), serum amyloid A (71 mg/L), γ-glutamyl transferase (175 IU/L), and alanine aminotransferase (124 IU/L). Tests for hepatitis B virus surface antigen (HBsAg), hepatitis B virus e antigen (HBeAg), and S1 antigen were negative, while tests for hepatitis B virus surface antibody (anti-HBs), hepatitis B virus e antibody (anti-HBe), and hepatitis B virus core antibody (anti-HBc) were positive. Cultures from blood samples were negative for both anaerobic and aerobic bacteria, and PCR testing for Mycobacterium tuberculosis complex DNA in the lung biopsy tissue was also negative.

To investigate the lung nodule further, the patient underwent a percutaneous transthoracic needle biopsy. Histopathological examination revealed chronic inflammation with organization and alveolar epithelial proliferation (Fig. 2A). Immunohistochemical staining showed that Napsin A and P40 were negative, while TTF-1, CK7, and Ki67 were positive. Though no hepatitis B virus DNA was detected in the blood, it was found in the lung biopsy tissue. Additionally, both Victoria Blue staining (Fig. 2B) and HBsAg testing (Fig. 2C) yielded positive results.

Fig. 2

The pathological staining of lung biopsy tissue. A: Hematoxylin-eosin (HE) staining shows chronic inflammation with organization in the lung tissue. B: Victoria blue staining reveals sky-blue round or oval aggregates. C: HBsAg immunohistochemical staining demonstrates focal brownish-positive cells

The patient was diagnosis of SOP associated with HBV. He was initiated on oral prednisone acetate at a dose of 10 mg three times daily. After one week, the dosage was adjusted to twice daily, and one month later, it was further modified to once daily. Follow-up chest CT revealed a significant reduction in nodule size and resolution of the ground-glass components (Fig. 1C). After two months, the dosage was adjusted to 5 mg per dose, and the prednisone was discontinued after five months. A subsequent chest CT displayed complete resolution of the nodule (Fig. 1D).

Discussion

The presented case illustrates a unique instance of SOP associated with HBV infection, highlighting the potential respiratory complications that can arise in patients with a history of hepatocellular carcinoma. Despite the absence of serological evidence of active HBV replication, the detection of HBV DNA in lung tissue substantiates the hypothesis that HBV may exert direct or indirect effects on lung function, potentially through mechanisms involving immune-mediated injury or direct viral cytotoxicity [12].

Organizing pneumonia caused by HBV is a rare extrahepatic manifestation. The key pathogenic mechanism behind most extrahepatic manifestations is believed to be driven by the immune response against HBV, characterized by the deposition of immune complexes in target tissues and widespread inflammation [2, 13]. Additionally, this may be influenced by the stage of infection (acute versus chronic), the extent of liver damage, and direct viral tissue infection. The potential consequences of extrahepatic manifestations include viral gene evolution, the development of resistance, and the potential for maintaining a low-level viral reservoir that could lead to reinfection of the liver [14]. For patients with HCC, HBV infection is not only a significant cause of the occurrence and progression of liver cancer but also a high-risk factor for recurrence and poor prognosis. According to the “Chinese Expert Consensus on Antiviral Therapy for HBV-related Hepatocellular Carcinoma” published in 2023, all patients diagnosed with liver cancer should routinely be screened for HBsAg, anti-HBs, and anti-HBc. Therefore, in HCC patients who present with unexplained infections, particularly HBV testing is essential to prevent secondary infections caused by HBV.

Timely and accurate identification of pathogens is crucial for the precise application of antimicrobial treatments, which helps improve patient prognosis and reduces the emergence of resistant bacteria. Conventional microbiological methods often fail to detect all pathogens; therefore, mNGS is increasingly applied to identify all possible pathogens, including newly emerging ones, due to its unbiased sampling capability [15]. In the diagnosis of pulmonary infectious diseases, mNGS is typically utilized to detect pathogenic microorganisms in blood and bronchoalveolar lavage fluid. However, there is currently no recognized threshold for blood cfDNA detection. Furthermore, when the abundance of pathogens is low, the sensitivity of blood testing may be limited. Studies have shown that combining mNGS of biopsy tissue with pathological examination can enhance the positive rate of pathogen identification, providing advantages over conducting histopathological examination alone, especially in the diagnosis of rare pathogen infections [16]. The management of organizing pneumonia typically involves corticosteroid therapy [17], which was successfully employed in this case, characterized by a significant reduction in nodule size and resolution of ground-glass opacities. The favorable response observed in the patient underscores the efficacy of corticosteroids in treating organizing pneumonia. Serial imaging and clinical follow-up are vital components in evaluating the effectiveness of treatment and ensuring complete resolution of lung lesions.

Previous studies have documented various extrahepatic manifestations linked to chronic HBV infection, including renal, hematological, and dermatological conditions [2]. This case suggests that the respiratory system may also be vulnerable to HBV-related complications. It is crucial for clinicians to be vigilant regarding the diverse manifestations of HBV, as undiagnosed respiratory conditions may lead to delayed management and poor outcomes.

Conclusion

This case highlights the rare pulmonary manifestations of HBV infection, specifically in the form of secondary organizing pneumonia. The presence of HBV DNA in the lung biopsy, combined with the histopathological findings of chronic inflammation and organizational changes, underscores the need for heightened awareness among clinicians regarding potential extrahepatic effects of HBV infections.