Cryptogenic brain abscess: Right-to-left shunt in pulmonary arteriovenous malformation and hepatopulmonary syndrome

Abstract

Background

Pulmonary arteriovenous fistula (PAVF) and hepatopulmonary syndrome (HPS) both cause right-to-left shunting, allowing pathogens to bypass the pulmonary filtration barrier and enter systemic circulation, leading to brain abscess. Despite distinct etiologies, both share the same pathological pathway—right-to-left shunt—resulting in the same devastating neurological complication.

Case presentation

Two male patients with cryptogenic brain abscesses caused by PAVM (59 years old) and HPS (52 years old), respectively, are reported. The patient with PAVM presented with fever, dyspnea, and headache, and was diagnosed by contrast-enhanced chest computed tomography. Fusobacterium nucleatum was detected in cerebrospinal fluid (CSF). The patient recovered following anti-infective therapy combined with surgical resection of pulmonary lesions, achieving a favorable prognosis at the 3-month follow-up. The HPS patient had a history of hepatitis C complicated by liver cirrhosis. He presented with headache, fever, and orthostatic hypoxemia. Diagnosis was confirmed by a contrast-enhanced transcranial Doppler bubble test (c-TCD). Blood culture identified Streptococcus intermedius. The brain abscess recurred after antibiotic treatment due to refusal of liver transplantation. At the 3-year follow-up, the patient could maintain only a sedentary lifestyle.

Conclusion

Both pulmonary arteriovenous fistula (PAVM) and hepatopulmonary syndrome (HPS) can cause cryptogenic brain abscess through right-to-left shunt. PAVM can be eradicated by intervention or surgery, while HPS fundamentally requires liver transplantation. Notably, Clinical and radiological improvement following antimicrobial therapy may not represent definitive cure if the underlying right-to-left shunt remains untreated, and recurrence remains possible.

Highlight

• •PAVM and HPS cause intrapulmonary shunting, bypassing capillary filter, letting pathogens reach systemic circulation and raising cryptogenic brain abscess risk.
• •Both show hypoxemia and wide A-a gradient. Dynamic testing: PAVM has no oxygen/orthostatic response; HPS has oxygen response with orthostatic desat.
• •HPS is functional, not excluded by negative CT. Vasodilation can't be locally corrected; cure requires treating liver disease, or relapse risk stays high.

Introduction

Cryptogenic brain abscesses account for approximately 20–30% of all brain abscess cases [1]. Their etiological diagnosis remains a significant clinical challenge in neurology and infectious diseases. RLS is an important pathological mechanism in cryptogenic brain abscesses, allowing venous blood containing pathogens to bypass pulmonary capillary filtration and enter systemic arterial circulation, causing hematogenous spread to the brain [2]. PAVM and HPS are two typical causes of pulmonary RLS with distinct pathological characteristics. PAVM is an anatomical shunt due to vascular malformation [3] HPS is associated with liver disease, characterized by widespread functional dilation of pulmonary microvessels throughout the lungs. The resultant right-to-left pulmonary shunt is a hallmark of this syndrome [4].

This report describes two cases of cryptogenic brain abscess caused by PAVM and HPS, respectively, detailing their clinical characteristics and differences in diagnosis and treatment.

Case 1

A 59-year-old male without significant medical history presented with fever (39.7°C), chills, fatigue, and persistent refractory dyspnea in August 2025. The patient was initially admitted to the department of respiratory medicine. Initial vital signs included temperature 36.5°C, blood pressure 106/78 mmHg, heart rate 78 beats/min, respiratory rate 20 breaths/min, and SpO₂ 93% on a 10 L/min oxygen face mask, with no other notable signs. Imaging and laboratory results: Non-contrast chest CT revealed a mass lesion in the right upper lobe; however, its nature was unclear. Arterial blood gas analysis under supplemental oxygen demonstrated persistent hypoxemia (PaO₂ 57 mmHg, PaCO₂ 34 mmHg), with a calculated A-aDO₂ of 257 mmHg and a PaO₂/FiO₂ ratio of 114 mmHg, indicating severe impairment of gas exchange. Inflammatory markers were elevated (CRP 30.39 mg/L, WBC 10.66 ×10⁹/L, neutrophil proportion 84%); blood cultures were negative.

Contrast-enhanced chest CT (Fig. 1 C) revealed a lesion in the right upper lobe communicating with the hilar vessels, consistent with PAVM. Although common pulmonary infection was initially suspected, the patient remained febrile (>39°C) with worsening fatigue and headache despite antibiotic therapy. Subsequent brain MRI (Fig. 1 A) demonstrated a lesion with ring enhancement in the left parietal lobe, prompting transfer to the neurology department.

Fig. 1.

Brain MRI(A and B), Contrast-enhanced chest CT(C), Lung histopathology (D). (A) Left parietal lesion (0.6–1.7 cm), T1WI hypointense, T2WI hyperintense, with oedema and rim enhancement. (B) Further formation of the abscess wall with localised consolidation of the lesion. (C) Patchy hyperdense opacity in the right upper lobe with marked enhancement and communication with the right hilar artery and vein. (D) Right upper lobe specimen: 90 g, 12 × 7.5 × 4 cm; honeycomb-like area (3 × 3 × 2 cm) adjacent to pleura. Microscopy: malformed vascular channels in lung parenchyma, consistent with arteriovenous malformation.

After transfer, the patient remained febrile (38°C) with persistent hypoxemia (PaO₂ 57–65 mmHg, SaO₂ 90–93%). Given the intracranial imaging findings, hematogenous brain abscess secondary to PAVM was considered the most likely diagnosis. Lumbar puncture revealed an intracranial pressure of 240 mmH₂O, yellowish turbid CSF, elevated WBC (1134 ×10⁶/L, 65% polymorphonuclear cells), glucose 3.01 mmol/L, and chloride 123.3 mmol/L. CSF metagenomic next-generation sequencing (mNGS) identified Fusobacterium nucleatum (28 sequences). But routine culture was negative, noting that the patient had received antibiotics before transfer to the neurology department. Whole-exome sequencing excluded hereditary hemorrhagic telangiectasia (HHT).

Treatment: The initial antibiotic therapy (piperacillin-tazobactam) was upgraded to meropenem, with the addition of ornidazole after obtaining CSF results. MRI repeated after 15 days of intravenous antibiotic therapy demonstrated that the lesion had become more localized (Fig. 1B). After 21 days of intravenous antibiotics, a repeat lumbar puncture showed improvement: the CSF changed from slightly turbid to clear, pressure decreased from 240 to 160 mmH₂O, and WBC count decreased from 1134 to 238 × 10⁶/L. Surgical resection of the right upper lobe lesion was performed by the thoracic surgery department. Pathological diagnosis confirmed PAVM (Fig. 1D).

Follow-up: After discharge, the patient continued oral antibiotics for two weeks. Chest DR performed two months after pulmonary lobectomy showed findings consistent with postoperative changes. In November 2025, the patient was in good condition without any discomfort, and repeat blood gas analysis revealed significantly improved A-aDO₂ (41 mmHg).

Case 2

A 52-year-old male with a history of hepatitis C complicated by liver cirrhosis (including splenectomy and esophagogastric variceal ligation) presented with headache, fever (maximum 38°C), and dyspnea in September 2022, and was admitted to the neurology department. On admission, the patient was afebrile (36.7°C) but hypoxemic (SpO₂ 90% on ambient air). Physical examination revealed abdominal distension with shifting dullness and nuchal rigidity. Arterial blood gas analysis on supplemental oxygen showed hypoxemia (PaO₂ 78 mmHg), hypocapnia (PaCO₂ 21 mmHg), and markedly widened A-aDO₂ (252 mmHg), indicating impaired gas exchange. Peripheral blood tests showed elevated neutrophils (7.13 ×10⁹/L) and CRP (21.48 mg/L), with blood cultures positive for Streptococcus intermedius. Cranial MRI revealed a ring-enhancing lesion in the left temporal lobe, approximately 2.3 × 1.3 cm in size(Fig. 2E). Lumbar puncture showed intracranial pressure of 100 mmH₂O, yellowish turbid CSF, elevated WBC (779 ×10⁶/L, predominantly polymorphonuclear cells), decreased glucose (1.45 mmol/L), and chloride (125.4 mmol/L).

Fig. 2.

Brain MRI (E, F, and G)and contrast-enhanced transcranial Doppler (c-TCD)(H) findings in a patient with hepatopulmonary syndrome (HPS). E: Left temporal lesion (2.3 × 1.3 cm): T1WI hypointense, T2WI hyperintense, with extensive oedema and rim enhancement. F: Left temporal lesion decreased (1.5 × 0.8 cm); new left lateral ventricle lesion (2.5 × 2 cm) with T1WI hypointensity, T2WI hyperintensity, extensive oedema, and rim enhancement. G: Decreased abnormal signal in left temporal and periventricular region. H (c-TCD): LMCA at 44 mm and 56 mm: microbubble signals at 5 s (curtain-like pattern). Positive for right-to-left shunt.

After intracranial infection was confirmed, the patient was initially managed as having a solitary brain abscess. Concurrently, the cause of dyspnea was investigated. Chest CT indicated bilateral interstitial pneumonia, while pulmonary artery CTA was normal. However, these imaging results did not explain the patient’s dyspnea. Further history revealed dyspnea worsened with activity and improved with rest, with some relief from supplemental oxygen after admission. Therefore, serial arterial blood gas measurements were obtained at different times and positions while on supplemental oxygen: Morning (standing): pH 7.49, PaCO₂ 26 mmHg, PaO₂ 79 mmHg, SaO₂ 97%; Noon (supine, resting): pH 7.51, PaCO₂ 26 mmHg, PaO₂ 101 mmHg, SaO₂ 98%; Afternoon (upright, active): pH 7.43, PaCO₂ 27 mmHg, PaO₂ 79 mmHg, SaO₂ 96%; Night (supine, sleeping): pH 7.52, PaCO₂ 25 mmHg, PaO₂ 107 mmHg, SaO₂ 99%. These findings demonstrated persistent hypocapnia (PaCO₂ 25–27 mmHg) and positional fluctuations in PaO₂, consistent with orthodeoxia, a diagnostic feature of HPS. Intrapulmonary vasodilation in HPS predominantly affects the gravity-dependent lower lung zones. A contrast-enhanced transcranial Doppler (c-TCD) bubble test was positive (curtain-like microbubbles appearing 5 s after injection at rest)(Fig. 2H), confirming the diagnosis of HPS. Additional evaluations revealed decompensated liver cirrhosis with ascites, moderate microcytic hypochromic anemia, hypoalbuminemia, and abnormal coagulation function.

Treatment: Vancomycin was administered for infection control. After 2 weeks of treatment, headache and fever improved, and CSF WBC decreased to 25 × 10⁶/L. However, a brain abscess recurred (New lesion in the left lateral ventricle, measuring approximately 2.5 × 2 cm) 45 days after admission (Fig. 2 F). At this stage, the lesion in the left temporal lobe had progressed into a cerebral abscess measuring approximately 1.5 × 0.8 cm, smaller than previously noted. Surgical drainage or resection was considered but deferred due to coagulopathy (PT 13.8 s, INR 1.21, PTA 70%, fibrinogen 1.57 g/L), anemia (HGB 72 g/L), positive fecal occult blood, and family refusal. Conservative therapy was continued. Hepatobiliary surgery recommended liver transplantation, which the patient refused. After two months of intravenous antibiotic treatment, the patient was discharged. The patient was discharged on oral antibiotics.

Follow-up: Cranial MRI 2 months after discharge showed reduced lesion size (Fig. 2 G). In November 2025 (3 years post-discharge), the patient had no significant dyspnea in daily life but was unable to engage in physical labor.

Discussion

Brain abscesses commonly arise from hematogenous spread, contiguous infection, neurosurgery, or trauma. Hematogenous abscesses often result from endocarditis, cardiac shunts, or pulmonary vascular malformations and are typically located within the middle cerebral artery territory [5].In both cases, brain abscesses developed primarily due to the failure of pulmonary filtration mediated by RLS. Under normal conditions, pulmonary capillaries effectively trap and eliminate bacteria and microemboli originating from the venous system [6]. However, in the presence of RLS, pathogens can directly enter the arterial circulation and seed the brain, resulting in abscess formation. The pathogens most commonly isolated from brain abscesses secondary to RLS are anaerobic or facultative anaerobic microorganisms of odontogenic origin [7]. In 2, Fusobacterium nucleatum was isolated; in 3, Streptococcus intermedius was identified. Both pathogens are commensal organisms in the oral cavity and upper respiratory tract, further supporting hematogenous spread as the route of infection. Notably, brain MRI in both patients demonstrated abscesses located within the middle cerebral artery territories. This commonality underscores the final step of a classic pathogenic pathway: oral bacteria→ venous entry → RLS → arterial dissemination → middle cerebral artery territory seeding.

Clinically, PAVMs are frequently associated with HHT [8]. However, the patient in 2 tested negative for HHT-related gene mutations, indicating that sporadic PAVM can also cause RLS. Chest CT is generally considered the gold standard for diagnosing PAVM; however, while CT is highly sensitive in detecting PAVMs, its specificity remains relatively low [9]. When non-contrast CT is inconclusive, contrast-enhanced imaging should be pursued. The diagnosis of HPS relies on a triad of liver disease, hypoxemia, and intrapulmonary shunting [10]. Orthostatic hypoxemia syndrome and a positive c-TCD test are key diagnostic criteria [11]. Notably, HPS cannot be ruled out even without significant abnormalities on chest CT.

When encountering cryptogenic brain abscesses, particularly in patients with dyspnea, arterial blood gas analysis should be performed in addition to routine head MRI and peripheral blood infection markers. If significant hypoxemia and widened A-aDO₂ are detected, RLS should be suspected. c-TCD is a non-invasive and sensitive initial screening tool [12]. It not only confirms the presence of RLS but also helps distinguish between intracardiac and intrapulmonary shunts based on the pattern of microbubble appearance [13]. In patients without cirrhosis or portal hypertension, intrapulmonary shunt should raise suspicion of PAVM, warranting chest CT or CTA. In patients with cirrhosis, intrapulmonary shunt with hypoxemia (particularly orthodeoxia) supports the diagnosis of hepatopulmonary syndrome (HPS).

Management of brain abscesses should be individualized based on abscess size, location, pathogen, and patient comorbidities. Surgical drainage or resection combined with intravenous antibiotics for six weeks or more is generally recommended for abscesses larger than 2.5 cm, particularly if significant mass effect or impending ventricular rupture is present [14]. However, conservative treatment may be appropriate in selected patients. Mathis et al. reported favorable outcomes in conservatively treated HHT-related brain abscesses among patients with small abscesses or high surgical risk, provided close imaging follow-up was maintained [15]. In our series, 2 (PAVM-related) underwent surgery combined with antibiotics for a cerebellar abscess and achieved a favorable outcome. In contrast, 3 (HPS-related) received conservative treatment due to severe decompensated cirrhosis, coagulopathy, and patient/family refusal of surgery. Although conservative treatment controlled the acute infection, 3 subsequently developed a new lesion in the left lateral ventricle, highlighting that if the underlying functional shunt in HPS remains uncorrected, recurrence risk persists despite initial antibiotic response. Therefore, treatment strategies for brain abscesses secondary to intrapulmonary shunts should address both the intracranial infection and the underlying shunt etiology.

Authors’ contributions

Lu You made contributions to the conception, acquisition, analysis, and interpretation of data；Wei-GuanLiu Zhang drafted and revised the manuscript. Jing Bai contributed to the treatment of the patient. Xiang Yin revised it critically for important intellectual content. All authors gave final approval for the version to be published.

CRediT authorship contribution statement

Wei-GuanLiu Zhang: Investigation, Data curation. Lu You: Writing – original draft, Methodology, Investigation, Conceptualization. Xiang Yin: Writing – review & editing, Methodology, Conceptualization. Jing Bai: Data curation.

Ethics approval and consent to participate

This study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of The First Hospital of Jilin University (Approval No. 2026–043)

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declarations of competing interest

The authors have no competing interests to declare.