Pulmonary arteriovenous malformations in patients with previous brain abscess: a cross‐sectional population‐based study

Abstract Background and purpose Pulmonary arteriovenous malformations (PAVMs) may cause recurrent brain abscess. The primary aim was to determine the prevalence of PAVM amongst survivors of brain abscess. The proportion with cardiac right‐to‐left shunts was also assessed post hoc. Methods This was a cross‐sectional population‐based study of adult (≥18 years) survivors of cryptogenic bacterial brain abscess in Denmark from 2007 through 2016. Patients were invited for bubble‐echocardiography to detect vascular right‐to‐left shunting and, if abnormal, subsequent computed tomography thorax for diagnosis of PAVM. Data are presented as n/N (%) or median with interquartile range (IQR). Results Study participation was accepted by 47/157 (30%) eligible patients amongst whom two did not appear for scheduled bubble‐echocardiography. The median age of participants was 54 years (IQR 45–62) and 19/57 (33%) were females compared with 59 years (IQR 48–68, p = 0.05) and 41/85 females (48%, p = 0.22) in non‐participants. Bubble‐echocardiography was suggestive of shunt in 10/45 (22%) participants and PAVM was subsequently confirmed by computed tomography in one patient with grade 1 shunting. The corresponding prevalence of PAVM was 2% (95% confidence interval 0.06–11.8) amongst all examined participants. Another 9/45 (20%) were diagnosed with patent in persistent foramen ovale (n = 8) or atrial septum defect (n = 1), which is comparable with the overall prevalence of 25% amongst adults in the Danish background population. Conclusions Undiagnosed PAVM amongst adult survivors of cryptogenic bacterial brain abscess is rare but may be considered in select patients. The prevalence of cardiac right‐to‐left shunts amongst brain abscess patients corresponds to the prevalence in the general population.

Previous studies suggest that patients with cryptogenic brain abscesses caused by oral cavity bacteria may have undiagnosed pulmonary arteriovenous malformations (PAVMs), usually as part of the hereditary haemorrhagic telangiectasia syndrome (HHT) [4,5].This may lead to right-to-left vascular shunting of transient bacteraemia and development of brain abscess.A cross-sectional study used a registry of 445 patients with HHT in the UK from 2005 to 2016 and found 37 patients (8.3%) with brain abscess either before (29/37, 78%) or after diagnosis of PAVM [4].Corresponding estimates were 7.8% amongst HHT patients with PAVM in Denmark [6].The association between HHT and brain abscess has also been confirmed in other retrospective cohort studies [5,[7][8][9][10].
However, data on systematic screening of patients with brain abscess for PAVM or HHT are lacking.Thus, the aim was to ascertain the prevalence of undiagnosed HHT in patients with previous brain abscess in Denmark from 2007 through 2016 by inviting survivors to a diagnostic work-up for PAVMs.In post hoc analysis, the prevalence of cardiac right-to-left shunts was also accounted for.

Diagnostic work-up for PAVM and HHT
First, participants were examined by bubble-echocardiography (i.e., injection of agitated saline containing microscopic air bubbles) to detect cardiovascular right-to-left shunting such as patent foramen ovale (PFO) or PAVM.Bubble-echocardiography has a high sensitivity for detection of PAVM and is recommended as a validated screening procedure for PAVM amongst HHT patients [11,12].Abnormal results were categorized as grade 1 (<10 bubbles in the left ventricle during the first heartbeat after injection of agitated saline), grade 2 (moderate amounts of bubbles), grade 3 (large amounts of bubbles, but less than on the right side) and grade 4 (similar opacification of the right and left ventricle).Next, participants with suspected PAVM were referred for computed tomography of the chest (5 mm slices) for further clarification.

Patient data
Information on clinical characteristics during admission for brain abscess was obtained from the medical records.Oral Bubble-echocardiography was suggestive of shunt in 10/45 (22%) participants and PAVM was subsequently confirmed by computed tomography in one patient with grade 1 shunting.The corresponding prevalence of PAVM was 2% (95% confidence interval 0.06-11.8)amongst all examined participants.Another 9/45 (20%) were diagnosed with patent in persistent foramen ovale (n = 8) or atrial septum defect (n = 1), which is comparable with the overall prevalence of 25% amongst adults in the Danish background population.

Conclusions:
Undiagnosed PAVM amongst adult survivors of cryptogenic bacterial brain abscess is rare but may be considered in select patients.The prevalence of cardiac rightto-left shunts amongst brain abscess patients corresponds to the prevalence in the general population.

Statistical analysis
Categorical variables were presented as n/N (%) with 95% confidence interval (CI) for the primary outcome, that is, the prevalence of PAVM.
Continuous variables were presented as median with interquartile range (IQR).Stata MP version 17 (StataCorp) was used for statistical analyses.

Ethical considerations
The study was approved to be carried out in adults by the Ethics Committee (N-20170067) and the Danish Data Protection Agency (2008-58-0028).

RE SULTS
The entire cohort comprised 315 cases of brain abscess in 313 individuals including two patients (0.6%) already diagnosed with HHT and one patient with nasopharyngeal cancer who had been hospitalized with three separate episodes of brain abscess.Of these, 157 adult survivors with a potential unclear source of bacterial brain abscess were eligible for study inclusion, which was accepted by 47/157 (30%) patients (Table 1).The observed prevalence of PAVM amongst patients with brain abscess in the current study is in line with previous reports [5,8,13] but lower than some studies of selected study populations or with unclear denominators [7,9,10].Other reasons for the discrepancies may include variations in the prevalence of PAVM/HHT between countries.A French multi-centre study found that 21/26 (75%) patients with brain abscess and PAVM were subsequently diagnosed with HHT at a mean of 81 months (SD 64) after treatment for brain abscess [7].Similarly, a Danish registry-based study of 1384 patients found that only 2/17 (12%) with HHT were known with this condition before hospitalization for brain abscess [13].Interestingly, patients with brain abscess and underlying PAVM frequently present with single, supratentorial brain abscess caused by oral cavity bacteria.Thus, HHT should be considered in such patients with unclear reason(s) for development of brain abscess, especially in recurrent brain abscess and/ or if combined with a history of epistaxis, gastro-intestinal haemorrhage or arteriovenous malformations elsewhere in the body.PFO has also been suggested as a risk factor for brain abscess by right-to-left vascular shunting of transient bacteraemia [14], but the occurrence in the current study was comparable to prior estimates of ≈25% in adults and does not provide convincing support for this notion [15].

DISCUSS ION
Limitations of the current study include a low response rate amongst eligible patients.Furthermore, some patients with undiagnosed PAVM or HHT may have died between the time of discharge for brain abscess and study onset.Misclassification of patients excluded due to, for example, ear−nose−throat infections or other predisposing conditions cannot be ruled out and some patients may have several risk factors for brain abscess.Common for all these limitations is a potential underestimation of PAVM as a risk factor for brain abscess.
In conclusion, undiagnosed PAVM amongst adult survivors of cryptogenic bacterial brain abscess is rare but may be considered in selected patients.

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E Y W O R D S brain abscess, cerebral abscess, hereditary haemorrhagic telangiectasia, HHT, PAVM, PFO, pulmonary arteriovenous malformation, shunt | 3 of 5 PULMONARY ARTERIOVENOUS MALFORMATIONS IN BRAIN ABSCESS cavity bacteria were defined as non-haemolytic streptococci, Fusobacterium, Actinomyces, Haemophilus and similar species.