Diagnosing BHD in the Lung

This month’s blog posts are focusing on Birt-Hogg-Dubé Syndrome (BHD) and the lung, in line with our Meet the Expert session happening later this month (see here for more details and to sign up for the event). Here, we present 2 recent studies focusing on diagnosing BHD from CT imaging of the lungs, and 1 case report of a woman presenting with a symptom not normally associated with BHD.

1: CT Findings of Pulmonary Cysts
Arango-Díaz et al.,(1) reviewed the CT imaging findings of diffuse cystic lung diseases (DCLD) to provide a practical approach for the evaluation of lung cysts. DCLD are a heterogeneous group of disorders, including BHD, that can be diagnosed based on CT. However, recognising the specific underlying cause of cysts can be challenging as many of these diseases have similar features. CT imaging enables definition of the cysts, including their relationship with the bronchovascular structure and distribution of the cysts within the lung which can be informative for diagnosis. The most common diagnoses are lymphangioleiomyomatosis (LAM) and Langerhans cell histiocytosis (LCH). BHD, Lymphocytic interstitial pneumonia (LIP), and the fungal pathogen Pneumocystis jiroveci can also be the cause of lung cysts and are described in this review. Arango-Díaz et al., summarise the main CT findings of lung cysts and identify features, or combination of features, that are unique to each disorder. They state the importance of taking into account the whole picture to get a true diagnosis, including other physical symptoms (e.g. the fibrofolliculomas and renal tumours associated with BHD), other factors (e.g. smoking, a major cause of LCH), and the distribution of the cysts within the lung. This is particularly crucial to the diagnosis of BHD, as the size and wall thickness of the cyst alone is not sufficient for diagnosis. Cysts in patients with BHD are found to affect the basal and paramediastinal regions of both lungs, a feature that is unique within DCLD.

2: Quantitative Analysis of Cystic Lung Diseases by Use of Paired Inspiratory and Expiratory CT
As discussed above, differential diagnosis of the underlying cause of cystic lung diseases can be done based on CT imaging alone, however, this can be very challenging when the number of cysts is relatively small. Furthermore, early diagnosis of the correct disorder is critical for ensuring that appropriate care is given on time.  The authors proposed to evaluate the ‘dynamic properties’ of cysts during respiration as another diagnostic tool and have devised an index called the cyst-airway communicating index (CACI)(2). The CACI takes into consideration the total lung volume (TLV) and the low-attenuation area volume (LAAV, areas that appear less intense on CT which are assumed cysts) at both inspiration and expiration. 71 patients (15 with BHD, 43 with LAM, and 13 ‘other’) were examined. No difference in the TLV was observed between the different groups, however the difference in LAAV between inspiration and expiration was statistically smaller for BHD compared to LAM or the other group. The CACI was also statistically smaller for BHD compared to LAM/other suggesting there is less communication between the cysts and the airway in BHD. There are limitations to this study which the authors discussed, including the small study size, particularly for the BHD and other groups, and the lack of pathological confirmation that the LAAV truly represented cysts, a major caveat of the study. The CACI may also not be applicable to patients with a large number of cysts, however it does appear to be a useful tool for differentiating BHD from other cystic lung diseases with mild pulmonary symptoms.

3: Birt-Hogg-Dubé Syndrome presenting with chronic progressive dyspnea
This case report describes a 42-year-old female with no history of smoking and a past medical history of asthma, sleep obstructive apnea, and gastroesophageal reflux disease(3). She reported wheezing and dyspnea (shortness of breath) and CT revealed DCLD for which a presumptive diagnosis of bullous emphysema was given. However, her age and lack of smoking prompted further investigation. A physical exam revealed numerous skin-coloured bumps on the face and neck which were later confirmed to be fibrofolliculomas. High-resolution CT imaging of the lungs showed many cysts predominantly in the lower lung. Upon genetic testing, a truncation mutation of folliculin was discovered and a diagnosis of BHD was given. Despite an optimised treatment regime for asthma, the patient continued to experience dyspnea and as such a decision to start continuous positive airway pressure (CPAP) was made.

In the context of BHD, this can be a difficult decision as there is a slightly increased risk of pneumothorax with CPAP treatment, however the benefits outweighed the risks in this circumstance and the patient was given detailed precautions regarding the symptoms of pneumothorax. There are currently no guidelines on the risk of pneumothorax with CPAP therapy in BHD and further research is required to address this issue. The authors also state the importance of considering BHD as a differential diagnosis for DCLD as BHD is not normally associated with significant pulmonary dysfunction, however the early diagnosis of BHD is very beneficial for the screening and early detection of renal tumours.

References

1. Arango-Dí­az A, Martí­nez-de-Alegrí­a-Alonso A, Baleato-González S, García-Figueiras R, Ecenarro-Montiel A, Trujillo-Ariza M V., et al. CT findings of pulmonary cysts. Clinical Radiology. 2021
This paper isn’t freely available but please contact us if you have any questions.
2. Suzuki K, Seyama K, Ebana H, Kumasaka T, Kuwatsuru R. Quantitative Analysis of Cystic Lung Diseases by Use of Paired Inspiratory and Expiratory CT: Estimation of the Extent of Cyst-Airway Communication and Evaluation of Diagnostic Utility. Radiol Cardiothorac Imaging. 2020
Full paper here
3. Reilly D, Pourzand L, Chima-Melton C. Birt-Hogg-Dubé Syndrome presenting with chronic progressive dyspnea. Respir Med Case Reports. 2021
Full paper here

Meet a BHD expert

Following the success of our last Meet the Experts session, we are excited to announce that we are hosting another Meet the Experts virtual event on Wednesday 23rd June at 7:30 pm BST (British Summer Time). Stefan Marciniak is a Professor of Respiratory Science at the University of Cambridge and Honorary Consultant at Addenbrooke’s and Papworth Hospitals and has a particular interest in the genetics of pneumothorax. Stefan will be sharing his insight and answering your questions about one of the main symptoms of BHD, pneumothorax!

Sign up now for the event: https://www.eventbrite.co.uk/e/meet-the-experts-pneumothorax-tickets-156227433459

If you are unable to attend the event, we will be recording it and posting it on our webpage.

Prevalence of BHD – an Epidemiological Study

The prevalence of Birt-Hogg-Dubé (BHD) is currently unknown and is particularly difficult to ascertain considering the wide range and variability of symptoms associated with BHD, even within the same family. Furthermore, the only definitive way of diagnosing BHD is through genetic testing for folliculin mutations, therefore many people go undiagnosed. Around one in four people with BHD experience one or more spontaneous pneumothorax (SP) in their life and it is thought that BHD is the cause of 5-10% of SP. To determine the prevalence of BHD, researchers from the University of Lausanne conducted a meta-analysis of previously published studies on the prevalence of SP among BHD patients and the general population using a statistical method called Bayes equation1. To estimate the prevalence of BHD they calculated the following 3 components:

Firstly, Muller et al., determined the prevalence of BHD in apparent primary SP (PSP) to be 9%. The calculation of the second component, prevalence of PSP in the general population, was a little more complicated as this factor is not directly measurable. Instead, they used a formula to estimate the prevalence based on the incidence and average duration of PSP. The overall incidence rate of PSP was 8.69 per 100,000 person-years. From this, Muller et al., determined the overall prevalence of PSP in the general population (using all available data and a duration of 30 days) as 0.77/100,000 people. Finally, the third component identifying the prevalence of PSP in BHD individuals, was determined to be 43%.

Combining the above components in the Bayes equation, and assuming the most accurate data came from studies post-2000, they estimated the prevalence of BHD to be around 2 cases per million people, with no difference in gender.

This is the first study of its kind to determine the prevalence of BHD, a statistic the field would greatly benefit from. However, this study is not without caveats and limitations, some of which the authors addressed in their discussion. There are only four articles in the literature, with a total of 827 cases of PSP, where BHD has been identified.  However, this does suggest that BHD isn’t rare in PSP and that lung abnormalities and a genetic cause in PSP should be investigated, especially in cases where there is a family history.

It is also important to note that the prevalence of BHD estimated here is based entirely on a single symptom of BHD, pneumothorax. This is a major caveat of this study as not every BHD patient experiences a pneumothorax.

Although this study does provide useful information on the prevalence of BHD based on pneumothorax, the limitations and caveats in this study, combined with the wide range of symptoms an individual with BHD can present with implies that prevalence of BHD will be higher than the figure estimated here. Further investigation into the prevalence of BHD that would encompass all patients with BHD, such as genetic screening for mutations in folliculin, is warranted and would be of great interest to researchers, clinicians and patients.

References

1.        Muller, M.-E., Daccord, C., Taffé, P. & Lazor, R. Prevalence of Birt-Hogg-Dubé Syndrome Determined Through Epidemiological Data on Spontaneous Pneumothorax and Bayes Theorem. Front. Med. 8, (2021).