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Pleural Disease

To the Editor

With regard to the article by Feller-Kopman and Light (Feb. 22 issue),1 the distinction between spontaneous pneumothorax that occurs in apparently healthy persons and pneumothorax caused by preexisting pulmonary disease may seem arbitrary in terms of treatment, but an important aspect of the management of this condition is an evaluation for genetic disorders.

A total of 10% of patients with spontaneous pneumothorax have a family history of pneumothorax.2 Heterozygous mutations in the tumor-suppressor gene FLCN predispose to the Birt–Hogg–Dubé syndrome, which is the most common genetic disorder in persons with familial pneumothorax. This syndrome, which is identified in 10 to 15% of persons with familial pneumothorax, is associated with renal cancer.3 Spontaneous pneumothorax is also a complication of certain genetic disorders that affect the integrity of connective tissue, transforming growth factor β signaling, or both. These disorders include Marfan’s syndrome, the Loeys–Dietz syndrome, vascular Ehlers–Danlos syndrome, and homocystinuria. Moreover, inhibition of mechanistic target of rapamycin (mTOR) is a therapeutic target for pulmonary disease in tuberous sclerosis and lymphangioleiomyomatosis.4

The identification of a genetic disorder that predisposes to pneumothorax is valuable in guiding surveillance for life-threatening extrathoracic manifestations and in counseling at-risk family members. Identification of molecular mechanisms presents possible therapeutic targets.

Houriya Ayoubieh, M.D.
Eyas Alkhalili, M.D
Johns Hopkins University, Baltimore, MD

No potential conflict of interest relevant to this letter was reported.

  1. 1. Feller-Kopman D, Light R. Pleural disease. N Engl J Med 2018;378:740751.

  2. 2. Abolnik IZ, Lossos IS, Zlotogora J, Brauer R. On the inheritance of primary spontaneous pneumothorax. Am J Med Genet 1991;40:155158.

  3. 3. Scott RM, Henske EP, Raby B, Boone PM, Rusk RA, Marciniak SJ. Familial pneumothorax: towards precision medicine. Thorax 2018;73:270276.

  4. 4. McCormack FX, Inoue Y, Moss J, et al. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med 2011;364:15951606.

To the Editor

Feller-Kopman and Light did not mention two possible therapeutic options for refractory hepatic hydrothorax. These options are placement of a transjugular intrahepatic portosystemic shunt (TIPS) and liver transplantation.

The use of a TIPS has been investigated in a number of uncontrolled studies and several case reports that show an overall clinically relevant response in approximately 70% of patients. The reported average 30-day survival among patients with refractory hepatic hydrothorax who have received a TIPS is approximately 80%, and the 1-year survival is approximately 60%. The use of a TIPS provides a higher rate of response than other treatments while maintaining favorable long-term survival.1 In addition, a TIPS is the only treatment option that has proved to be effective in controlling refractory ascites, the cause of hepatic hydrothorax. According to the guidelines of the American Association for the Study of Liver Diseases, a TIPS is the most appropriate treatment for refractory hepatic hydrothorax.2

The median expected survival among patients with hepatic hydrothorax is less than a year. Thus, referral to a transplantation center should also be considered because liver transplantation provides favorable long-term survival (approximately 80% at 1 year).3

Giovanni Perricone, M.D.
Aldo Airoldi, M.D.
Marcello Vangeli, M.D.
Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda, Milan, Italy

No potential conflict of interest relevant to this letter was reported.

  1. 1. Rössle M. TIPS: 25 years later. J Hepatol 2013;59:10811093.

  2. 2. Runyon BA. Management of adult patients with ascites due to cirrhosis: update 2012. AASLD Practice Guideline. Alexandria, VA: American Association for the Study of Liver Diseases, 2012.

  3. 3. Xiol X, Tremosa G, Castellote J, et al. Liver transplantation in patients with hepatic hydrothorax. Transpl Int 2005;18:672675.


The authors reply: We agree in full with the comments by Ayoubieh and Alkhalili that clinicians must consider the mentioned genetic disorders when caring for patients with pneumothorax. Because of space limitations, these entities were not mentioned in our review article. The distinction between primary and secondary pneumothorax is arbitrary, since each of these genetic disorders is associated with abnormalities that predispose to pneumothorax; thus, “primary spontaneous pneumothorax” is not an accurate reflection of the underlying disease. Since these disorders have clinical implications (such as renal cancer), a thorough evaluation including computed tomographic assessment of the abdomen and possibly genetic evaluation should be performed.

We agree with Perricone and colleagues that the best treatment for hepatic hydrothorax is treatment of the underlying disease (i.e., cirrhosis), ideally by liver transplantation. Given the high morbidity and mortality among patients with hepatic hydrothorax, we agree that they should be evaluated by a multidisciplinary transplantation team. If transplantation is not an option, a TIPS is the next best option in patients who can undergo this procedure. In addition to thoracentesis, indwelling pleural catheters, talc pleurodesis, or the combination of these two methods should be considered in patients in whom definitive therapies are contraindicated (e.g., a TIPS is contraindicated in patients who are at risk for encephalopathy) or if other options are not available or appropriate.

David Feller-Kopman, M.D.
Johns Hopkins University, Baltimore, MD

Richard Light, M.D.
Vanderbilt University, Nashville, TN

Since publication of their article, the authors report no further potential conflict of interest.

Source: Massachusetts Medical Society: New England Journal of Medicine: Table of Contents