Neumo Casos Htp Mas Enfisema

1654 Selected Reports

carcinoma (12%), GI tumors (10.7%), pulmonary tumors (10.7%), urinary tumors (7%), and others (14%). 1 These patients included fi ve (8.9%) with lung cancer, with patient age ranging from 57 to 69 years. Moreover, data show only one patient presenting with vesicle lesions, three with tho-racic dermatomal involvement, and one without metastasis (two with lymph nodes). The time from lung cancer diag-nosis to zosteriform skin metastasis varied from being simul-taneous to 1 year. 1

Several theories reportedly explain the mechanisms of zosteriform skin metastasis. Some reported on previous herpes zoster infection over the same areas of skin metastasis wherein the skin loses its immunologic ability (Koebner-like phenomenon). 2 In others, surgical implantation was reported as the cause of skin metastasis. However, in the present case, the patient did not have a history of herpes zoster, trauma, or surgical procedures. Further, other reports implied a pathogenesis related to the lymphatic system, which was demonstrated by focal cancer embolism in enlarged lymphatic vessels. 3 The retrograde fl ow due to mass obstruction may lead to skin metastasis. 4

In the current case, the patient developed new-onset zosteriform skin metastasis over the right-side upper chest wall just after right-upper-limb and shoulder erythematous swelling. The condition may be explained by cancer embo-lism in dilated lymphatic ducts shown by pathology study, which included the obviously delayed lymphatic fl ow and dermal backfl ow over the right upper limb (compatible with the right-upper-limb swelling and band-like skin metas-tasis) documented by lymphoscintigraphy. Thus, it can be assumed that backfl ow of the chest wall also developed, bringing tumor emboli to the skin as zosteriform metasta-sis. On the other hand, radiation therapy is not considered a major cause because the site of therapy was on the right-side back not on the exact areas of zosteriform metastasis.

One study of 579 patients with lung cancer showed that large cell carcinoma has the greatest tendency for spread to the skin (10.3%), whereas epidermoid carcinoma has the least tendency to do so. Most patients with skin metastasis have adenocarcinoma. 5 Median survival interval after skin involvement is about 4 months. 5 The patient died 13 months after diagnosis of zosteriform skin metastasis.

Acknowledgments Financial/nonfi nancial disclosures: The authors have reported to CHEST that no potential confl icts of interest exist with any companies/organizations whose products or services may be dis-cussed in this article .

References 1 . Savoia P , Fava P , Deboli T , Quaglino P , Bernengo MG . Zos-

teriform cutaneous metastases: a literature meta-analysis and a clinical report of three melanoma cases . Dermatol Surg . 2009 ; 35 ( 9 ): 1355 - 1363 .

2 . Zalaudek I , Leinweber B , Richtig E , Smolle J , Hofmann-Wellenhof R . Cutaneous zosteriform melanoma metastases arising after herpes zoster infection: a case report and review of the literature . Melanoma Res . 2003 ; 13 ( 6 ): 635 - 639 .

3 . Kamisawa T , Takahashi M , Nakajima H , Egawa N . Gastroin-testinal: zosteriform metastases to the skin . J Gastroenterol Hepatol . 2006 ; 21 ( 3 ): 620 .

4 . Kondras K , Zalewska A , Janowski P , Kordek R . Cutaneous multifocal melanoma metastases clinically resembling herpes zoster . J Eur Acad Dermatol Venereol . 2006 ; 20 ( 4 ): 470 - 472 .

5 . Hidaka T , Ishii Y , Kitamura S . Clinical features of skin metas-tasis from lung cancer . Intern Med . 1996 ; 35 ( 6 ): 459 - 462 .

Severe Pulmonary Hypertension Associated With Emphysema

A New Phenotype?

Yochai Adir , MD, FCCP ; Robert Shachner , MD ; Offer Amir , MD ; and Marc Humbert , MD, PhD

Mild to moderate precapillary pulmonary hyperten-sion (PH) is a common complication of COPD and has typically been related to severe airfl ow limitation associated with chronic hypoxemia. Previous studies focusing specifi cally on patients with emphysema found that worsening PH was associated with pro-gression of airfl ow obstruction. In the present report, we describe a new phenotype of COPD with severe pre-capillary PH in patients presenting with progressive dyspnea, normal spirometry, severely reduced diffusion capacity of the lung for carbon monoxide, and high-resolution CT scans of the chest showing diffuse centri-lobular emphysema. CHEST 2012; 142( 6 ): 1654 – 1658

Abbreviations : D lco 5 diffusion capacity of the lung for carbon monoxide ; HRCT 5 high-resolution CT ; mPAP 5 mean pulmonary artery pressure ; PAP 5 pulmonary artery pressure ; PH 5 pulmo-nary hypertension

Mild to moderate precapillary pulmonary hyperten-sion (PH) is a common complication of COPD and

is associated with increased morbidity and mortality. 1 , 2 Severe precapillary PH (mean pulmonary artery pressure [mPAP] . 35-40 mm Hg and pulmonary artery wedge pressure � 15 mm Hg) is unusually reported in COPD patients. 3 , 4 These patients may exhibit a distinctive pattern with less severe airfl ow limitation but more severe hypoxemia, hypocapnia, decreased diffusion capacity of the lung for car-bon monoxide (D lco ), and signifi cantly impaired survival. 5

Manuscript received November 4 , 2011 ; revision accepted March 24 , 2012. Affi liations: From the Pulmonary Division (Dr Adir ), the Radiology Division (Dr Shachner), and the Cardiology Division (Dr Amir), Carmel Medical Center, Faculty of Medicine, The Technion, Insti-tute of Technology, Haifa, Israel; Université Paris-Sud (Dr Humbert), Faculté de Médecine, Le Kremlin-Bicêtre; Assistance Publique Hôpitaux de Paris (Dr Humbert), Service de Pneumologie, Hôpi-tal Bicêtre, Le Kremlin-Bicêtre; and Institut National de la Santé et de la Recherche Médicale (Inserm) U999 (Dr Humbert), Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France . Correspondence to: Yochai Adir, MD, FCCP, Pulmonary Divi-sion, Carmel Medical Center, 7 Michal St, Haifa, Israel; e-mail: [email protected] © 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.11-2816

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Table 1 — Clinical Characteristics of the Three Patients

Patient No. Age, y BMI, kg/m 2 Smoking, pack-y Duration of Symptoms BD, mo CAD HTN DM HPLCT Scan Score

Emphysema Ratio, %

1 74 24.8 90 18 1 1 1 1 2.6 2 87 23.5 100 24 1 … … … 9.4 3 82 23.2 40 12 1 1 … … 3.2

BD 5 before diagnosis; CAD 5 coronary artery disease; DM 5 diabetes mellitus; HPL 5 hyperlipidemia; HTN 5 hypertension.

Figure 1. High-resolution CT scan of the chest. Representative images of the upper and lower lung zones, showing diffuse emphysema. 1A, 1B, Patient 1. 2A, 2B, Patient 2. 3A, 3B, Patient 3.

In the present report, we describe a new phenotype of patients with severe precapillary PH, presenting with severe dyspnea, normal spirometry, markedly reduced D lco , and high-resolution CT (HRCT) scans of the chest showing dif-fuse centrilobular emphysema.

Case Report

We report three elderly, male, heavy smokers, who pre-sented with progressive dyspnea, marked hypoxemia, and hypocapnia ( Table 1 ). On evaluation by an experienced radiologist, a helical angioscan of the chest excluded pul-monary thromboembolic disease but was notable for diffuse emphysema with no evidence of interstitial lung disease ( Fig 1 ). Quantitative measures of emphysema for the whole lung (CT scan emphysema score) were performed using lung density software on a dedicated CT scan workstation (Extended Brilliance workspace 4.5; Philips Healthcare) ( Fig 2 ). Of note, lung function tests revealed normal spi-rometry ( Fig 3 ) with severely reduced D lco and normal lung volumes (measured by body plethysmograph) ( Table 2 ). Doppler echocardiography showed elevated estimated systolic pulmonary artery pressure, with no evidence of congenital heart disease or patent foramen ovale, normal left ventricular function, and right ventricular enlarge-ment with reduced function. There was no evidence on echocardiography of diastolic dysfunction. Other causes

of PH were excluded. Oxygen therapy failed to reduce pul-monary artery pressure (PAP). Right-sided heart catheter-ization was performed, revealing severe precapillary PH ( Table 3 ).

Discussion

Mild to moderate PH has been reported in up to one-third of patients with COPD and has typically been related to severe airfl ow limitation associated with chronic hypoxemia. 1 , 4 Previous studies focusing specifi cally on patients with emphysema found that worsening PH was associated with progression of airfl ow obstruction. 6 , 7 Classi-cally, PH in emphysema has been attributed to several fac-tors, including hypoxia leading to reactive vasoconstriction and pulmonary vascular remodeling, the loss of a signif-icant portion of the pulmonary vascular bed, and com-pression of alveolar vessels from hyperinfl ation. However , moderate COPD is observed in a small subgroup of patients with disproportionate pulmonary vascular disease. This subgroup is characterized by moderate airway obstruction contrasting with signifi cant hypoxia, normo- or hypocapnia, and signifi cantly impaired survival.

Chaouat et al 3 evaluated 998 patients with stable COPD for the presence of PH by right-sided heart catheteriza-tion. Eleven patients (1.1%) had severe PH (defi ned as mPAP . 40 mm Hg) with a similar phenotype combining


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Figure 2. Three-dimensional image of the right lung (created by the software for calculating the CT scan emphysema score) dem-onstrating diffuse emphysema (in red).

mild to moderate airway obstruction (median FEV 1 , 50% predicted), severe hypoxemia, hypocapnia, and a very low D lco . Thabut et al 5 assessed pulmonary hemody-namic characteristics in 215 patients with COPD who were candidates for lung volume reduction surgery or lung transplant. Sixteen patients (3.7%) had severe PH (defi ned as mPAP . 45 mm Hg) and similar clinical features.

These studies suggest that this small subgroup of patients with severe PH may represent a subset of patients with COPD in whom pulmonary vascular disease is predomi-nant. Furthermore, although spirometry is mandatory for the diagnosis of COPD and for determining its severity, no correlation was found between the severity of airfl ow obstruction and PAP in these patients.

Our reported cases had clinical characteristics similar to those described by Chaouat et al 3 and Thabut et al, 5 with the important exception of a normal spirometry. The coexis-tence of emphysema and normal spirometry was described

previously, especially in patients with mild emphysema. 7 In patients with severe emphysema, the associated loss of lung elastic recoil pressure usually leads to expiratory airfl ow limitation. However, because maximal expiratory fl ow depends on elastic recoil pressure, it is possible that hyperinfl ation maintained recoil pressure at near-normal values, explaining the normal spirometry results. These patients had evidence of severe emphysema on HRCT scan in concert with markedly reduced D lco and normal spirometry. According to GOLD (Global Initiative for Chronic Obstructive Lung Disease) guidelines, based on spirometry alone, they would not even be considered as having COPD. Contrasting with FEV 1 measures, there was a clear association between the severity of emphy sema on HRCT and the reduction in D lco .

A broadly similar phenotype was described in patients with combined pulmonary fi brosis and emphysema syn-drome. 8 These patients had features similar to those of the patients here, such as dyspnea, hypoxemia, normohy-pocapnia, severely reduced D lco, and severe PH. However, in these patients, the combination of hyperinfl ation and high compliance of the emphysematous areas of the lungs probably compensated for the volume loss due to fi brosis of the lower lobes, explaining the normal spirometry values.

Severe hypoxemia with high alveolar-arterial gradient was observed in these patients. When emphysema predomi-nates, the main cause of hypoxemia is usually ventilation-perfusion mismatch. 9 However, the severe degree of hypoxemia suggests that other factors may have been involved, such as right to left shunting, although we were unable to demonstrate intracardiac shunt. In addition, low cardiac output might contribute to the observed hyp-oxemia, with increased oxygen tissue extraction in patients with impaired hemodynamic status.

The reasons why patients with emphysema and no airfl ow obstruction but with signifi cant hypoxemia and severely reduced D lco may develop severe PH require further discussion. One explanation may be an individual sensitivity of the pulmonary vasculature to alveolar hyp-oxia. Indeed, it has been shown that some predisposed individuals could respond to acute hypoxia with a marked increase in pulmonary vascular resistance and PAP. 10 Chronic

Figure 3. Spirometry results of the three patients demonstrating normal spirometry in each patient. A, Patient 1. B, Patient 2. C, Patient 3.


CHEST / 142 / 6 / DECEMBER 2012 1657journal.publications.chestnet.org

hypoxia in these patients might lead to pulmonary vascu-lar remodeling, thus resulting in persistent increases in PAP. Genetic predisposition could be responsible for the different individual responses to alveolar hypoxia. A pre-vious study suggested that the serotonin (5-HT) transporter gene polymorphism could determine the severity of PH in hypoxic patients with COPD. 11 An insertion/deletion polymorphism in the promoter region of the 5-HTT gene results in long (L) and short (S) forms. Of note the L allele drives a two- to three-fold higher rate of 5-HTT gene tran-scription than the S allele. In that study, Eddahibi et al 11 showed that patients carrying the 5-HT transporter gene LL genotype had higher mPAP compared with their SS and LS counterparts. However, these patients had less pro-nounced hypoxemia than did the patients here or the patients described by Thabut et al 5 and Chaouat et al. 3 Another hypothesis that may explain severe PH in these patients is the coexistence of emphysema and pulmonary vascular disease, which could be somewhat similar to idio-pathic pulmonary arterial hypertension. However, more epidemiologic and morphologic studies are needed to sup-port this hypothesis.

Detection of PH in patients with COPD can be chal-lenging because symptoms such as dyspnea and fatigue are common and are usually the results of airfl ow limita-tion and hyperinfl ation in COPD. Indeed, in these patients, there was a prolonged duration of symptoms until the diag-nosis of severe PH was made. Therefore, when a patient presents with severe dyspnea somewhat disproportionate to the severity (or even absence in our present cases) of airfl ow limitation, the presence of PH might be suspected. It is important to identify this subgroup of patients because they have a poor prognosis and may be candidates for spe-cifi c management. 12 Long-term oxygen therapy is recom-mended in patients with COPD and hypoxemia. However, although in patients with mild to moderate PH long-term oxygen therapy improves or at least stabilizes PAP, in patients with severe PH, oxygen therapy appears insuffi -cient to reverse or even stabilize PAP. 13 In the absence of lung pathologic assessment in these patients, we can only

speculate that the severe PH might be due to a signifi cant and irreversible pulmonary vascular remodeling compo-nent, similar to that observed in pulmonary arterial hyper-tension. This hypothesis might argue in favor of the use of drugs approved for pulmonary arterial hypertension in this group of patients, but, based on the present evidence, it is strongly recommended not to treat patients with COPD with drugs dedicated to pulmonary arterial hyper-tension outside randomized controlled trials. Obviously, eligible patients should be considered for lung transplant when they present with this severe phenotype, but this was not possible in this elderly population. Interestingly, these patients were older and had comorbidities, including systemic hypertension. As in the systemic circulation, the pulmonary vasculature may be affected by age-associated arterial remodeling, 14 leading to pulmonary vascular stiff-ness and increases in systolic PAP. A recent population-based study 15 demonstrated that PAP increases with age.

In conclusion, we describe three patients with diffuse emphysema and severe PH, with a similar phenotype com-prising severe dyspnea, normal spirometry, and severely reduced D lco . Further studies are needed to better describe this subgroup of patients and their management.

Acknowledgments Financial/nonfi nancial disclosures: The authors have reported to CHEST the following confl icts of interest: Dr Humbert has relationships with drug companies including Actelion Pharmaceuti-cals Ltd; AstraZeneca; Bayer; Chiesi Ltd; GlaxoSmithKline; Eli Lilly and Company; Merck & Co, Inc; Novartis AG; Takeda Pharma-ceuticals International GmbH; Pfi zer, Inc; Stallergenes; Teva Pharmaceuticals; and United Therapeutics Corp. In addition to being an investigator in trials involving these companies, relation-ships include consultancy services and membership on scientifi c advisory boards. Drs Adir, Shachner, and Amir have reported that no potential confl icts of interest exist with any companies/organi-zations whose products or services may be discussed in this article.

References 1 . Weitzenblum E . Chronic cor pulmonale . Heart . 2003 ; 89 ( 2 ):

225 - 230 .

Table 2 — Laboratory and Lung Function Data of the Three Patients

Patient No.

Pa o 2 , mm Hg

Pa co 2 , mm Hg

D lco, % Predicted

FEV 1 , % Predicted

FVC, % Predicted FEV 1 /FVC, %

FEF 50 , % Predicted

MMEF 75-25 , % Predicted

TLC, % Predicted

RV, % Predicted

1 43 28 23 90 94 74 71 48 91 95 2 50 32 24 114 117 71 52 65 106 104 3 40 34 18 123 122 72 59 63 104 101

D lco 5 diffusion capacity of the lung for carbon monoxide; FEF 50 5 forced expiratory fl ow at 50% FVC; MMEF 75-25 5 maximal midexpiratory fl ow (the average expiratory fl ow over the middle half of the FVC curve); RV 5 residual volume; TLC 5 total lung capacity.

Table 3 — Echocardiographic and Hemodynamic Data of the Three Patients

Patient No. LA size, cm IVS size, cm

sPAP, mm Hg TAPSE, cm

RAP, mm Hg

mPAP, mm Hg

PWP, mm Hg

Cardiac Index, L/min/m 2 PVR, mm Hg/L/min/m 2

1 4.0 1.1 78 1.6 9 40 12 2.0 7.3 2 3.3 1.0 118 1.1 10 39 9 2.7 6.7 3 3.5 1.0 77 1.5 3 35 9 2.1 8.4

IVS 5 intraventricular septum; LA 5 left atrium; mPAP 5 mean pulmonary artery pressure; PVR 5 pulmonary vascular resistance; PWP 5 pulmo-nary wedge pressure; RAP 5 right atrial pressure; sPAP 5 systolic pulmonary artery pressure; TAPSE 5 tricuspid annular plane systolic excursion.


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2 . Skwarski K , MacNee W , Wraith PK , Sliwinski P , Zielinski J . Predictors of survival in patients with chronic obstructive pulmonary disease treated with long-term oxygen therapy . Chest . 1991 ; 100 ( 6 ): 1522 - 1527 .

3 . Chaouat A , Bugnet AS , Kadaoui N , et al . Severe pulmonary hypertension and chronic obstructive pulmonary disease . Am J Respir Crit Care Med . 2005 ; 172 ( 2 ): 189 - 194 .

4 . Kessler R , Faller M , Weitzenblum E , et al . “Natural history” of pulmonary hypertension in a series of 131 patients with chronic obstructive lung disease . Am J Respir Crit Care Med . 2001 ; 164 ( 2 ): 219 - 224 .

5 . Thabut G , Dauriat G , Stern JB , et al . Pulmonary hemody-namics in advanced COPD candidates for lung volume reduc-tion surgery or lung transplantation . Chest . 2005 ; 127 ( 5 ): 1531 - 1536 .

6 . Scharf SM , Iqbal M , Keller C , Criner G , Lee S , Fessler HE ; National Emphysema Treatment Trial (NETT) Group . Hemo-dynamic characterization of patients with severe emphysema . Am J Respir Crit Care Med . 2002 ; 166 ( 3 ): 314 - 322 .

7 . Clark KD , Wardrobe-Wong N , Elliott JJ , Gill PT , Tait NP , Snashall PD . Patterns of lung disease in a “normal” smoking population: are emphysema and airfl ow obstruction found together? Chest . 2001 ; 120 ( 3 ): 743 - 747 .

8 . Cottin V , Le Pavec J , Prévot G , et al . Pulmonary hypertension in patients with combined pulmonary fi brosis and emphysema syndrome . Eur Respir J . 2010 ; 35 ( 1 ): 105 - 111 .

9 . Wagner PD , Dantzker DR , Dueck R , Clausen JL , West JB . Ventilation-perfusion inequality in chronic obstructive pulmo-nary disease . J Clin Invest . 1977 ; 59 ( 2 ): 203 - 216 .

10 . Weitzenblum E , Schrijen F , Mohan-Kumar T , Colas des Francs V , Lockhart A . Variability of the pulmonary vascular response to acute hypoxia in chronic bronchitis . Chest . 1988 ; 94 ( 4 ): 772 - 778 .

11 . Eddahibi S , Chaouat A , Morrell N , et al . Polymorphism of the serotonin transporter gene and pulmonary hypertension in chronic obstructive pulmonary disease . Circulation . 2003 ; 108 ( 15 ): 1839 - 1844 .

12 . Oswald-Mammosser M , Weitzenblum E , Quoix E , et al . Prognostic factors in COPD patients receiving long-term oxygen therapy. Importance of pulmonary artery pressure . Chest . 1995 ; 107 ( 5 ): 1193 - 1198 .

13 . Weitzenblum E , Sautegeau A , Ehrhart M , Mammosser M , Pelletier A . Long-term oxygen therapy can reverse the progres-sion of pulmonary hypertension in patients with chronic obstruc-tive pulmonary disease . Am Rev Respir Dis . 1985 ; 131 ( 4 ): 493 - 498 .

14 . Mackay EH , Banks J , Sykes B , Lee G . Structural basis for the changing physical properties of human pulmonary vessels with age . Thorax . 1978 ; 33 ( 3 ): 335 - 344 .

15 . Lam CS , Borlaug BA , Kane GC , Enders FT , Rodeheffer RJ , Redfi eld MM . Age-associated increases in pulmonary artery systolic pressure in the general population . Circulation . 2009 ; 119 ( 20 ): 2663 - 2670 .


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Neumo Casos Htp Mas Enfisema