Faculty Bibliography

Biomarkers can be important predictors of disease severity and progression. The intense exposure to particulates and other toxins from the destruction of the World Trade Center (WTC) overwhelmed the lung's normal protective barriers. The Fire Department of New York (FDNY) cohort not only had baseline pre-exposure lung function measures but also had serum samples banked soon after their WTC exposure. This well-phenotyped group of highly exposed first responders is an ideal cohort for biomarker discovery and eventual validation. Disease progression was heterogeneous in this group in that some individuals subsequently developed abnormal lung function while others recovered. Airflow obstruction predominated in WTC-exposed patients who were symptomatic. Multiple independent disease pathways may cause this abnormal FEV1 after irritant exposure. WTC exposure activates one or more of these pathways causing abnormal FEV1 in an individual. Our hypothesis was that serum biomarkers expressed within 6 months after WTC exposure reflect active disease pathways and predict subsequent development or protection from abnormal FEV1 below the lower limit of normal known as WTC-Lung Injury (WTC-LI). We utilized a nested case-cohort control design of previously healthy never smokers who sought subspecialty pulmonary evaluation to explore predictive biomarkers of WTC-LI. We have identified biomarkers of inflammation, metabolic derangement, protease/antiprotease balance, and vascular injury expressed in serum within 6 months of WTC exposure that were predictive of their FEV1 up to 7 years after their WTC exposure. Predicting future risk of airway injury after particulate exposures can focus monitoring and early treatment on a subset of patients in greatest need of these services.

BACKGROUND: Destruction of the World Trade Center (WTC) towers on September 11, 2001, released massive dust, gas, and fumes with environmental exposures for community members. Many community members have lower respiratory symptoms (LRSs) that began after September 11, 2001, and remain persistent. We evaluated whether systemic inflammation measured by C-reactive protein was associated with WTC dust exposures, persistent LRS, and lung function. METHODS: Community members self-referred for the treatment of symptoms related to September 11, 2001. C-reactive protein and lung function measurements, including spirometry and forced oscillation tests (impulse oscillometry system), were included as routine analyses in patients (2007 to 2012). RESULTS: Increased C-reactive protein levels were associated with the type of WTC dust exposure, LRS, reduced spirometry, and increased forced oscillation measurements (n = 724). CONCLUSIONS: Ongoing systemic inflammation measured years after the event was associated with WTC dust exposures, persistent LRS, and abnormal lung function in a community cohort. These findings have implications for treatment and surveillance.

Morquio A syndrome (mucopolysaccharidosis IVA) is a lysosomal storage disorder associated with skeletal and joint abnormalities and significant non-skeletal manifestations including respiratory disease, spinal cord compression, cardiac disease, impaired vision, hearing loss, and dental problems. The clinical presentation, onset, severity and progression rate of clinical manifestations of Morquio A syndrome vary widely between patients. Because of the heterogeneous and progressive nature of the disease, the management of patients with Morquio A syndrome is challenging and requires a multidisciplinary approach, involving an array of specialists. The current paper presents international guidelines for the evaluation, treatment and symptom-based management of Morquio A syndrome. These guidelines were developed during two expert meetings by an international panel of specialists in pediatrics, genetics, orthopedics, pulmonology, cardiology, and anesthesia with extensive experience in managing Morquio A syndrome.

INTRODUCTION: A case report of a patient with severe lung disease on methadone with chronic hypercapnia. Specific mechanism for chronic hypercapnia is explored with spirometry, ventilation awake and asleep, and CO₂ response. CASE PRESENTATION: A 68 year old man with a history of hypertension, tobacco use, methadone maintenance, presented with chronic hypercapnia (pH 7.43, PCO₂ 55mmHg, CO₂ 30 mmol/L). He had acute dyspnea, cough and wheezing. Chest radiograph was compatible with emphysema. Spirometry confirmed obstructive dysfunction with FEV1 = 0.63 liter (32% predicted) and FEV1/FVC = 32%. Resting ventilation was elevated at 11.7 liter/minute with an elevated dead space fraction (V_D/V_T = 56%). Sleep evaluation revealed multiple central apneic events. He was treated with albuterol and prednisone, and his methadone was discontinued. Thirty-six hours after methadone discontinuation the hypercapnia resolved (pH 7.41, PaCO₂ 37 mmHg, CO₂ 23 mmol/L). Repeat evaluation revealed improved FEV1 = 1.33 liter with severe persistent obstruction (FEV₁/FVC = 45%) and unchanged dead space fraction (V_D/V_T = 53%). A repeat sleep study showed reversal of his central sleep apnea. CO₂ response test revealed a normal ventilation slope. Based on these data, patient was transitioned to Suboxone, a partial opioid mu-receptor agonist with potential for less respiratory suppression. Repeat blood gas remained normal (pH 7.42, PaCO₂ 36, CO₂ 23). DISCUSSION: This case describes the evaluation of a patient with chronic hypercapnia from multiple potential etiologies. Testing revealed obstructive lung disease with increased dead space consistent with COPD. Despite minimal improvement in FEV₁ after therapy, there was no change in the physiologic dead space. Although minute ventilation was elevated during wakefulness, sleep study revealed central apnea compatible with ventilatory depression. Despite the persistence of severe lung disease, the patient was able to achieve eucapnia and remained eucapnic when Suboxone was substituted for Methadone. CONCLUSIONS: Assessment of ventilation both during wakefulness and during sleep uncovered mechanisms for hypoventilation related to methadone use that provided the basis for therapy in a patient with severe lung disease. Understanding the pathophysiology of hypercapnia is required to determine appropriate therapy. Suboxone may be an alternative therapy in patients with chronic hypercapnia