History of present illness
A 49-year-old Caucasian woman was referred to the pulmonary clinic complaining of 2-year worsening dyspnea and sporadic dry cough despite treatment with inhaled bronchodilators and corticosteroids due to atopic asthma. Chest radiograph revealed a diffuse reticular pattern without pleural effusion.
Past medical history
The patient was a steelworker with minimal exposure to mineral oil. She never smoked, had never been pregnant, and had no familial history of pulmonary diseases. She had arterial hypertension and several years earlier was diagnosed with atopic asthma. Skin prick testing revealed sensitization to grass pollen, olive pollen, and dust mites. Previous spirometry showed a partially reversible airflow obstruction.
Her daily medical treatment included inhaled β 2 -agonists and corticosteroids and oral 5 mg amlodipine. She sometimes used oral antihistamines and had taken a birth control pill for 3 years in the past. Drug allergies were not reported.
Physical examination and early clinical findings
The patient was in good general condition. Oxygen saturation measured by pulse oximetry (SpO 2 ) was 95% on room air, heart rate was 80 beats/min, respiratory rate was 14 breaths/min, and blood pressure was 120/75 mmHg. Chest examination revealed a diffuse reduction of vesicular murmur without additional breath sounds. No pallor, clubbing, or peripheral edema was apparent.
Clinical course
Spirometry revealed a severe airflow obstruction with forced expiratory volume in 1 second (FEV 1 ) 47.1% of predicted value and forced vital capacity (FVC) 71% of predicted. Bronchodilator reversibility testing was negative. Diffusing capacity of the lungs for carbon monoxide (DLCO) was severely impaired (31.2% of predicted value) ( Fig. 20.1 ).
A high-resolution computed tomography (HRCT) scan of the chest revealed multiple and diffuse radiolucent areas together with interstitial thickening and parenchymal destruction. These findings deserved a differential diagnosis between cysts and emphysematous blebs/bullae ( Fig. 20.2 ).
The chest CT scan was revised by an experienced radiologist, and multiple, round, well-circumscribed cysts diffusely distributed throughout the lung parenchyma were identified. There was no evidence of nodules or other interstitial abnormalities ( 
) .
Laboratory exams were then requested. Hemoglobin was 16.7 g/dL (normal values 12–16 g/dL), hematocrit was 49.1%, and leukocytes and renal and hepatic function indexes were within the normal range. Antinuclear antibodies (ANAs), antibodies against extractable nuclear antigen (ENA), as well as perinuclear and cytoplasmic anti–neutrophil cytoplasmic antibodies (pANCAs and c ANCAs) were absent. Protein electrophoresis and free light chains dosage were in the normality range. Human immunodeficiency virus (HIV) types 1 and 2 autoantibodies were negative. Serum α 1 -Antitrypsin level was 134 mg/dL (normal value > 80 mg/dL; genetic sequencing was taking much longer to get ready), and C-reactive protein was 0.3 mg/dL (normal value < 0.5 mg/dL). Serum vascular endothelial growth factor (VEGF) D was 1387.6 pg/mL. Abdominal magnetic resonance imaging (MRI) revealed bilateral renal angiomyolipomas, abdominal tubular structures with irregular development with internal septa, and pseudo-cystic dilatations along iliac vessel in periaortic region. The findings were compatible with lymphangioleiomyomas ( Fig 20.3 ).
A final diagnosis of LAM was made. A 6-minute walk test in room air was interrupted after 3 minutes because of severe desaturation (nadir SpO 2 82%) associated with exertional dyspnea. Arterial blood gas analysis revealed mild hypoxemia with PaO 2 66.5 mmHg, PaCO 2 33 mmHg, pH 7.44, and HCO 3 – 23.4 mmol/L. Overnight oximetry reveals severe nocturnal respiratory (mean SpO 2 86%, nadir SpO 2 83%). Oxygen supplementation was prescribed during night and exertion.
To explore the hypothesis of a tuberous sclerosis complex associated with LAM (TSC-LAM) further, clinical evaluations were performed. TSC findings were not found during the dermatological examination, in the brain CT scan, or during eye fundus examination. Echocardiography resulted in regular with normal ejection fraction (55%), systolic pulmonary artery pressure (PAPs) of 31 mmHg, and no signs of rhabdomyomas. Since the evidence of bilateral angiomyolipomas, mutations in TSC1 and TSC2 genes were also searched in peripheral blood through denaturing high-performance liquid chromatography (DHPLC) and with multiple ligation-dependent probe amplification (MLPA). No mutations were identified.
Recommended therapy and further indications
Yearly immunization against influenza and Streptococcus pneumoniae was recommended, and avoidance of estrogen-based therapy was advised. The patient was notified about the most common LAM acute complications (e.g., pneumothorax).
Because of her asthma history and obstructive pattern on pulmonary function tests, therapy with inhaled β 2 -agonist, antimuscarinic, and corticosteroids was prescribed.
Due to impaired lung function and latent respiratory failure, treatment with a mammalian target of rapamycin (mTOR) inhibitor was also prescribed (2 mg/day of oral sirolimus). Before starting therapy, testing for HIV antibodies and screening for hepatitis infections were both negative. Liver and renal functions were normal, and a mild hypercholesterolemia was observed (total cholesterol 202 mg/dL; normal value ≤ 115 mg/dL). Outpatient follow-up visits in the pulmonary clinic were scheduled with clinical and functional evaluation.
Follow-up and outcomes
The exertional dyspnea improved with supplemental oxygen during physical activity, and the 6-minute walk test was successfully completed without oxygen desaturation (oxygen flow used 2 liters/minute). Hemoglobin and hematocrit levels lowered to 14.7 g/dL and 43.6%, respectively. Sirolimus serum level, complete blood count, hepatic and renal function, and cholesterol levels were monitored 15 and 30 days after starting therapy and then every 4 months. During the follow-up, the patient developed worsening hypercholesterolemia, unresponsive to a low-fat diet and requiring a low-dose statin therapy. She also experienced diarrhea, which was easily controlled with dietary indications and symptomatic drugs. Consequently, sirolimus dosage reduction was not required.
Given the presence of respiratory failure and functional impairment, the patient was quickly referred to a transplant center.
Two years after the diagnosis, a thoracic CT scan and echocardiography were repeated. There was no evidence of worsening in parenchymal cystic involvement, but an increased pulmonary pressure (PAPs of 41 mmHg) was detected.
The patient is currently undergoing a clinical and functional follow-up, with overall stability of the course of the disease.
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