Thromboembolic Disease

Thromboembolic disease is probably the most common important lung problem not related to smoking which affects women. This, of course, is because of the risk conferred by endogenous or exogenous estrogens. Dyspnea in a pregnant woman or one on an oral contraceptive always has to prompt consideration of deep vein thrombosis/pulmonary embolism, especially if the chest x-ray is normal. Blood gases will typically show both low pO2 and pCO2. In diagnosing this disease, compression Doppler studies afford a sensitive and specific noninvasive technique. Nuclear Medicine V/Q scans are feasible during pregnancy if a lower dose of isotope is given. CT angiography is beginning to supercede V/Q scans and is not contraindicated in pregnancy. These patients should be worked up for genetic causes of thrombophilia. One study showed that 60% of pregnant patients who developed thromboemboli had Factor V Leiden.¹

In the treatment of this disease, the pregnant women can be started on heparin in the hospital and discharged on subcutaneous low-molecular weight heparin. Prophylaxis of patients at higher risk, either because of previous episodes or one of the various forms of thrombophilia, is more controversial. Warfarin has always been considered teratogenic and contraindicated in pregnancy. In a British study of pregnant patients with prosthetic heart valves, however, warfarin therapy was more effective than heparin in preventing thromboemboic disease, and associated with fewer bleeding complications.² A meta-analysis of such patients showed a 6.4% incidence of warfarin embryopathy when warfarin was used through the pregnancy. Conversion to heparin during weeks 6-12 eliminated the risk of embryopathy but increased the incidence of thromboembolism from 3.9% to 9.2%.³ The American College of Chest Physicians continues to recommend only heparin as prophylaxis in pregnant patients at higher risk.⁴

The high-risk woman with a prior episode of DVT or PE who is on chronic warfarin should try to plan pregnancy and be switched to outpatient heparin before conception. With unplanned pregnancy, warfarin should be stopped and heparin started immediately. In the event of significant bleeding from any source, placement of an inferior vena cava filter must be considered.

Amniotic fluid embolism is another condition exclusive to the peripartum patient. Manifesting as acute dyspnea with pulmonary infiltrates and DIC, this diagnosis is made clinically but may be confirmed with aspiration of uterine or fetal cells through a pulmonary artery catheter. It is treated supportively.

Pulmonary Hypertension

Primary or idiopathic pulmonary hypertension (PPH) is well known as a disease of women in the childbearing years, and has been seen in older women on estrogen replacement. While the pathogenesis remains unclear it has been suggested that patients may have increased stimulation of pulmonary vascular smooth muscle by serotonin. The majority of patients with PPH expressed a gene for overexpression of the serotonin transporter (5-HTT) which was also expressed in cultured cell from their lungs.⁵ PPH was long treated with vasodilators but was relentlessly progressive. Prostacyclin analogs have greatly improved therapy in that they exclusively dilate the pulmonary vessels and lead to less systemic hypotension. At present, such prostaglandins (chiefly iloprost) must be given intravenously or as an inhaled aerosol with a short-lived effect. In a recent study, the effectiveness of inhaled iloprost was enhanced by the addition of oral sildenafil, a phosphodiesterase 5 inhibitor. Sildenaphil (as in penile erection) enhances vasodilating levels of cGMP. ⁶ Inhaled nitric oxideacts in a similar fashion in the acute setting. Lung or heart-lung transplantation can extend life span in these patients.

Airway Disease

Asthma is increasing in prevalence and more rapidly in women. In the decade 1982-1992 its prevalence in the U.S. increased by 82% in women versus 29% in men.⁷ While there does not appear to be a gender bias in terms of objective pulmonary function, studies have shown differences between men and women asthmatics in presentation. Women asthmatics enrolled in an HMO were more likely to complain of symptoms, more likely to visit the doctor and generally used more medication.⁸ While a number of studies concluded that hormones influenced severity of asthma, i.e., relation to menstrual cycle, a study of 288 asthmatic women showed no relation of emergency room visits to menstruation, and only 13% of the patients identified menses as a precipitating factor to their disease.⁹

Vocal Cord Dysfunction Syndrome is now well recognized and occurs almost exclusively in women, who present with sudden attacks of dyspnea.¹⁰ Their stridor is often mistaken for wheezing due to asthma. They rapidly improve after admission. The diagnosis can be confirmed by direct laryngoscopy at the time of the attack showing vocal cord spasm.

Obstructive sleep apnea occurs in both sexes with a male predominance. Studies have shown gender differences, however. For a given measure of obesity (BMI and other indices) women manifest a less severe degree of sleep apnea than men and their apneas are more clustered during REM sleep.^11,12 One explanation may relate to the different anatomy of the pharynx, which allows less collapse during exhalation in women as in men.¹³

Malignancy in the Lung

Primary lung cancer has always been a male-predom-inant disease because of the strong association with smoking. In recent decades, however, the rates of lung cancer in women have been increasing faster than those for men. Lung cancer now kills more women than breast cancer.¹⁴ Many studies have looked at the differences in susceptibility to the effects of tobacco between men and women. It seems clear that the risk of lung cancer is higher in women than men for any level of smoking history, at least for small cell or adenocarcinomas. Among patients with squamous cell carcinomas of the lung, however, women are more likely to have been non-smokers than men.¹⁵ A study which looked at the relation between diet and lung cancer in women showed increased risk associated with red meat and decreased risk associated with yellow-green vegetables.¹⁶

Because of the tendency of breast cancer to metastasize to the lung, it should be suspected in a woman without symptoms who has nodules on chest x-ray. Breast cancer also frequently causes malignant pleural effusions as can ovarian carcinoma.

Thymoma, which is seen in 15% of patients with myasthenia gravis will more often be found in a woman, and represents one example of an important type of anterior mediastinal mass, others being substernal goiter, germ cell tumor and lymphoma. In a study of outcomes after thymectomy in patients with myasthenia, 79% of the patients were women.¹⁷ Female sex was associated with a more favorable outcome in terms of amelioration of the myasthenia.

Pleural Effusion

Pleural effusions are a frequent manifestation of rheumatoid disease, particularly in SLE, a predominantly female disease. Curiously, in Rheumatoid Arthritis, pleural effusions tend to occur mostly in males.

Lymphangioleiomyomatosis (LAM) affects women in the child-bearing years and occasionally seniors on ERT. It causes milky chylous (high triglycerides) pleural effusions because of lymphatic obstruction in the lung. The underlying pathology is an abnormal proliferation of lymphatic smooth muscle. These patients can also suffer spontaneous pheumothorax. Their chest x-rays are characterized by large lung volumes with obstructive defects on pulmonary function testing. High resolution CT scans in LAM are very characteristic with large cystic spaces surrounded by areas of increased interstitial markings. LAM appears to be related to Tuberous Sclerosis. One-third of female patients with Tuberous Sclerosis were found to have the characteristic CT scan features of LAM.¹⁸ Sporadic cases of LAM have been shown to possess mutations in the Tuberous Sclerosis Complex gene TSC2.¹⁹ In common with Tuberous Sclerosis, patients with sporadic LAM have a high incidence of meningiomas.²⁰

Meig's Syndrome is the association of a pleural effusion with a pelvic tumor in women. The originally described tumors were benign, but such effusions arenow known to occur with malignancies in the pelvis as well, and their presence appears to correlate with the size of the primary. The effusions themselves are benign but may be bloody. There may be ascites as well. While sometimes bilateral they occur most frequently on the right side. Removal of the primary tumor usually results in resolution of the effusion.

The "ovarian overstimulation syndrome" induced by exogenous human chorionic gonadotropin can cause unilateral or bilateral pleural effusions. Patients usually present with abdominal distension, nausea and dyspnea. Yellow Nail Syndrome is another lymphatic disease in which patients, primarily women, develop pleural effusions, lymphedema, bronchiectasis, and yellowish nails.

Pneumothorax

Besides LAM as a cause of spontaneous pneumothorax in women, there is another syndrome exclusive to women known as Catamenial Pneumothorax. At the time of menstruation, these women may become acutely short of breath and experience spontaneous pneumothorax, almost always on the right. The etiology has been ascribed both to diaphragmatic fenestration and endometriosis in the lung with breakdown of the tissue causing lung rupture.^21,22 Patients may also experience hemoptysis. This disease has been treated with medical oophorectomy using agents such as danazol or GRH. More current approaches include minimally invasive surgery using thora-coscopy.²³

Tuberculosis

Interestingly, during both the rise and decline of TB prevalence, regardless of ethnicity, both the incidence and severity of TB in women has been consistently less than in men.²⁴ This was confirmed in a recent San Francisco study, which showed a male to female ratio of 2:1 in primary TB. The age-specific rates were also greater for males in those with reactivation disease.²⁵ The relatively few studies of gender differences in TB have generally come from Third World countries. These studies suggest differences in diagnosis, treatment and societal perceptions of TB in women, usually to their disadvantage, and reflecting their lower social status in many societies.²⁶ The authors of this study concluded that the differences in rates were probably due to transmission dynamics rather than diagnosis or reporting biases. Women present special problems in the treatment of TB. Latent TB (exposure only, no active disease) is often detected during pregnancy with PPD skin testing. Such patients are at higher risk of hepatotoxicity due to isoniazid and prophylaxis should be delayed until about three months post-partum or until breast-feeding stops. The pregnant patient with active or strongly suspected active disease should be treated in the usual way (four drug regimen) with careful monitoring of hepatic function. The neonate should be followed with monthly PPD skin tests (as well as all other close contacts).

Pulmonary Edema

In addition to causing effusions, SLE may present as non-cardiogenic pulmonary edema (Lupus Pneumonitis). It presents similarly to ARDS, but may respond to high-dose steroids and cyclophos-phamide.²⁷ In the peri-partum period, women may develop acute pulmonary edema after the use of beta-adrenergic tocolytics such as terbutaline or isoxuprine. There is no specific treatment other than supportive care.

Interstitial Lung Disease

Scleroderma, a predominatly female disease, is the rheumatologic condition with most frequent lung involvement. Most scleroderma patients at autopsy show pulmonary fibrosis. Because of their esophageal motility abnormalities, scleroderma patients may also be chronic aspirators. Scleroderma patients may give evidence of air trapping on pulmonary function testing. However, their elevated residual volumes are not due to airway obstruction but rather to abdominal muscle weakness which prevents a normal maximal exhalation. Pulmonary hypertension is a frequent end-stage complication of scleroderma. A Japanese study

(M:F = 9:1) suggested that there are subsets of scleroderma patients in whom pulmonary hypertension is the direct result of the fibrotic change, and others where it results from an arteriopathy.²⁸ Severity of the lung disease in terms of function has been shown to be associated with antibodies to tropoisomerase I and the frequency of such antibodies was higher in African-Americans (M:F = 3:1).²⁹ Sjogren's syndrome is also associated with the development of lymphocytic interstitial pneumonia (LIP) and may rarely progress to lymphoma.

Chronic eosinophilic pneumonia is an uncommon disease occurring typically in middle-aged women who may present with productive cough, wheezing, fevers, sweats and weight loss. Eosinophils may bepresent either in the peripheral blood or bronchoalveolar lavage fluid and the sedimentation rate tends to be high. The x-ray typically shows peripheral and fleeting infiltrates often described as the "photographic negative" of pulmonary edema. One study with long-term follow up showed a dramatic response of this condition to corticosteroids but with frequent relapses when therapy was withdrawn.³⁰ In this group of women prognosis was good but therapy with corticosteroids was often required for years.

Conclusion

There are thus a wide variety of pulmonary conditions found exclusively or primarily in women. This review will hopefully alert the primary clinician and raise the index of suspicion for these conditions.