European Respiratory Society
Respiratory Diseases in Women

Present day insights into the relationship between gender and health emphasise the necessity of taking sex and gender differences into consideration. Sex refers to biological characteristics such as chromosomes, physiology and anatomy that distinguish females and males. Gender refers to the array of socially constructed roles and relationships, personality traits, attitudes, behaviours and values that society ascribes to the two sexes on a differential basis. In health-related research, both sex differences and differences resulting from gender are implied. The present issue of the Monograph offers an excellent overview of the present knowledge about sex and gender differences in the different domains of respiratory medicine and aims to contribute to a better “sex and gender perspective” on health and healthcare in clinical practice and research.

  • European Respiratory Society Monographs
  1. Page a
  2. Page b
  3. Page d

    φαíνεταí μοι κη∼νος ı `´σος θε ´οισιν

    ε `´μμεν' ω `´νηρ, o`´ττις ε `ν∠ ´ντιóς τοι

    ìσδ∠ ´νει καì πλ∠ ´σιον ∠ ´∼δυ φωνεí-

    σας ùπακοúει

    καì γελαíσας íμε ´ροεν, τó μ' η ´∼ μ∠ `ν

    καρδíαν ε `ν στη ´θεσιν ε `πτóαισεν,

    ω `ς γ∠ `ρ ε `´ς σ' ı `´δω βρóχε' ω `´ς με φω ´ναι-

    σ' οùδ' ε `´ν ε `´τ' εı `´κει,

    ∠ `λλ' ∠ ` ´καν με `ν γλω ˜σσα ε `´αγε λε ´πτον

    δ' αù ´τικα χρω ˜ι πũρ ùπαδεδρóμηκεν,

    òππ∠ ´τεσσι δ' οùδ' ε `´ν o`´ρημμ', ε `πιρρóμ-

    βεισι δ' ∠ ` ´κουαι,

    ?ε ´καδε μ' ı `´δρως ψũχρος κακχε ´εται? τρóμος δε ´

    παı ˜σαν ∠ ` ´γρει, χλωροτε ´ρα δε ` ποíας

    ε `´μμι, τεθν∠ ´κην δ' òλíγω ' πιδεúης

    φαíνομ' ε `´μ' αù ´ται.

    ∠ `λλ∠ ` π∠ `ν τóλματον ε `πεì καì πε ´νητα

    Fragment 31. Sappho et Alcaeus. Fragmenta, Amsterdam 1971 (E.M. Voigt).

  4. Page 1
    Correspondence: M. Saetta, Dept of Clinical and Experimental Medicine, Section of Respiratory Diseases, University of Padova, Via Giustiniani 3, 35128 Padova, Italy.

    Gender differences in airway anatomy, although receiving little attention, are an important determinant of the clinical manifestations of airway pathologies. This chapter reviews the knowledge about gender differences in dimensions, structure and function of the airways, and their relationship with lung mechanical properties over the entire human lifespan.

    During foetal development, maturation appears to be more advanced in female than male lungs in terms of both foetal breathing and surfactant phospholipid profile. In line with these observations, female neonates are less likely than male neonates to develop both transient tachypnoea of the newborn and respiratory distress syndrome.

    Although female lungs are smaller than their male counterparts, they exhibit higher flow rates during the whole lifespan. In fact, the ratio of forced expiratory volume in one second to forced vital capacity is higher in girls and women than in boys and men. Since flow rates seem to be strongly influenced by airway length, the larger lungs of males operate in unfavourable conditions, as their airways are both longer and narrower than those of smaller female lungs. This effect is more prominent in the growing lung, since, at variance with females, in males the airways grow at slower rates than parenchyma.

    Gender differences in the lung physiological behaviour are less striking in the adult lung, probably because a considerable number of factors other than lung anatomy can influence this behaviour in the two sexes. These factors include the effects of sexual hormones, variations in the immunological response involving the tracheobronchial tree and different exposures to environmental pollutants harmful for the lung.

    Clinical implications of the above described gender–related differences in lung size, structure and function are routinely used in respiratory medicine practice, since reference values for flow rates used worldwide are gender specific. Conversely, in clinical studies, awareness of the implication of gender–related differences is lacking and sex is often thought only as a factor to standardise for. Instead, stratification for gender would allow a correct understanding of differences in the potential risk factors and in the natural history of pulmonary diseases. Therefore, gender–related differences in airway behaviour, that encompass the whole lifespan, would deserve better consideration, not only for clinical and public health practice, but also for correct research designs.

  5. Page 8
    Correspondence: M.R. Becklake, Respiratory Epidemiology Unit, McGill University, 1110 Pine Avenue West, Montréal, Québec, H3A 1A3, Canada.

    Airway behaviour is influenced by sex­related (biological) as well as gender­related (socio­cultural) determinants across the human lifespan. Dimensional (including structure/function relationships), immunological and hormonal factors (all sex­based) interact to different degrees and directions with environmental exposures often differently experienced by girls and women compared with boys and men. Their effects on their airway behaviour also vary in different age/time windows. There may also be sex­based differences in susceptibility to the same environmental exposures (sex­exposure interactions). For these reasons, generalisations about sex and gender effects based on limited age/time windows are not only inappropriate but may also be misleading. Awareness of these sex and gender­based differences in airway behaviour (and of the resultant differences in the clinical manifestations of airway disease) is important for informed clinical and public health practice, as well as for research, whether descriptive, aetiological or evaluative. The mechanisms underlying these sex­based differences should be the focus of research in these opening years of the 21st Century.

  6. Page 26
    Correspondence:E.Mund, Roslagsgatan 8, 113 51 Stockholm, Sweden.

    Female sexual hormones, such as progesterone and oestrogen, control fertility in women by the specific suppression of the maternal immune system, preventing the semiallogenic descendant from being rejected. The increased activity of cytotoxic (CD8+) lymphocytes and the shift from T‐helper 1 for T‐helper 2/3 response, promoted by progesterone, inhibit the invasion and activity of T‐helper (CD4+) lymphocytes, which are responsible for such rejection. This physiological hormonal immune suppression in women causes significant differences between the sexes, particularly when it ceases, i.e. when the production of progesterone and oestrogen comes to an end in the ovaries and the fertile period of a woman's life is over. Menopause means liberation of the immune system when T‐helper potential becomes markedly dominant over a decreased cytotoxic potential. In parallel, the number of immune cells increases in general; this is in contrast to men in whom immune cells and activity successively decrease with age. A significantly changed relationship between T‐helper and T‐cytotoxic capacity was shown in the lower airways in women but not in men aged >42 yrs, compared with women and men aged <40 yrs.

    T‐lymphocytes play a central role in controlling immune responses. Accumulation of T‐helper lymphocytes at menopause leads to cells with potentially disturbed function capacity, owing to the physiological ageing of the immune system. The presence of a large number of autoreactive cells, deteriorated function to manage clonal expansion and apoptosis, might be predisposing factors for the phenomenon that autoimmune connective tissue and vascular diseases develop mostly in women, usually in middle age. The decreasing and increasing levels of progesterone and oestrogen during the menstrual cycle, the extremely high hormone levels at pregnancy, including the rapid drop a month before delivery, are also supposed to influence the immune system; conditions exclusive to women.

  7. Page 39
    Correspondence: C.S.Rand The Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224, USA

    When women must cope with respiratory disease in the face of significant psychological, social or cultural challenges, such as depression, economic burdens, competing family responsibilities or disease stigma, the risk of nonadherence may increase. Although research has generally found gender not to be a consistent mediator of adherence, gender may be a more important determinant of adherence in cultures where women experience the greatest number of social, cultural and economic barriers. Effective therapeutic management must therefore recognise and address the contributions of psychological and socioeconomic factors to the management of respiratory diseases.

    Toward this goal, the clinician should discuss with the patient their anxieties and concerns associated with respiratory illness, the prescribed therapies and possible barriers to adhering with therapy, including depression, anxiety, cost and social stigma. Effective interventions to improve women's adherence with therapy for acute and chronic respiratory illnesses will address psychosocial barriers by providing support (tangible and intangible), enhancing coping skills and reducing anxiety. Clinicians should also recognise that a woman's psychosocial and economic resources and barriers are often shaped by influences that are outside of her control. The social environment that each woman lives in can facilitate or hinder her ability to follow therapy appropriately.

  8. Page 50
    Correspondence: D.S. Postma, University Hospital Groningen, Dept of Pulmonology, Hanzeplein 1, PO Box 30.001, 9700 RB Groningen, the Netherlands

    This review describes a number of differences in the natural course of asthma and chronic obstructive pulmonary disease (COPD), and associated risk factors, between men and women throughout different phases of life. The incidence and prevalence of asthma is higher in boys than girls in childhood and throughout puberty. In adulthood, the incidence of asthma is higher among females, and specific factors that are associated with female reproduction affect the course and severity of asthma throughout this phase of life. There is lack of clarity with regard to whether males or females suffer worse symptoms and greater deficits of lung function and there is clearly a need for further longitudinal studies concerning possible gender differences in airway remodelling and impact of asthma duration on subsequent symptoms and lung function.

    COPD is more prevalent in adult males compared with females, but data highlights that this is most likely due to the historically higher prevalence of smoking among males. Further research could focus on exploration of gender differences in the direct inflammatory and longitudinal effects of cigarette smoking, specifically taking other risk factors, such as airway hyperresponsiveness into account. The literature suggests that females are more susceptible to the deleterious effects of smoking and have more frequent and severe airway hyperresponsiveness than males. A point not addressed in the literature that needs further attention is possible gender-related differences in treatment response.

  9. Page 74
    Correspondence: D.S. Postma, Dept of Pulmonology, University Hospital, Hanzeplein 1, 9531 GZ Groningen, the Netherlands.

    The existing body of literature on gender differences in the natural history of most respiratory diseases is very small, and often unhelpful, since study design has mostly precluded the opportunity to look at gender differences. This is not surprising, since the importance of gender differences in the natural history of disease and the response to treatment has only recently been recognised. Consequently, it is hard to gain insight into gender differences and where they exist, to the underlying causes. Studies investigating interactions between gender and treatment response are also urgently needed.

  10. Page 82
    Correspondence: J. Black, Dept of Pharmacology, University of Sydney, NSW, Australia, 2006.

    Since for many years, women of child-bearing age were excluded from participating in clinical studies, information regarding gender-dependent responses to drugs in general and to respiratory drugs specifically, has been lacking. However, there are some reported differences in the way in which men and women respond to drugs, which may be related to differences in the volume of distribution and body-fat content. In contrast, gender-specific responses to β2‐adrenoceptor stimulation appear to be unrelated to these parameters and more closely associated with phase of the menstrual cycle, pregnancy and the presence of asthma. However, most of these studies have been conducted on peripheral blood lymphocytes, which may or may not be an adequate surrogate for lung β2‐adrenoceptors. Finally, prescribing profiles in the community for respiratory drugs in asthma, such as oral steroids, may differ between men and women.

  11. Page 90
    Correspondence:C.E. Mapp, Dept of Clinical and Experimental Medicine, Section of Hygiene and Occupational Medicine, University of Ferrara, Via Fossato di Mortara 64/b, 44100 Ferrara, Italy.

    Asthma is a complex disease resulting from the interaction between genetic and environmental factors. Gender as a congenital factor in asthma has received little attention. This chapter provides some information on gender differences with regard to the prevalence of atopy and asthma, and to the severity of the disease. It appears that asthma involves a complex interaction of genetic susceptibility, host defence and environmental factors. A better understanding of gender-related differences in asthma will provide knowledge on how to manage this condition, especially in tailoring educational programmes, behavioural interventions and management plans to individual patients.

  12. Page 103
    Correspondence: C.S. Ulrik, Virum Overdrevsvej 13, DK-2830, Virum, Denmark.

    Presently, tobacco use is the single largest and most preventable cause of premature adult death throughout the world. Unfortunately, the global tobacco epidemic shows little sign of abatement, primarily because of the rapid increase in tobacco use in developing countries.

    Although the health hazards of smoking have been known for decades, the prevalence of smoking among women has declined at a much slower rate than among men in the developed countries. In the developing world smoking is linked with an affluent lifestyle, and many, especially young, women, fuelled by aggressive tobacco marketing, are likely to take up smoking, resulting in an increased prevalence of smoking among women in developing countries. These trends, with a latency period of 2–3 decades, will translate into a rapid worldwide increase in smoking–related mortality among women.

    Women are clearly not immune to tobacco–related diseases and it is now well–documented that whenever smoking characteristics, including number of cigarettes smoked per day, of women equal those of men, their RR of death from smoking–related diseases is at least similar to that of men. At least one–half of all female cigarette smokers will therefore eventually be killed by their habit.

    Women have experienced a rapid increase in COPD and lung cancer mortality over the last 2 decades, reflecting past smoking behaviour, and it must be anticipated that female mortality from COPD and lung cancer will at least match that of men within the next 2 or 3 decades. Furthermore, the association between increasing life–time tobacco exposure (pack–yrs) and risk for death from tobacco–related lung disease may be stronger for females than for males, although presently available evidence does not permit valid conclusions regarding this point, primarily because of major gender differences in past smoking behaviour.

    Although active smoking appears not to be a risk factor for asthma, evidence suggests that active smoking is a risk factor for death from asthma in patients suffering from asthma, and again, female asthmatic smokers might be at higher risk than their male counterparts.

    The world faces an epidemic of smoking–related mortality in women and strong tobacco control efforts are clearly needed in both developed and developing countries to decrease tobacco use among women.

  13. Page 118
    Correspondence: P.D. Blanc, Division of Occupational and Environmental Medicine, Dept of Medicine and Cardiovascular Research Institute, University of California, Box 0924, San Francisco, CA 94143-0924, USA

    Household exposures can pose a risk for adverse respiratory effects whose burden is borne disproportionately among women, much of it preventable. Relevant exposure risks fall into three categories. Exposures may arise out of the routine household activities including cooking, cleaning and laundering. Cooking can lead to exposure to particulate material and gases, each with potential adverse respiratory effects. Worldwide, cooking with biomass fuels and coal may carry the greatest health risk for women among domestic exposures. Food preparation can also lead to allergic disease, including asthma associated with handling common foodstuffs. Cleaning-chemical exposures can lead to irritant inhalation, most commonly from mixing misadventures involving hypochlorite bleach. Laundering also carries risks, either from dust-contaminated work clothes or from detergents and related products. A second group of exposures with a potential gender differential derives from domestic indoor-air quality. Exposures can include bioaerosols, environmental tobacco smoke and chemical off-gassing. To the extent that women spend more time indoors in these environments, they are at greater risk of adverse effects. Finally, sporadic yet important domestic exposures can occur through hobby or vocational activities, such as home maintenance or crafts work.

  14. Page 131
    Correspondence: S.M. Tarlo, Toronto Western Hospital, Edith Cavell Wing 4‐009, 399 Bathurst St, Toronto, Ontario, M5T 2S8, Canada

    An increase in occupational lung disease in women has been identified in several studies, especially relating to occupational asthma (OA) and airway diseases. This may reflect increasing participation by women in occupations which were previously predominantly male and may also in part reflect the increasing prevalence of cigarette smoking in women. For example, in one study, the proportion of women among accepted claims for OA related to diisocyanates increased from 28 to 45% over the 7‐yr periods before and after 1987, reflecting changes in exposure. There is also evidence that airway aerosol deposition may be greater in larger airways in women than in men and that women may be more susceptible to developing chronic bronchitis, though to date this potential to increased susceptibility has not been assessed in relation to work exposures. Predominantly female occupations with exposures relevant to occupational lung diseases include healthcare, laboratory animal workers, domestic cleaners, textile workers and pastry makers. Women in office buildings may develop building-related lung disease, including hypersensitivity pneumonitis and asthma, as well as respiratory symptoms as a component of sick-building syndrome. Approximately 5% of lung cancer mortality in women has been linked to employment in occupational exposures. Employment of the husband or a household member in selected industries and occupations yielded significantly increased odds ratio suggesting second-hand exposure may also be relevant to development of lung cancer in women, and women are frequently employed in casinos, bars and other areas with second-hand tobacco smoke exposures. Less common occupational lung diseases can also occur in women, and both current and former workplace exposures should be considered when diagnosing lung disease in women as well as in men.

  15. Page 146
    Correspondence: C.M. Dresler, 57 Summer Street, Arlington, MA 02474, USA.

    Women appear to be more susceptible to tobacco carcinogens in the development of lung cancer. Women usually smoke less and start smoking later than men. They may have increased activity of specific cytochromes, localised in the pulmonary tissue, that metabolise both oestrogens and inhaled carcinogens. Such increased activation of cytochromes, such as CYP1A1, could lead to increased deoxyribonucleic acid adducts from altered oestrogen metabolism. How these mechanisms interact to result in the more readily developed lung cancer in women is, as yet, unclear. Evidence suggests that women may survive longer once the diagnosis of lung cancer has been made. However, this finding awaits further validation. More attention needs to be addressed to the oestrogen status of women patients with lung cancer, with regard to menopausal status, history or duration of birth-control pills or hormone-replacement therapy and actual smoking history during such medication, and as well as family history of smoking, cancer, and particularly lung cancer. In addition, further exploration of the interaction of smoking and oestrogen metabolism should lead to better understanding of the mechanism underlying the putative increased susceptibility of women to tobacco carcinogenesis and lung cancer.

  16. Page 152
    M. Chan-Yeung, University Dept of Medicine, Queen Mary Hospital, Hong Kong, SAR, China.

    Tuberculosis is a leading cause of death in women worldwide. Notification rates of tuberculosis vary considerably between countries, but are generally higher in men than in women. Although under-recognition and under-reporting of the disease in women due to socioeconomical and cultural factors may account for these differences, there is evidence to suggest that biological mechanisms, such as hormonal or genetic susceptibility differences, may also be responsible. The prevalence of tuberculous infection is similar between boys and girls aged <12 yrs, after which there is a predominance of infection in males. The progression from infection to disease is similar between the two sexes aged <12 yrs; during adolescence and early adulthood, disease occurs predominantly among females. In patients aged >45 yrs, the rate of progression to disease is ∼2.5- times higher in men. Mortality from tuberculosis is higher in women than men in both high and low-income countries. Extrapulmonary tuberculosis and lymph node involvement is more common in women than in men. In men, pleural disease is more common. Tuberculosis has a greater adverse impact on the lives of women than men, especially in low-income countries. Tuberculosis control programmes should be sensitive to the issues of gender differences and should make treatment available to both women and men.

  17. Page 167
    Correspondence: J.F. Cordier, Dept of Respiratory Diseases, Louis Pradel Hospital, 69394 Lyon, France.

    Most interstitial lung diseases may affect women but some of them have specific importance in women, including 1) diseases that are specific of the female gender and are not be observed in males, such as lymphangioleiomyomatosis; 2) disorders with female predominance, due to the underlying disease or cause (such as interstitial lung disease related to breast cancer or its treatment), interstitial lung disease associated to connective tissue diseases or interstitial lung disease related to the use of drugs for disorders that affect more women than men; 3) idiopathic interstitial lung disease that predominate in women, such as idiopathic chronic eosinophilic pneumonia; and 4) interstitial lung disease that have been reported predominantly in women, but for which the reason of this specificity remains yet unknown. It is thus important for the respiratory physician to take into account the female gender as a specific risk factor for some interstitial lung diseases.

  18. Page 190
    Correspondence: G. Rolla, Allergologia e Immunologia Clinican Ospedale Mauriziano Umberto I, Largo Turati 62, 10128 TorinoItaly

    The incidence rates of the most common connective tissue diseases which often involve the lung are significantly higher in women, compared to men. Sex hormones, cytokines produced by sex organs and microchimerism are the most important biological determinants of gender-related differences in autoimmune diseases. Despite the fact that collagen vascular diseases show higher prevalence in women, the pleuropulmonary manifestations of some of these diseases are more frequent in men, such as the pleural effusion in rheumatoid arthritis. By contrast, in Wegener's granulomatosis, a disease with equal sex distribution or slight male prevalence, tracheal narrowing is more frequent in women.

    Gender may also affect the prognosis of autoimmune diseases. Specifically, rheumatoid arthritis has an excess mortality rate which is much greater in women than in men, while Behçet's disease generally has a more favourable course in women.

    The knowledge of sex prevalence relative to the specific respiratory manifestations of autoimmune diseases may help the pulmonary physician both in the diagnostic assessment and in disease management.

  19. Page 204
    Correspondence: E.O. Bixler, Dept of Psychiatry, Pennsylvania State University, College of Medicine, 500 University Dr, MC H073, PA, USA

    Women are at decreased risk for sleep-disordered breathing (SDB) compared to men. Menopause increases the risk for SDB; premenopausal women appear to be protected as are postmenopausal women with hormone-replacement therapy (HRT). Within both of these groups of women obesity appears to play a major role for the presence of SDB. Further support for the role of hormones/metabolic alteration in the mechanism of SDB comes from the finding that women with the endocrine disorder of polycystic ovary syndrome (PCOS) are at increased risk for SDB. Hypertension is a major cardiovascular risk associated with the presence of SDB. The strength of the association between SDB and hypertension appears to be similar between men and women i.e. once a woman has SDB she has similar risk for hypertension as a man with the same severity of SDB. Further study, with particular attention to the mechanisms, is needed to better understand the differences between SDB in men and women. In contrast, women are at increased risk for insomnia compared with men. Psychopathology, especially dysthymia, is commonly associated with insomnia and women are at increased risk for depression including dysthymia. Both depression and insomnia are associated with increased levels of cortisol suggesting a common mechanism for the two disorders. The prevalence of insomnia appears to increase with age while the rates for dysthymia are constant between the ages of 18–64 yrs and then decline. The increased wakefulness in response to cortisol with age suggests that a deteriorating physiological sleep mechanism may be a contributing factor for the increased prevalence of insomnia with age. Menopause is associated with subjective complaints of sleep disturbance and HRT has been used to alleviate these complaints. Objective polysomnographic data collected to date have provided little confirmation of these subjective complaints. Further study is needed to understand more clearly the complex interaction between psychopathology, gender, hormones, menopause and age for the mechanism of insomnia.

  20. Page 219
    Correspondence: N. Galiè, Istituto di Cardiologia, Università di Bologna, via Massarenti n° 9, 40138-Bologna, Italy.

    Pulmonary arterial hypertension (PAH) is a severe clinical condition, characterised by a progressive increase of pulmonary vascular resistance leading to right ventricular failure and premature death. Several large case series documented a great preponderance of the female gender in adult patients with PAH, both in primary pulmonary hypertension (PPH) and in the associated forms of PAH. In children there is no evidence of gender preponderance (gender ratio 1:1) and the significant increased incidence of PPH in females has been shown with the onset of puberty. Moreover, it has been also reported that a higher incidence of PPH occurs in women shortly after delivery and there have been cases in which hormone replacement therapy (HRT) in obligate carriers of familial PPH seems to have triggered the manifestation of the disease. For these reasons it has been hypothesised that female sex hormones could represent a trigger factor for the development of PAH. Nevertheless, a definite pathobiological mechanism to explain the association between female sex hormones and PAH has never been identified. The link the between pregnancy and PPH is also uncertain. However, the haemodynamic and hormonal changes that occur during gestation and labour increase the risk of pregnancy-related mortality in women with PAH and early termination should be considered. When PAH is not diagnosed until late in pregnancy an elective vaginal delivery under epidural analgesia has been recommended. Oral contraceptives and HRT have been considered to be unlikely risk factors for PAH in epidemiological surveys. However, the use of female hormones for birth control and postmenopausal replacements in PAH patients still remains controversial.

  21. Page 228
    Correspondence: A. Papi, Centro di Ricerca su Asma e BPCO, Università di Ferrara, Via Savonarola 9, 44100 Ferrara, Italy.

    A gender approach in health, while not excluding biological differences between women and men, considers the critical roles that social and cultural factors and power relations between women and men play in promoting and protecting or impeding health. More males die each year than females. The Center for Disease Control reports that in the USA, from 1940–1998, death rates were higher for men than women. The hypothesis that male-biased death rates are due to increased susceptibility to infection has received considerable attention. Despite the paucity of clinical studies performed on this topic, there are a few respiratory infections where a predominance gender has been demonstrated. This can be explained by differential risk of exposure to infection between women and men or by differences in susceptibility. Despite the paucity of the data available in the literature on the relationship between gender and susceptibility to infections, there are clinical and experimental studies that show a gender-related predominance of some viral, bacterial, fungine and parasitic infections. In the majority of cases, the cause of this increased susceptibility is unknown. However, an increasing number of experimental studies have discovered numerous effects of sex steroids at the cellular and molecular level on immune function and/or the growth of infectious agents. This emerging area deserves further research to clarify these complex interactions between humans and infectious agents. A female related condition, i.e. pregnancy, is associated with specific problems related to both the risks of transmission of the infection to the foetus and the risks of the antimicrobial treatment.