DEAR MAYO CLINIC: I have chronic obstructive pulmonary disease (COPD), and my doctor is recommending an antibiotic drug long term. Why is this needed?
ANSWER: For certain people with COPD, long-term use of an antibiotic drug — specifically azithromycin (Zithromax) — is a fairly new option to reduce exacerbations. Exacerbations are episodes when symptoms of COPD become worse than their usual day-to-day variation. Some exacerbations may be caused by a viral or bacterial infection. An exacerbation, if severe, can lead to hospitalization and even respiratory failure and death.
For people with COPD, short-term use of antimicrobials — antibiotics and antiviral agents — can help fight respiratory infections, such as acute bronchitis, pneumonia and influenza, and be used as part of the treatment of an exacerbation. A 2011 study indicated that long-term, continued use of azithromycin helps prevent COPD exacerbations — even for those who don’t have an active respiratory infection. In addition to its antibacterial effects, azithromycin has anti-inflammatory and immune-modulating effects that likely contribute to its ability to improve COPD management.
The study included people who had COPD with an increased risk of exacerbations, most of whom already were taking other medications to prevent exacerbations. Among those who took azithromycin daily for a year, the risk of having an exacerbation declined by about 27 percent, compared to those who took an inactive substance (placebo).
There are five classes of medications that may be used to help prevent COPD exacerbations. The classes include the antibiotic azithromycin. The other classes are inhaled corticosteroids, long-acting beta agonists, long-acting muscarinic antagonists, and phosphodiesterase-4 inhibitors. It’s common for more than one of these to be used at the same time, and there are multiple inhalers that combine two of these agents.
Azithromycin isn’t often the first drug prescribed for exacerbation prevention, but it may have an important role for some people with COPD.
One potential side effect of long-term azithromycin is hearing loss. In addition, people with a certain electrocardiogram abnormality — a prolonged QT interval — shouldn’t take azithromycin. Also, there appears to be a slightly increased risk of death due to heart rhythm problems associated with use of azithromycin. There also is controversy regarding the risk of antibiotic-resistant bacteria with long-term use of azithromycin. (adapted from Mayo Clinic Health Letter) — Dr. Paul Scanlon, Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota
You may well wonder what the connection might be between the title of this editorial and the famous Western The Good, the Bad and the Ugly. Well, we know that antibiotics are effective in treating bacterial infections (the good), are not as harmless as both clinicians and patients may think (the bad), and may have adverse effects and do not work in viral infections (the ugly). There is an increasing awareness that we have to challenge the problems caused by the overuse of antibiotics. Beliefs, expectations and incentives are the drivers of antibiotic overuse among the concerned parties: patients, physicians and society. Therefore, social norms would have to be altered, resulting in a fundamental change in patients' expectations, marketing, indications for antibiotic use and, particularly, physicians’ prescription behaviour. In a recent paper by the McDonnell Norms Group [1], some radical solutions were suggested, ranging from “changes in the way physicians are paid for prescribing antibiotics” and “looking at accuracy and limitation of antibiotic use” to “patients might be reimbursed differently for antibiotic prescriptions”.
Antibiotic resistance is inevitably related to excessive antibiotic use. The frequency of antibiotic resistance in bacteria among different countries is proportional to their relative rate of antibiotic use [2]. This is generally expressed in defined daily doses per 1,000 inhabitants per day (DID). Countries in southern and eastern Europe have the highest DID, whereas consumption is much lower in northern Europe [1, 3]. Antibiotic consumption differs among various countries in Europe. In 2008, the proportion of outpatient penicillin use ranged from 30.1% in Germany to 62.6% in Denmark, whereas the proportional use of quinolones ranged from 3.1% in the UK to 17.0% in Russian. Efforts to control overprescribing of antibiotic use can be successful, as has been shown in studies from Finland and Iceland. Reduction in resistance (up to 30%) can be achieved by implementing specific recommendations that discourage antibiotic treatment [4, 5].
Antibiotics are often prescribed, as well as to chronic obstructive pulmonary disease (COPD) patients, for illnesses such as colds, acute bronchitis and related respiratory tract infections caused by viruses that will not respond to antibiotic drugs. The rate of antibiotic prescriptions in the USA, measured from 1995 to 2002, has reduced in those respiratory infections in which antibiotics are rarely indicated [6]. However, the proportion of prescribed antibiotics classified as broad-spectrum antibiotics for these visits increased from 41% to 77%. In 2002, data from 360 hospitals reported that 69,820 US adults were hospitalised for an acute exacerbation of COPD (AECOPD) [7]. 87% of these patients were treated with antibiotics, resulting in broad-spectrum coverage in 74% of cases. However, sputum cultures were performed in only 14.4% of the patients. One may wonder whether omitting verification of a bacterial infection is justified, and whether it is acceptable to choose the use of broad-spectrum antibiotics for these patients.
Although as many as two-thirds of all cases of AECOPD may be due to viral infections, COPD treatment guidelines nevertheless recommend antibiotic treatment for patients with purulent sputum and either an increase in sputum production or an increase in dyspnoea [8, 9]. The evidence supporting these recommendations comes from a meta-analysis studying 11 trials performed between 1965 and 1992 demonstrating that antibiotics can reduce short-term mortality and treatment failure [10]. Nine trials were performed with hospitalised patients, one of which took place in the intensive care unit and two were carried out in the community. The largest and most leading study is that of Anthonisen et al. [11]. In this study three types of exacerbations were introduced, namely: type 1, defined by the triad of increased dyspnoea, sputum volume and sputum purulence; type 2, defined by the presence of two of these symptoms; and type 3, characterised by one of the three symptoms with evidence of fever or an upper respiratory tract infection. A significant benefit from antibiotics was largely reported for (out)patients with type 1 exacerbations, whereas there was no significant difference between antibiotic and placebo in patients with type 3 exacerbations. That type 1, and to a lesser extent type 2, exacerbations should be treated with antibiotics has been adopted by several guidelines [9, 12, 13]. Recently, Daniels et al. [14] reported a placebo-controlled trial in which antibiotic treatment in hospitalised patients (type 1 and type 2 exacerbations) had the same clinical success at day 30, but showed a higher rate of clinical cure on day 10 than placebo treatment.
When using the criteria of Anthonisen et al. [11], the question remains as to whether the reported purulence of sputum is the key message in prescribing antibiotics. Not all patients routinely inspect their expectorated sputum and the patient’s response to the doctor’s question could be a “best guess”. Moreover, sputum may change rapidly, especially during exacerbations. Sputum purulence assessed by a colour chart in the laboratory is related to an increased inflammation and higher bacterial load [15–17]. However, sputum colour is less reliably related to bacterial load if it is reported by patients [17].
Are there any other justifications for antibiotic treatment in AECOPD? We know that systemic inflammation is increased in AECOPD and more pronounced in the presence of bacteria [18, 19]. Biomarkers such as C-reactive protein and procalcitonin, especially when increased levels are detected, are indicative for bacterial infection and may guide antibiotic treatment [20–22]. However, interventional studies should be conducted, looking at the optimal strategy for determining the antibiotic cut-off point.
If antibiotic treatment is indicated, recent European guidelines (European Respiratory Society/European Society for Clinical Microbiology and Infectious Diseases) differentiate between outpatient treatment and hospitalised patients [13]. In the community setting, amoxicillin or tetracycline are preferred, whereas in hospitalised patients, amoxicillin or amoxicillin/clavulanic acid are recommended. Ciprofloxacin and moxifloxacin or levofloxacin are only indicated in patients with risk factors for Pseudomonas aeruginosa and clinically relevant bacterial resistance rates against all first-choice agents, respectively.
In the current issue of the European Respiratory Journal, Wilson et al. [23] report the results of the MAESTRAL study. In this study, the primary end-point was met, showing non-inferiority of moxifloxacin to amoxicillin/clavulanic acid. Only in patients with a positive sputum culture at baseline was moxifloxacin superior to that in patients treated with amoxicillin/clavulanic acid. Is this good news? In my opinion it is not, because a number of objections can be made. First, only one-third of the included patients were treated with a supplemental course of corticosteroids. In the study design it was decided, for medical ethical reasons, that the option to use steroids must be made available to physicians. A recent meta-analysis of 11 studies showed that treatment with corticosteroids (in both out- and in-patients) significantly reduces the rate of treatment failure and the need for additional medical treatment, as well as shortening the hospital stay [24]. For an optimal comparison of both antibiotic treatments concomitant medication should be standardised.
Secondly, at presentation clinicians do not know whether AECOPD patients have bacteria-positive sputum samples. Generally, sputum cultures will only be available 48–72 h after a specimen is obtained. Considering the observation that sputum colour reported by patients is not a reliable marker, it is difficult to assess which patients need antibiotics. This study does not answer the question of whether culture-initiated introduction of moxifloxacin is superior to other antibiotic treatments. The potent effect of moxifloxacin was demonstrated in another study indicating that the drug may prolong the time to the next exacerbation [25].
Thirdly, the participation of many countries with different healthcare systems may influence the generalisation of the findings of the MAESTRAL study. For instance, inhaled corticosteroids are used more often in Western Europe than in other countries; in this study, that is ∼53% overall [23]. Since inhaled corticosteroids, either combined with long-acting bronchodilators or not, may reduce the number of AECOPD, outcome may be affected by differences in prescription. Another point of concern regarding this type of study is the risk of selection bias, which is introduced when small numbers are entered by many countries.
What direction do we take with AECOPD? In my opinion, AECOPD should not be treated with antibiotics as standard. A pitfall is the sputum colour reported by the patient. Clinicians, especially in the outpatient setting, may not actually see sputum specimens and, thus, may respond to the patient's report and prescribe antibiotics if sputum is discoloured. How can we change this attitude? Assessment of sputum colour using a nine-point colour chart may be an option [16, 26]. If outpatient sputum is cream, white or clear, the yield from bacteriological analysis is low. Another way to reduce antibiotic use is to delay its prescription in patients who are not severely ill. Wait and see how effective treatment with corticosteroids and bronchodilators is and, in those patients who fail to improve, add an antibiotic after 4 days. And, if an antibiotic is prescribed, do this for just a short period [27]. As mentioned earlier, we have to change our social norms towards antibiotic use. Solutions to reduce the number of exacerbations, such as azithromycin maintenance therapy and moxifloxacin pulse therapy, may be attractive in the short term, but eventually we have to face the threat of resistance and economic impact [28, 29].
Further studies should be undertaken investigating biomarkers to guide antibiotic treatment and investigate the optimal duration of antibiotic treatment.
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Chronic obstructive pulmonary disease (COPD) is characterised by incompletely reversible airflow limitation and its severity has been categorised using the level of forced expiratory volume in 1 s (FEV1) [1]. Because marked heterogeneity existed between subjects with comparable FEV1 [2], it has been proposed that identification of subgroups of COPD subjects could represent an alternative to the current FEV1-based classification [3]. A consensus report proposed that COPD phenotypes, as defined by “a single or combination of disease attributes that describes differences between individuals with COPD as they relate to clinically meaningful outcomes (symptoms, exacerbations, response to therapy, rate of disease progression or death)”, could represent the future of COPD [4].
Chronic cough and sputum production (chronic bronchitis) have long been recognised as a consequence of tobacco smoking. In the 1960s, the British hypothesis proposed that chronic cough and sputum production encouraged bronchial infection, which promoted airway and alveolar damage and led to airflow limitation [5]. In their classical study reported in 1976, Fletcher and Peto [6] concluded that while chronic cough and sputum production and airflow limitation both occurred in smokers, they were largely unrelated disease processes. Almost 20 yrs later, Vestbo et al. [7] reported that chronic cough and sputum production were associated with an excess FEV1 decline and increased risk of hospitalisation because of COPD. Data from the Lung Health Study further indicated that chronic cough and sputum production were associated with increased lower respiratory illnesses (exacerbations) in subjects with mild airflow limitation [8]. These two studies shed new light on the potential importance of chronic cough and sputum production in subjects with COPD. They were followed by studies suggesting that chronic cough and sputum production were associated with increased mortality risk [9–11] and exacerbations [12, 13] in COPD patients.
In the present issue of the European Respiratory Journal, Montes de Oca et al. [14] examined the prevalence of chronic bronchitis in subjects with and without COPD identified in a cross-sectional, population-based study in five Latin American cities (PLATINO study). Although the prevalence of chronic bronchitis was rather low in this population, the authors reported that COPD subjects with chronic bronchitis had worse lung function and general health status, and had more respiratory symptoms, physical activity limitation and exacerbations [14]. The authors proposed that chronic bronchitis in COPD subjects was possibly associated with increased disease severity and represented a COPD phenotype [14]. The study by Montes de Oca et al. [14] follows several recent cross-sectional studies that compared clinical characteristics of COPD subjects with and without chronic cough and sputum production [2, 15–17]. These studies yielded somewhat variable results regarding the prevalence of chronic cough and sputum production in COPD subjects and their association with other COPD characteristics or outcomes (table 1).
Table 1– Summary of cross-sectional studies that compared clinical characteristics in chronic obstructive pulmonary disease subjects with and without chronic cough and sputum production
Variations in the prevalence of chronic bronchitis among several studies may be related to differences in its definition and to differences in the study populations. Chronic bronchitis is usually defined by “cough and phlegm (or sputum production) most days for >3 months in two consecutive years”. The study by Montes de Oca et al. [14] shows that the use of another definition based on “phlegm on most days for at least 3 months per year for ≥2 yrs” almost doubled the prevalence of chronic bronchitis. Other investigators have defined chronic bronchitis (or chronic mucus hypersecretion) by using a definition based on the “emission of >30 mL of sputum daily at least 3 months a year, for >1 yr” [12, 18]. Because all these definitions were based on expert opinion, it is unclear which one should be adopted. Regardless of the definition used, the prevalence of chronic cough and sputum production consistently increased with increasing airflow limitation [2, 15, 17, 19], and this finding may, in part, account for the low prevalence of chronic bronchitis in the PLATINO study, in which COPD subjects had mild airflow limitation.
Montes de Oca et al. [14] reported that COPD exacerbations were twice as frequent in patients with chronic phlegm production (although this difference was not statistically significant, probably due to lack of power), confirming results obtained in two other studies [15, 16]. However, no association was found between chronic cough and sputum production and exacerbations in the cross-sectional analysis of the ECLIPSE study [2]. During the first year of longitudinal follow-up of the ECLIPSE study, Hurst et al. [20] reported that chronic cough at study entry was associated (OR 1.20, 95% CI 1.01–1.42) with the occurrence of exacerbations, but this association did not remain significant in the multivariate analysis. In the latter study, chronic bronchitis or chronic phlegm production were not associated with exacerbations [20]. Thus, the relationship of chronic cough and/or sputum production to COPD exacerbations, an important clinical outcome, is not consistent among studies. To date, the reasons for these discrepancies remain to be established.
Several studies reported that subjects with chronic cough and sputum production had more severe dyspnoea [14, 16, 17], but these findings were again not reproduced in the ECLIPSE study [2]. Furthermore, it is unclear whether chronic cough and sputum production are independent determinants of dyspnoea in COPD subjects.
Assessment of chronic cough and sputum production relies on patient perception and recollection of symptoms, which is subject to bias. It may be affected by several factors including social behaviour (e.g. females often had lower prevalence of chronic cough and sputum production [2, 17], suggesting that they may be less prone to report such symptoms) and cultural factors in various geographic areas. It is also conceivable that the recent occurrence of a COPD exacerbation, in which cough and sputum production increase, result in increased reporting of chronic cough and sputum production. Furthermore, investigators have consistently reported that chronic cough and sputum production were more prevalent in current versus ex-smokers with COPD [2, 14–17]. These considerations may explain why chronic cough and sputum production were persistent over time in some, but not all, COPD subjects [7, 11], further complicating the understanding of their potential impact.
In the end, can we really consider that chronic cough and sputum production is a clinical COPD phenotype? It is suggested that chronic cough and sputum production cannot in itself be considered as a clinical COPD phenotype because: 1) conflicting data exist regarding its association with important clinical manifestations (e.g. dyspnoea) and outcomes (e.g. exacerbations); and 2) the two studies suggesting that chronic bronchitis was associated with increased mortality in COPD subjects will require confirmation before any definitive conclusion can be made [9, 11]. However, it is likely that chronic cough and sputum production are not innocent symptoms and may help in identifying specific COPD phenotypes. Interesting data supporting this view come from the results of recent clinical trials. Post hoc analysis of studies assessing the efficacy of roflumilast (a phosphodiesterase-4 inhibitor) [21, 22] or pulsed moxifloxacin [23] for the prevention of COPD exacerbations suggested that these interventions were efficacious in the subset of COPD subjects with chronic cough and/or sputum production at study entry. Such post hoc analyses have been used to define characteristics of patients included in a prospective clinical trial that demonstrated the reduction of exacerbations by roflumilast in a specific subset of COPD subjects [22, 24]. These subjects with severe airflow limitation (FEV1 <50% predicted), repeated exacerbations and chronic cough and sputum production experienced improvement with roflumilast [24], whereas no effect was found when selecting subjects only on the basis of severe airflow limitation [21].
Finally, COPD is a very heterogeneous disease and it seems unlikely that a single disease attribute would be sufficient to identify a specific patient phenotype. A working hypothesis is that the combination of multiple characteristics (including gene–environment data, age, comorbidities, imaging, biomarkers, etc.) and their analysis using mathematical techniques may be more suitable for the identification of clinically meaningful COPD phenotypes [25–27].
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For over 30 years I have been advising my patients with pulmonary hypertension (PH) to be physically active to a level of exertion that does not produce severe dyspnoea persisting post-exercise, dizziness, syncope or chest pain, based on the assumption that inactivity was bad both physically and mentally. This empirical advice meant little in the years before effective medical and surgical methods of treating PH were developed, but gained importance both as a conditioning practice for patients considered for transplantation or pulmonary endarterectomy, and as an adjunct to long-term medical therapy [1]. Only recently, however, has evidence supporting a meaningful benefit of physical activity been generated, dispelling the notion that there may be more harm than good resulting from attempting to increase blood flow through a restricted and presumed noncompliant pulmonary vascular bed [2]. In this issue of the European Respiratory Journal, Grünig et al. [3] bring our understanding of the effects of exercise in PH a leap forward by demonstrating that an intensive 3-week in-hospital rehabilitation programme followed by a regimented home exercise programme resulted in marked improvements in a variety of exercise parameters, as well as indices of quality of life. Furthermore, these effects persisted in the cohort re-evaluated after 15 weeks of training. These results are even more impressive when one considers that similar results were seen irrespective of the aetiology and functional severity of PH. The authors emphasise, however, that supervision and monitoring are important, since episodes of presyncope and syncope were observed, although no fatalities resulted. Taken together, these data provide guidance for instructing patients on the potential benefits and risks of intensive training.
Not all of the individual results of this study are as compelling as the sum of its parts, however. The improvements in 6-min walk test reported by Grünig et al. [3] are greater than those observed in any clinical trial with medical therapy for PH, and even more dramatic when considering that most patients were already on combination therapy. However, the 6-min walk test is highly subject to a “learning effect”, even without a rigorous training regimen, and the 6-min walk results in unblinded trials have typically been much greater than those achieved in subsequent double-blind trials [4]. Furthermore, increases of 50 m or more have been observed in placebo-treated subjects in PH clinical trials [5]. In addition, reliably estimating resting pulmonary artery systolic pressure using Doppler echocardiography is dubious, at best, in patients with PH [6]; reliably estimating pressure during exercise should be considered more art than science at present. Similarly, assessing functional class can be quite subjective and susceptible to unblinding bias. Nevertheless, improvement in the more objective parameters, including maximal oxygen consumption, resting and maximal heart rate, are convincing and support benefit. That even those patients who failed to improve exercise capacity nevertheless improved their quality of life indices is strong evidence in support of a programme that incorporates physiotherapy and psychosocial support for PH, along with medical care.
Grünig et al. [3] point out that this was not a randomised, blinded trial, which would be impossible to achieve with this therapy. It is also worth noting that this is a single centre experience, and duplication of these results from other centres is needed, not only to confirm them, but to demonstrate that this aggressive programme is feasible elsewhere as well, and therefore of potential relevance to many more patients. The expense and need for the 3-week in-hospital phase should also be reconsidered, since this is not feasible in many parts of the world. Additionally, the authors applied the “last observation carried forward (LOCF)” statistical method to analyse the results of patients who did not complete the full 15-week programme. However, the non-completers comprised a large percentage (40%) of the total population, and LOCF would give an overestimate of the “true” treatment effect if those who dropped out did so because of worsening for any cause [3]. Finally, as with medical therapy for PH, it will be important to evaluate the maintenance and durability of these effects over a longer period of observation.
In this Olympic year we are enthralled by the gracefulness of trained athletes and reminded of the benefits of physical activity even for those of us who do not compete. Grünig et al. [3] now provide evidence that one of the prescriptions that we write for our PH patients should be for physical activity and exercise. I can now look forward to the day when we will hold a PH Special Olympics.
Statement of Interest
None declared.
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In 1905, Robert Koch ended his Nobel Lecture on “The current state of the struggle against tuberculosis” with the optimistic sentence: “If the work goes on in this powerful way, then the victory must be won” [1]. At the end of the 1970s and the beginning of the 1980s, many believed that tuberculosis (TB) was nearly vanquished [2]. Now, more than 100 years after Koch’s Nobel Lecture, TB has emerged as an even greater public health problem, mainly for two reasons: co-infection with HIV and the development of complex mycobacterial drug resistance patterns [3].
The World Health Organization (WHO) estimates that of the 8.8 million new cases in 2010, ∼3% were caused by multidrug-resistant (MDR) strains of Mycobacterium tuberculosis [4], defined as resistance to at least the two most powerful anti-TB drugs, isoniazid and rifampicin. Furthermore, ∼30,000 cases were thought to be due to extensively drug-resistant (XDR) strains, defined as MDR plus resistance to any fluoroquinolone and at least one second-line injectable anti-TB drug (amikacin, capreomycin or kanamycin). The estimated prevalence of MDR-TB in new and previously treated cases in 2010 was 650,000 worldwide [4].
MDR- and XDR-TB are man-made phenomena that emerge as a result of inadequate treatment of TB and/or poor airborne infection control in healthcare facilities and congregate settings [5]. To resolve the epidemic of MDR-TB, several interventions are needed urgently: rapid case detection, proper infection control, timely access to quality-assured first- and second-line drugs within appropriate regimens, capacity-building to deliver treatment effectively, standardised recording and reporting of treatment outcomes [6] within effective national TB control programmes, and the commitment of national governments [7].
Nine of the countries with the greatest MDR-TB burden worldwide are located in the WHO European Region, which had, in 2009, an estimated 81,000 MDR-TB patients [5]. The highest proportions of MDR-TB, up to 26% and 65% among new and previously treated cases, respectively, are seen in the countries of the former Soviet Union (FSU), with an estimated 66,000 reported cases in total. However, less than one-third are diagnosed throughout the European Region because of limited access to the new WHO-approved rapid diagnostic methods [5].
Treatment of MDR-TB (and even more of XDR-TB) is complicated, expensive and often unsuccessful, with low cure and high mortality rates [6]. Only 2–3% of an estimated global prevalence of 1–1.5 million MDR-TB cases was known to be treated according to WHO recommendations [8].
To date, there is no clear scientific evidence focused on the economic burden of MDR/XDR-TB management in the WHO European Region. Health economic analyses could be used to estimate the value and the economic impact of different healthcare interventions in order to adequately allocate public money and resources. Yet, over the last few decades, private companies and policymakers working in the public sector have been adopting health economic evaluations (i.e. Health Technology Assessment) to increase the efficacy and the efficiency of their choices and decisions as one way to respond to perceived scarcity in global resources for equitable healthcare.
Applying this methodology to the aforementioned scientific gap, this issue of the European Respiratory Journal (ERJ) includes two relevant economic studies focused on drug-resistant TB in Europe.
The study by Floyd et al. [9], carried out in Estonia and Russia (Tomsk Oblast), both middle-income countries, compared the cost of MDR-TB treatment before and after the introduction of WHO guidelines. Furthermore, the authors evaluated the cost-effectiveness of this treatment, using cure rates, deaths averted and disability-adjusted life years (DALYs) averted as outcomes. It follows the outline of two WHO economic studies performed in non-European countries, those previously reported from Peru [10] and the Philippines [11].
Their findings highlight that treatment success increased from 15% to 76% in Tomsk Oblast and from 52% to 61% in Estonia; the death frequency fell from 64% to 4% in Tomsk Oblast and from 24% to 13% in Estonia. After the introduction of the WHO guidelines in 2001 and 2002, the majority of MDR-TB patients enrolled in Estonia had a high degree of drug resistance (79% were resistant to five or more anti-TB drugs or XDR versus 28% in Tomsk Oblast), whereas in Tomsk Oblast, stricter enrolment criteria were applied with priority for treatment given to more seriously ill patients, due in part to shortages of drugs during the study period. After the introduction of the guidelines, the WHO Green Light Committee supported the supply of second-line drugs at the lowest possible price to both countries.
The average cost per patient treated for MDR-TB almost doubled in Estonia, from US$4,729 to US$8,974, and in Tomsk Oblast it increased four- to five-fold, from US$2,282 to US$10,088, mainly due to higher costs for in-patient care (related to higher income levels) and for drugs, which together accounted for 69–90% of total costs. The net increase in total costs was about US$0.5 million in Estonia and US$1.0 million in Tomsk Oblast. These additional costs of treatment according to WHO guidelines resulted in a large number of averted deaths and DALYs, the cost per DALY averted being US$400–US$600, and thus provide clear evidence for the cost-effectiveness of the new treatment programme according to the WHO guidelines. In 2010, due to the increase in the gross national income per capita, the estimated costs per patient would reach US$14,370 in Estonia and US$9,910 in Russia.
Although the data from this study have been collected from cohorts enrolled in 2001–2002, these are contemporaneous with other publications. In Peru [10] and the Philippines [11], the costs for treating one MDR-TB patient were calculated at US$2,381 and US$3,355, respectively, mainly because hospitalisations were avoided to a large degree, and, when used, the cost of hospitalisation was lower than in the European countries. By comparison, Rajbhandary et al. [12] calculated substantially higher costs for the USA. On the basis of an analysis of 13 MDR-TB patients in three different illness severity categories, the average direct (in-patient and outpatient) costs per patient amounted to US$44,881 (range US$12,495–US$115,393) plus indirect costs due to productivity loss at an average of US$32,964 (range US$9,208–US$66,099) for those who survived and US$686,381 (range US$496,995–US$1,256,395) for those who died.
These data for direct costs are quite consistent with the data from Germany reported by Diel et al. [13] in this issue of the ERJ. In their analysis, the authors estimate direct (combined in-patient/outpatient) costs of €52,259 (at the time of writing of this editorial, €1∼US$1.3) per MDR-TB patient, which are much higher than the costs in Estonia and Russia. This is probably due to substantially higher wages and drug prices in Germany. However, these costs may even be underestimated. Although the number of MDR-TB cases was relatively small (in 2009, 63 cases, i.e. 2.1% of all cases with susceptibility testing or 1.4% of all 4,444 cases), they significantly contributed (8.5%) to the total treatment costs of almost US$50 million for TB treatment in Germany. Thus, TB must still be classified in Germany, with its low incidence rate of 5.4 cases per 100,000 population, as a disease of economic significance. As a country located not far from the countries of the FSU, the number of MDR-TB (and XDR-TB) cases may possibly rise in the future. XDR-TB patients were not included in the present cost analysis (in 2004–2006, the costs of treating XDR-TB patients in Germany amounted up to more than €170,000 per patient [14]) as well as possible surgical interventions, expensive second-line anti-TB drugs such as linezolid and HIV co-infection, since these factors play only a marginal role in the German scenario at present.
Another interesting finding described in the study by Diel et al. [13] is related to the lower direct costs of treating drug-sensitive TB patients, which amounted to €7,364 in adults and €7,300 in children in 2009, compared with the higher costs computed in 2001 (€14,301 and €16,634 in adults and children, respectively). This decrease is explained mainly by the reduction in hospitalisations (from 80.0% to 71.2%) plus the considerably reduced length of hospitalisation (from a mean of 50 days to 30 days). The comparison of costs between treatments for drug-sensitive TB and MDR-TB highlights the disproportionate contribution of drugs and hospitalisation to the overall cost for MDR-TB treatment [9, 13], as noted above. The drug costs for MDR-TB among the studies mentioned represent from just over 30% (Peru and the Philippines) and as much as 50% (Germany) of the total treatment costs. In all cases, the costs of drugs for treatment of MDR-TB are considerably higher than those for drug-susceptible TB; in the report by Diel et al. [13], almost 50 times high. This is, in part, due to the extended duration of MDR-TB treatment (three to four times as long as treatment for drug-susceptible TB). But cure rates are considerably lower, estimated at 62% in one recent meta-analysis of MDR-TB treatment compared with 85–90% for treatment of drug-sensitive TB [15]. These observations underscore the urgent need for new drugs for the treatment of MDR-TB and improved production and distribution of existing drugs, many of which remain very expensive, despite being off patent [6].
Similarly, the cost of hospitalisation, in places where it was routine, comprised between 30% (Estonia under WHO guidelines) and 51% (Tomsk Oblast under WHO guidelines) of total treatment costs. Moreover, the overall cost of MDR-TB treatment in those places was five to 30 times more than treatment in places where routine care was ambulatory (Peru and the Philippines). This increase in cost was not matched by significant improvement in effectiveness; a recent report by Fitzpatrick and Floyd [16] revealed that the cost per DALY averted in Peru and Philippines was one-quarter to one-fifth that of the cost in Estonia and Tomsk Oblast.
Floyd et al. [9] extrapolate on the basis of results from Tomsk Oblast that the annual cost of MDR-TB treatment for the whole of Russia would amount to US$375 million. This would already require a substantial increase in funding for TB control in Russia. Since India and China have much higher numbers of MDR-TB cases, with about half of the world’s estimated cases, the cost of MDR-TB control alone in these two countries would require, even with the low costs achieved in the Philippines and Peru, enormous investments. Thus, if the tide cannot be reversed in the near future, with new drugs and diagnostics, as well as broader introduction of more cost-effective models of care, global MDR-TB control may become unaffordable.
The countrywide evaluation of the costs and benefits of policies, guidelines and diagnostic/treatment practices represents a new tool for the management of TB, drug-resistant TB and TB/HIV co-infection in the near future. Moreover, the current economic crisis demands innovation in the development of tools as well as in decision-making processes for the introduction (or elimination) of useful (or harmful) healthcare approaches, tools and activities. Cost analysis, cost-effectiveness and cost–benefit studies provide useful insight into the efficiency of novel healthcare interventions and highlight opportunities for improvements in tools and care models that could improve effectiveness.
Statement of Interest
None declared.
Page 5
The readers of the European Respiratory Journal are well aware of the importance of environmental exposures on the incidence and aggravation of several respiratory disorders, including asthma and chronic obstructive pulmonary disease (COPD), leading in some cases to mortality. Almost each month, one or more scientific articles deal with environmental lung diseases or with environmentally induced cardiovascular conditions (including ischaemic heart disease, heart failure and stroke), often in patients already affected by smoking-related pulmonary diseases.
When dealing with the environment, there are three areas of great importance: indoor air pollution, outdoor air pollution and the health consequences of climate change. Research over many decades has highlighted the extent of the effects of outdoor air pollution on the respiratory system, the complex mechanisms of these effects and the fact that adverse health effects occur at low pollution levels, similar to those of the air that Europeans in many parts of the continent breathe. Indoor air, which is often more polluted than outdoor air, has been associated with many harmful respiratory effects, although there is considerable uncertainty about what concentrations or periods of exposure are necessary to produce these health problems. Worldwide, the total figure for indoor air related deaths is 1.6 million per year. Lastly, evidence is accumulating on how climate change, notably changes in heat, humidity and precipitation, and extreme weather events, impact on the distribution of respiratory disease and on its risk factors (e.g. infections, air pollution, pollens and moulds).
On all these aspects, in addition to the broadening body of research, we are experiencing increased public awareness and participation in production of proposals for integrated policy decisions both at European and individual national levels. These moves are progressing quickly and are difficult to follow, especially during a period of economic crisis when the environment tends to be less important than issues such as industrial production and unemployment. Clearly, today as in the past, different views and opinions are often related to diverging economic and societal interests. It is not a surprise, for example, that the global warming controversy (a variety of disputes about the nature, causes and consequences of global warming) and the “climate sceptics” have been linked to strong industrial and petroleum interests. The tobacco industry story is repeating itself again.
Against this background, the Environment and Health Committee of the European Respiratory Society (ERS) has launched several initiatives to provide respiratory physicians and other health professionals with instruments and tools to better understand the complicated issues related to the health effects of environmental exposures. The main initiatives are as follows.
1) Two position papers on air pollution. The first was published in 2007, when the European Parliament was approving the European Union (EU) directive on air pollution [1], and the second in 2010 on the subject of air pollution at work [2].
2) Two position statements on climate change. These were published in 2009 and 2010 [3, 4].
3) The book Air Quality and Health published in September 2010 to coincide with the ERS Annual Congress in Barcelona, Spain [5]. It was written as a tool to empower physicians and other health professionals to promote better air quality and defend the health needs of patients and citizens, and also to provide politicians, journalists and informed lay readers with an overview of the current knowledge about the nature and health consequences of the prevailing environmental problem of air pollution.
4) More recently, 10 concise principles for clean air have been developed [6]. They are based on the scientific state of the art and provide guidance for public health policy. The first of these principles (that citizens are entitled to clean air, just like clean water and safe food) simply underlines that millions of Europeans live in areas where it is unsafe to breathe the air around them, whereas air should be a “common good”.
5) A position paper is presently in preparation on indoor air pollution.
However, all these efforts need to be continued in view of the continuously changing policy perspectives. Among the important future deadlines, there is the review of the EU Air Quality Directive [7]. We propose here a new series that covers indoor, outdoor and climate, as follows. 1) A review of indoor air pollution in low and medium income countries by Kurmi et al. [8], published in this issue of the European Respiratory Journal. Following this, in forthcoming issues of the journal, there will be articles on: 2) indoor air pollution in high income countries, by M. Hulin and co-workers; 3) ambient air pollution as a cause for COPD, by T. Schikowski and co-workers; and 4) climate changes: effects on air pollution and respiratory health by M. De Sario and co-workers.
We hope readers of the European Respiratory Journal will take advantage of these well-written and up-to-date reviews.
Statement of Interest
None declared.
Page 6
First described in 1899 [1], sarcoidosis is a multi-organ granulomatous disorder that remains an enigma and challenges researchers and clinicians due to its unknown aetiology, variegated presentation and an unpredictable, and occasionally severe or even fatal, outcome despite therapy. As over 90% of patients have involvement of the lungs and thoracic lymph nodes, most chest physicians encounter sarcoidosis regularly in their practice, and have to manage this disorder with a risk of delayed or inadequate care [1].
Sarcoidosis may cause significant morbidity, as it persists as a chronic disease in approximately one-third of cases [1]. It most commonly affects individuals aged 20–39 yrs [2]. The prevalence of disease varies widely throughout the world and in ethnic groups, with a mean estimate of 15 cases per 100,000 persons, roughly corresponding to one in 6,000 persons in the general population [3]. In Ireland, England, central Europe and Scandinavia the prevalence ranges between 40 and 60 cases per 100,000 and associations with environmental and occupational exposure have been reported [4–8].
In the past, the European Respiratory Journal (ERJ) has disseminated advances in knowledge of sarcoidosis and is committed to doing so consistently. To this end, the ERJ has, in the June issue, started a new series on sarcoidosis that will provide an in-depth overview of the tremendous progress made in this field in recent years. This series of articles intends to provide readers with the most up-to-date and comprehensive reviews. The authors are among the world’s leading experts in the field of sarcoidosis, and the articles are intended to be practically oriented and relevant for practicing physicians without neglecting the cutting edge of research. Topics developed in the series were carefully chosen as those with the most recent and important developments, be it in the setting of clinical manifestations, investigations, pathophysiology or therapeutic approach; some articles are related to approaches already applicable in practice, while others are anticipating developments in the near future.
One of the highlights of the series will consist of two articles on the imaging of sarcoidosis. The diagnosis of sarcoidosis is based on compatible clinical and radiological manifestations, with histologic evidence of noncaseating epithelioid-cell granulomas in one or more organs and in the absence of identifiable cause, especially microorganism or exposure to antigens that may cause granulomas [9]. Therefore, chest imaging dominated by chest computed tomography (CT) is key to the diagnosis of sarcoidosis. T. Nunes will review the eminently variegated imaging features of sarcoidosis; the typical pattern which is highly suggestive of the diagnosis when predominant (i.e. bilateral hilar lymphadenopathy with peri-lymphatic micronodules), or bilateral hilar retractile masses with scarring and traction bronchiectasis (characteristic of stage IV sarcoidosis). Less characteristic patterns include cavitation, nodular and alveolar opacities, and the recently described patterns of sarcoid galaxy and sarcoid cluster, as well as rare patterns (ground-glass opacities, linear opacities and cystic destruction). The authors will further review the evidence regarding imaging and functional correlations at baseline (including various features associated with airflow limitation) and during evolution (imaging as predictor of outcome), and the impact of imaging evaluation on clinical management. Examples are provided of how chest CT can guide diagnostic interventions [10] and may allow the diagnosis of most complications that carry significant morbidity in pulmonary sarcoidosis.
18F fluorodeoxyglucose positron emission tomography (PET) scanning identifies areas with active metabolic (inflammatory) activity [11], which can be targeted by biopsies [12], and suggests the presence of disease in organs that are difficult to access and with potential morbidity, especially the brain and the heart. PET scanning has progressively replaced gallium-67 scanning in most centres. However, it is expensive, nonspecific and associated with significant radiation; therefore, it can’t be routinely recommended in patients with sarcoidosis. In the article by J. Grutters, the authors synthesise the available evidence and suggest situations where PET scanning is useful, especially in the diagnosis of cardiac sarcoidosis, provided that images are acquired specifically to address this question and in close collaboration with knowledgeable specialists in nuclear imaging.
Among all organs (all of which can be involved by sarcoidosis), the heart is the one associated with the most difficult challenge in diagnosis and management. U. Costabel will review the accumulating evidence that cardiac sarcoidosis is more common than previously evaluated, although often not causing any clinical manifestation [13], and occasionally occurring in the absence of apparent disease elsewhere in the body. Potentially life-threatening, heart involvement by sarcoidosis may be found in up to 25% of patients during post mortem in the USA [14], and can affect any part of the heart especially the conducting system (causing complete heart block) and the myocardium (with granulomas and fibrosis causing heart failure, syncope or sudden death due to ventricular arrhythmias) [1]. The relative strengths and weaknesses of available investigations will be discussed, with the most commonly used tests being PET scanning (the results of which can be affected by anti-inflammatory drugs) and delayed enhancement magnetic resonance imaging (which is not widely available). U. Costabel will address the question of whether cardiac sarcoidosis detected by systematic imaging techniques in asymptomatic patients requires treatment. Indications for electrocardiogram, echocardiography, cardiac electric monitoring and advance electrophysiologic studies will also be discussed, as well as involvement of other non-thoracic organs relevant for chest physicians.
Another issue of particular interest is that of chronic fatigue, a disabling symptom causing impaired quality of life and reported in up to 50–80% of sarcoidosis patients [15], as reviewed by Drent et al. [16] in this issue of the ERJ. Usually multifactorial and enhanced by comorbidities (including anaemia, depression, anxiety, hypothyroidism, altered sleep patterns, etc.), and possibly by complications of corticosteroid therapy, fatigue-associated sarcoidosis may persist despite the treatment of possible causes, and is not correlated with clinical parameters of disease activity. This suggests that other pathogenic factors may take place, providing targets for specific therapy once identified.
Two articles in the series are devoted to the therapy and management of patients with sarcoidosis, with a focus on severe complications of the disease. R. Baughman will discuss the standard treatment for pulmonary sarcoidosis, especially corticosteroids (which represent the standard therapy) and steroid-sparing agents such as methotrexate, azathioprine and leflunomide [17]. Important practical considerations concern the indications for therapy and measures used to assess the response. The authors will further review the potential role of newer biological agents (infliximab and adalimumab) that are being evaluated in patients with sarcoidosis especially those with extra-pulmonary refractory involvement, although the role of these agents in the management of patients with pulmonary sarcoidosis is currently marginal [18].
Although a minority of sarcoidosis patients progress to advanced stages of their disease, complications at this stage are challenging. In a recent issue of the ERJ, Schlobin and Nathan [19] comprehensively reviewed the evidence regarding pulmonary hypertension associated with sarcoidosis. Seven case series and one clinical trial [20–27] using therapy specific for pulmonary arterial hypertension collectively suggest a possible benefit of these agents in specific patients with sarcoidosis-associated pulmonary hypertension, although this requires further study. Schlobin and Nathan [19] also discussed the specificities of lung transplantation in the setting of sarcoidosis, with the main particularities being the multi-organ involvement, the risk of infection (fungal infections developing in cavities) and surgical difficulties due to bulky hilar adenopathy and perihilar fibrosis, pleural thickening or pulmonary hypertension.
More fundamental issues are addressed in the final three articles of the series, namely genetics, immunopathogenesis and biomarker development; topics that are immediately relevant for clinicians. Familial clustering of sarcoidosis may be found in 5–10% of patients, and represents, together with genome-wide scanning for susceptibility genes [28], one of the best ways to progress in the understanding of this disease of elusive aetiology. In 2005, dentification of butyrophilin-like-2 as a main genetic determinant of sarcoidosis was reported [29]. This was a landmark discovery that has stimulated further research in sarcoidosis genetics, yielding new susceptibility gene variants [28, 30] and even susceptibility loci shared by sarcoidosis and another granulomatous disorder [31]. Recent progress in the immunopathogenesis of this condition notably includes the probable role of regulatory T-cell lymphocytes and natural killer T-cells in granuloma formation, and the role of the shift from T-helper 1 to T-helper 2 lymphocytes in fibrogenesis. Finally, P. Rottoli will review the state-of-the-art regarding biomarker development in sarcoidosis and the search for simple tests that are useful for diagnosis and assessing disease activity.
We hope readers of the ERJ will enjoy reading these outstanding series articles, which will enhance our clinical skills and our comprehension of disease pathogenesis.