The basic events in the development of COPD’s symptoms

Starting the offense and defense

When COPD starts to develop in a susceptible smoker, the progression of events is led by airflow reduction. Patients may undergo a long process of decrease in airflow that leads to retention of some air inside the lungs. The retention of air is the resultant of an extended expiratory phase that needs to be interrupted to take oxygen again. Year after year, the smoker restricts their normal balance between expiration and inspiration. The loss of equilibrium between the respiratory phases intensifies during physical activities when the oxygen requirements increases. Of course, the pulmonary system suffers due to the air trapping and the whole body will feel that the oxygen requirement is not completely satisfied.

More oxygen to work

The body requirements of oxygen during physical activity puts the smoker in disadvantage. The smoker will require more rest intervals than a non-smoker during active motion. The issue is that everybody needs to move and if the insult to the lungs continue, some normal activities start to look like exercise to the smoker.

During physical activity a smoker, now with an continuously irritated airway have a persistent reduction in airway caliber. The easiness of expiration disappears and the oxygen requirement makes of immediate inspiration a solution. Air with CO2 that needed to leave lungs gets trapped during breathing but the lung elasticity allows the adaptation of the gas until the pressure inside the lungs at the end of expiration start to increase.

Do I look powerful?

When pressure at the end of expiration increases there are additional changes or adaptations at the respiratory system. Muscles that used not to work as intense as they could, now begin to work and when more muscles are working more energy is required. The excess energy requested by the body translates into excess oxygen requirement and the chronic smoker will not be able to satisfy this demand. At this point, the positive lung internal pressure results in an exaggerated inflation that will be visible externally by any good observer. The smoker, already a patient, has hyperinflation and the adapted diafragm, intercostals, and some cervical and shoulder muscles are working during activities that weren’t strenuous before.

Forgetting to move

The whole situation makes the patient to do less. Doing less leads to reduced fitness and with more physical movement the hyperinflation gets worse manifested with breathlessness. Then with less physical activity the breathlessness is more apparent. The patient becomes sedentary and the quality of life is reduced.

When did it start?

And all this, just because the subject needed some tranquilizer, some garbo, or some powerful look or was anxious and started lighting cigarettes. This started a chain of airway irritation, airflow reduction, gas retention, excess lung inflation, breathlessness during exercise, exercise restriction, breathlessness during activities, activities restriction, sedentary lifestyle, lost good quality of life.

Inflammation at a molecular level (simplified)

Inflammation seems to be a kind of well known body reaction to many agressions. How it happens has been debated for decades. Physicians have gone throught the simplification of this subject in order to facilitate therapy. Many drugs work there but how they do that in detail is still under clarification. We can’t admonish ourselves (of course) for not being clear in the process we are attacking to. However, some insight has been recently presented by very sharp experts. How does it start? What are the steps in the development of the inflammatory disease? What factors are involved?

Some chemical factors are released during a noxious exposure. The DNA has the genes with the information required to produce those substances. The DNA is compressed in the nuclei of cells. DNA is packed in a compressed structure called chromatin. Chromatin is not only composed by DNA but also by proteins called histones. Histones are basic (not acid) proteins that give the skeleton of the chromosome. Histones (H2A, H2B, H3 and H4) form an octomer (8 units bound) with 2 units of each type. Around this octomer are base pairs of DNA (146) and together (octomer of histones and base pairs) constitute nucleosomes. Nucleosomes one after other then form the chromatin in the nucleus of the cell.

When the chromatin is closely packed as described there’s no chance for new formation of messenger RNA (the messenger carrying the key composition of many proteins, including proinflammatory).

Some molecules generate the de-essembling of the chromatin. These molecules are large and called coactivator molecules. Coactivator molecules have intrinsic “histone acetyltransferase activity”. This means that coactivatro molecules have the property to acetylate histones. Whe histones are acetylated their charge turns into negative wich open the chromatin structure. The result is the opening of DNA showing  the genes to RNA polymerase. The gene transcription starts and a resultant messenger RNA now have the information with inflammatory proteins to act and potentiate the inflammatory process.

The exposure of cells to some interleukins and other chemokines results in acetylation of the aminoacid lysine in H4 (one of the histones in the nucleosomes). This lead to increased expression of genes encoding inflammatory proteins in this process.

To enjoy more an explanation about these molecular process I would refer to a Review written by Peter J. Barnes with many thoughts and facts around this fsacinating world of inflammation now turning into a more understandable process. (British Journal of Pharmacology 2006. 148;245-254)

Asthma versus COPD: any difference?

Making a literature seach in terms of differences between asthma and COPD (especially their inflammatory response) I found a review performed by Peter K. Jeffery (Thorax 1998;53:129-136).

Asthma and COPD may look alike…

There is a clear overlap between some COPD patients and some asthmatics. The reason for the overlap is mainly based on the similaties found among COPD patients with some reversibility in their obstructive component and asthma patients with some fixed component at the same parameters.

The degree of slow motion when a different approach is being looked for has impacted guidelines, research, academic opinions, and so farth. However, Jeffery points out several structural and inflammatory changes particularly seen in COPD or in asthma. Unfortunately, these diseases have a diagnosis mainly based in physiological than hystological parameters.

Inflammation and obstruction

What it is clear is that airways in in both clinical conditions are or have been markedly inflamed but the type and place of response seems to be inequal.

Some locations are relevant in COPD. For example in the proximal bronchi there is a reaction called Chronic Bronchitis where there are changes in the amount and composition if secretions. These secretions are composed by glycosaminoglycans, glycoproteins, lypids, and transudate and their proportion may change after the continous irritation by smoke or other pollutants. The glands and cells responsible for their production get large and hyperplasic respectively. In asthma. Jeffery points out the presence of plugs in the airways as well as “patchy loos of surface epithelium” among other features.

Getting the cells

Most of the new characterisitcs on the cells at the surface of the airways favor the bacterial colonisation too.

The assessment of sputum tend to show what is happening up to the sixth generations of bronchial branching. Beyond that, the material need to be obtained by bronchoalveolar lavage. The transformation of the cellular composition (mucous metaplasia) lead to other noxious effects that potentiate the proteolytic destruction of the lung tissue. This is due to the imbalance between the protective and reparing process.

The effect in the lung tissue is Emphysema which is also definitively associated to smoking. This is a consequence (together with the right heart effect) typical in COPD but not in asthma.

Proportions as a clue

The cellular population involved in both entities may vary importantly. Tobacco smoke recruit more netrophils to the lung and their transit time at this level is increased (delayed) due to their reduced deformability at the local capillary level.  COPD patients have more mononuclear cells including: lumphocytes, plasma cells, and macrophages. From lymphocytes, T lymphocytes (CD8+) are predominant while tissue eosinophils found in COPD do not degranulate.

Patients with asthma also have an inflammatory infiltrate but it comprises other population of lymphocytes (CD25+ and CD4+) activated and T helper as wells as activated eosinophils.

Of course, this structural changes are different in many ways and the chemical mediators tend to differ also in proportions with a different response that may require more specific mechanisms.

The suggested conclusion: there’s a difference like in many diferential diagnosis and, although it is not easy to stablish it clinically or physiologically, it is important to keep this in mind when assessing, managing, and follow up these overlapped gropu of patients.

COPD pharmacological control

Management of COPD has been recommended to be classified according to its main goal:

• Management of Stable COPD
• Management of Exacerbations

Medicine Categories in Asthma vs COPD

In asthma, phatrmacologic treatments are categorized as controllers or relievers. In COPD although suggested, there’s no such classification.

Medicine categories in Stable COPD

The medications indicated for stable COPD are to be used by the inhaled route. Most of them have benefits in terms of bronchodilation and subsequent relieve of some symptoms, with improvement in several physiological variables. These medications are intended to avoid the need for frequent dosing of different medications given that the disease seems to be under some control.

Controlled Progression

There’s no medication that delay the progression but quitting smoking. But now it seems to bring a question: If it is a progressive disease how can you keep it under “control”? what is the medication controlling?

It’s certainly interesting to read the previous question. The disease is stable then it needs “Control”? Yes, because it is progressive and the patient may have it in stable status, it is time to control it. Control means to maintain stable, to avoid or not having crisis after crisis easily. That’s when the chronic definition needs to be brought to mind. If the disease is stable… keep it as it is (control it).

What’s for what?

Using therapy to keep the disease under control doesn’t mean there will not be need for some additional doses of other medications. Other inhaled medication may be taken while the patient is receiving continous controller therapy. This other medication will onset its action pretty quick when the patient has a new onset symptom or a sudden worsening of a typical or already known one.

The relievers are not to be prohibited because a patient is receiving continued therapy. A key point is keeping in mind the mechanisms of action for not overwhelm the available mechanisms for drugs to work.

However, although drugs may have same mechanism of action it doesn’t imply they will work at the same level nor they will fight competing to start what has already been done by the previous taken drug. These drugs will support what’s been done by those inhaled medications that have been administered regularly.

Again: Training and Practice

As always, COPD patient needs to be trained in their disease. They need to take their medication and will need to recognize changes that may require additional strategies. Be sure to understand the relation among stable, controlling, and relieving as in all chronic conditions.

Cardiovascular effect in COPD

It’s always said: COPD seems to be a systemic disease although others say that it is a lung disease with systemic consecuences. Furthermore, many specialists agree in this being a manifestation of smoking effects that will be found with comorbidities. But in the meantime… where are we in the understanding of the cardiovascular effects of COPD.

Reasearch in the field of CV events and COPD

A recent correspondance sent by Alain Boussuges and Marion Gouitaa from Marseille, France to the AJRCCM (Am J Resp Crit Care Med 2008 Apri 15;177(8):929; author reply 929-30) opened the forum for more discussion about this topic. Boussuges and Goiutaa commented their personal experience where COPD patients showed increased periferal arterial stiffness when compared with healthy patients. These changes in arterial compliance were clearly correlated with COPD stages.

This comment was also based on a previous article by Ramsey Sabit and coleagues from UK (Am J Respir Crit Care Med 2007;175:1259–1265). Sabit assessed arterial stiffness and osteoporosis in COPD in 75 subjects with different degrees of COPD. This assessment was guided based on the typical association between an increased risk of cardiovascular events and COPD as well as this with osteoporosis.

Arterial Stiffness as a effect of COPD?

Sabit found that COPD severity was in close relation with increased arterial stiffness which may be a key factor in the development of the excess risk for cardiovascular disease in COPD.

How is it possible that they occur together?

As part of the reasons responsible for this association, Boussuges and Gouitaab pointed out the coincidence of many physiological consequences in COPD. For example, the excess sympathetic tone (activation) due to “Hypoxia, systemic inflammation, and obstruction of the bronchi” could lead to the impairment of the arterial compliance with vascular smooth muscle activation and subsequent stiffness.

Although the association or order of events has not been clearly established, the fingers are signaling to where everything starts: Smoking as way to activate the sympathetic system as well as inducing the reaction in the bronchi.

More complicated than expected

COPD is a manifestation and cardiovascular events are there, growing and growing in number in these patients. COPD is a lung disease with many comorbidities that need to be addressed during therapy. Many factors need to be addressed during the COPD treatment.

COPD that suddenly got worse

COPD is a chronic disease with repercusions beyond lungs. Patients may understand this concept but they may also forget the possibility of getting worse sometimes. How a patient can recognize a deterioration early and avoid worsening of their disease is a key element in their education. Admonishing a patient or relatives because they didn’t come before the worsening is not a solution.

Let’s contribute to the accretion in their understanding of their disease.

Exacerbation in COPD

Exacerbations have been defined in many ways. Three definitions have become popular in the medical arena sometimes to consider a hospital admission. Anyone of them support decisions regard to treatment and potential changes in lifestyle.

Few words and some clarity

One of the definitions of Acute Exacerbation of COPD or COPD Acute Exacerbation (COPD-AE in most clinical trials) is very simple. Dr. Roberto Rodriguez-Roisin from Barcelona, Spain has been a good contemporary analyst of COPD-AE. In his paper published in Chest 2000 May;117(5 Suppl 2):398S-401S, Dr. Rodriguez-Roisin opened the abstract giving a typical patient’s perspective: “an acute worsening of respiratory symptoms”. However, trying to reach a consensus at a workshop they defined COPD-AE as follows: “a sustained worsening of the patient’s condition, from the stable and beyod normal day-to-day variations, that is acute in onset and necessitates a change in regular medications in a patient with underlying COPD”.

The typical COPD-AE symptoms

In the 1980s, Nicholas R. Anthonisen (one of the most identified specialists in the field)  based his definiton based on increased intentisity of symptoms, number of symptoms, and systemic response. This approach helped to categorize COPD-AE into types that were numbered (I, II, III) if the were increases in symptoms (dyspnea, sputum volume, sputum purulence), combination of them, and/or other associated non-respiratory symptoms.  (Annals of Int Med 1987;106:196-204).

Say Yes or No

Two major criteria or one minor plus one major during 3 days is an COPD-AE according to East London Cohort (Am J Resp Crit Care Med 2000 161;1608-13). The major criteria considered by them are: increased cough, sputum volume, purulence, and dyspnea. The minor criteria are wheeze, fever, and cold symptoms.

What the patient should know

What is clear is that COPD-AE can be recognized according to changes in symptoms and how they are also reflected in the whole body. Patients may be trained to know that they have the symptoms they easily mention and some of them may vary in a day to day basis. However new respiratory symptoms, sustained worsening of those already existing, and new non-respiratory symptoms may preclude a COPD-AE and should be followed up in the short term.

Let’s see any change as something new but not necessarily as something to accept but to adapt in order to have positive outcomes.