Management of a patient

Main clinical signs in chronic bronchitis and bronchial asthma. Chronic obstructive pulmonary disease.

Pneumonias, symptoms and syndromes on the basis of clinical, instrumental and laboratory examinations. Pneumosclerosis. Lung cancer.

Clinical, instrumental and laboratory examination methods of patients with chronic gastritis, stomach and duodenal  peptic ulcer. Main symptoms and syndromes.

 

Chronic Bronchitis.  Chronic obstructive pulmonary disease (COPD)

Chronic bronchitis is defined as the presence of chronic cough and sputum production for at least three months of two consecutive years in the absence of other diseases recognised to cause sputum production. In chronic bronchitis, epidemiologically the bronchial epithelium becomes chronically inflamed with hypertrophy of the mucus glands and an increased number of goblet cells (Figure 1.2). The cilia are also destroyed and the efficiency of the mucociliary escalator is greatly impaired. Mucus viscosity and mucus production are  increased, leading to difficulty in expectorating. Pooling of the mucus leads to increased susceptibility to infection. Repeated infections and infl ammation over time leads to irreversible structural damage to the walls of the airways  and to scarring, with narrowing and distortion of the smaller peripheral airways.

The vast majority of smokers will eventually fulfi l the above epidemiology defi nition. However, only 20% of this group will develop signifi cant airfl ow obstruction (i.e. COPD). In the past these individuals have received the label ‘chronic obstructive bronchitis’ as opposed to ‘chronic simple bronchitis’.

Emphysema

Emphysema is defined in terms of its pathological features, characterised by abnormal dilatation of the terminal air spaces distal to the terminal bronchioles, with destruction of their wall and loss of lung elasticity  Bullae may develop as a result of overdistention if areas of emphysema are larger than 1 cm in diameter. The distribution of the abnormal air spaces allows for the classifi cation of the two patterns of emphysema: panacinar (panlobular) emphysema, which results in distension, and destruction of the whole of the acinus, particularly the lower half of the lungs.

Centriacinar (centrilobular) emphysema involves damage around the respiratory bronchioles affecting the upper lobes and upper parts of the lower lobes of the lung.

The destructive process of emphysema is predominately associated with cigarette smoking. Cigarette smoke is an irritant and results in low-grade infl ammation of the airways and alveoli. It is known that cigarettes contain over 4000 toxic chemicals, which affect the balance between the antiprotease and proteases within the lungs, causing permanent damage. The inflmmatory cells (macrophages and neutrophils) produce a proteolytic enzyme known as elastases, which destroys elastin, an important component of lung tissue.

Emphysematous chest

 

Bronchial Asthma

Asthma is a bronchial hypersensitivity disorder characterized by reversible airway obstruction, produced by a combination of mucosal edema, constriction of the bronchial musculature, and excessivesecretion of viscid mucus, causing mucous plugs.

Atopic, or “extrinsic,” asthma has been thought to result from sensitization of the bronchial mucosa by tissue-specific antibodies. The antibodies produced are specific immunoglobulins of the IgE (type I) class, and the total serum IgE concentration is usually elevated. Exposure to the appropriate allergens by inhala-tion results in an antigen-antibody reaction, that releases vasoactive bronchoconstrictive chemical mediators, causing the characteristic tissue changes (picture 1). More recent work suggests that immunoglobulin G (IgG) may play a role similar to that of IgE in some cases.

Approximately 50% of asthmatics are of the nonatopic (“intrinsic”) type in which the bronchial reaction occurs in response to nonimmunologic stimuli such as infection, irritating inhalants, cold air, exercise, and emotional upset. These patients do not demonstrate elevated IgE antibodies in their serum, and the history does not suggest hypersensitivity to specific allergens, although there may be other immunologic mechanisms that have not yet been demon strated.  Agrowing list of agents encountered in the work place have been shown to cause asthma. Some organic materials such as wood dust act through an immunologic mechanism, whereas certain chemicals and metal dusts apparently cause direct irritation or protein denaturation in low concentrations. Susceptible individuals may be affected by concentrations well below those allowed by US government standards. Occupational asthma should be suspected when symptoms occur repeatedly at work or within several hours there after and improve away from work. Improvement may require several days Beta-adrenergic blocking agents such as propranolol cause intense bronchial constriction in patients with asthma, apparently due to parasympathetic nerve stimulation. Aspirin and nonsteroidal antiinflammatory agents may cause severe asthma in some patients.

Inflammed bronchial mucosa. Secretion of purulent sputum in exacerbation of bronchitis

 

CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)

Clinically significant, irreversible, generalized airways obstruction associated with varying degrees of chronic bronchitis, abnormalities in small airways, and emphy­sema. The designation was introduced because chronic bronchitis, small airways abnormalities, and emphysema often coexist and it may be difficult in an individ­ual case to decide which is the major factor producing the airways obstruction.

When it is clear that the patient’s entire disease can be explained by emphysematous changes in the lung, the diagnosis “chronic obstructive emphysema” is pre­ferred to the more general designation COPD. Similarly, the diagnosis “chronic obstructive bronchitis” should be used when the obstructive abnormality is a di­rect result of an inflammatory process in the airways.

To avoid the semantic confusion often encountered in discussions of these dis­orders, the following definitions are provided. Chronic bronchitis, when unquali­fied, is defined as a condition associated with prolonged exposure to nonspecific bronchial irritants and accompanied by mucus hypersecretion and certain structural alterations in the bronchi. Clinically, it is characterized by chronic productive cough and is usually associated with cigarette smoking. Pulmonary emphysema is defined as enlargement of the air spaces distal to the terminal nonrespiratory bronchioles, accompanied by destructive changes of the alveolar walls. Airways obstruction is defined as increased resistance to air flow during forced expiration. It may result from narrowing or obliteration of the airways secondary to intrinsic bronchial disease or from excessive collapse of airways during forced expiration secondary to pulmonary emphysema.

The interrelationships between chronic bronchitis, pulmonary emphysema, and COPD are depicted in fig. 34-1. Some degree of emphysematous change is ex­tremely common in the general population, but not all patients with emphysema have sufficient airways obstructive problems to be considered as having COPD. Similarly, many cigarette smokers have evidence of chronic bronchitis, but only a minority have clinically significant airways obstruction, usually associated with marked changes in the small airways of the lung. As noted, most patients with clinically significant irreversible airways obstruction (COPD) have some combination of chronic bronchitis and emphysema. It is uncertain, however, whether this overlap results from a common causal factor or whether emphysema and chronic bronchitis predispose to one another.

Picture 1 Smoking and COPD

Etiology

The development of chronic bronchitis, emphysema, and chronic airways ob­struction appears to be determined by a balance between individual susceptibility and exposure to provocative agents.

The basic lesion of emphysema apparently results from the effect of proteolytic enzymes on the alveolar wall. Such enzymes can be released from leukocytes participating in an inflammatory process. Thus, any factor leading to a chronic inflammatory reaction at the alveolar level encourages development of emphysematous lesions. Smoking presumably plays a role due to its adverse effects on lung defense mechanisms (particularly by impairing the function of the alveolar macrophage) permitting low-grade inflammatory reactions to develop with conse­quent recurrent or chronic release of leukocytic proteolytic enzymes. Fortunately, most people caeutralize such enzymes as a result of antiproteolytic activity of the «i-globulin fraction of their sera. In a rare condition known as homozygotic antitrypsin deficiency, however, the serum antiproteolytic activity is markedly diminished. In such patients, emphysema may develop by middle age even in the absence of exposure to substances that interfere with lung defense mechanisms. In the absence of severe deficiency of ai-globulin in the serum, how­ever, the factors which make some cigarette smokers more susceptible to develop­ment of emphysema than others remain uncertain. It is also uncertain why persons with similar degrees of emphysema may have considerably varying de­grees of severity of airways obstruction.

With sufficient exposure to bronchial irritants, particularly cigarette smoke, most persons develop some degree of chronic bronchitis. The lesion essential to development of severe airways obstruction is apparently located in the small air­ways and may be basically different from the ordinary large airways abnormality which leads to hypersecretion of mucus in most smokers. The reason why small airways abnormalities develop in some patients with chronic bronchitis is uncer­tain, but viral or bacterial pulmonary infections in childhood, an unidentified immunologic mechanism, a mildly impaired ability to inactivate proteolytic en­zymes (as in heterozygotic antitrypsin deficiency), or unidentified genetic char­acteristics could be predisposing factors. While typical allergic bronchial asthma is not a common precursor of COPD, the exact interrelationships of these disor­ders are not known.

COPD is a major cause of disability and death. In the USA, it is second to heart disease as a cause of disability in Social Security statistics, and reported mortality rates have been doubling about every 5 yr. Its true mortality probably exceeds that from lung cancer. Some of this increase reflects the longer survival of patients who previously would have died of bacterial pneumonia before their COPD became known. Overall, it has been estimated that COPD affects as many as 15% of older men. Symptomatic COPD affects men 8 to 10 times more often than women, presumably as a result of the more frequent, prolonged, and heavier smoking in men; however, the incidence in women is now increasing.

Pathology

In patients with severe emphysema, the lungs are large and pale and often fail to collapse when the thorax is opened. Microscopic examination reveals “departitioning” of the lung due to loss of alveolar walls. Large bullae may be present in advanced disease. Changes may be most marked in the center of the secondary lobule (centrilobular emphysema) or more diffusely scattered throughout the lobule (panacinar emphysema). In all forms, the normal architecture is destroyed; rupture of septa results in air sacs of various sizes. The number of capillaries in the remaining alveolar walls is reduced, and the pulmonary arterial vessels may show sclerotic changes. These abnormalities lead not only to a reduction in the area of alveolar membrane available for gas exchange, but also to the perfusion of non-ventilated areas and to the ventilation of nonperfused parts of the lung; i.e., ventilation/perfusion abnormalities. They also lead to poor support of the airways of the lung, accounting for excessive collapse of airways on expiration.

In chronic bronchitis, the bronchial walls are thickened, there is mucus in the lumen, and the number of goblet cells and mucous glands is increased. There may be purulent secretions and inflammatory changes in bronchial walls and sur­rounding lung parenchyma if infection is present. Such large airways changes do not account for severe airways obstruction, however, and in patients dying of COPD, narrowing or obliteration, or both, of small airways may be observed.

Right ventricular hypertrophy (cor pulmonale) is common in patients with ad­vanced respiratory insufficiency.

Diagnosis

Diagnosis of COPD should be considered in any patient who has the following:

• symptoms of cough

• sputum production or

• dyspnoea or

• history of exposure to risk factors for the disease.

The diagnosis requires spirometry; post-bronchodilator FEV1/forced vital capacity <0.7 confirms the presence of airflow limitation that is not fully reversible.

 

Spirometric classification

Spirometric classification has proved useful in predicting health status, utilisation of

healthcare resources, development of exacerbation  and mortality in COPD. It is

intended to be applicable to populations and not to substitute clinical judgment in the

evaluation of the severity of disease in individual patients.

 

Assessment of severity: staging

It is accepted that a single measurement of FEV1 incompletely represents the complex clinical consequences of COPD because: 1) many patients are practically asymptomatic; 2) persistant cough and sputum production often precede the development of airflow limitation and, in others, the first symptom may be the development of dyspnoea with previously tolerated activities; and 3) in the clinical course of the disease, systemic consequences, such as weight loss, and peripheral muscle wasting and dysfunction, may develop. Due to these and other factors, a staging system that could offer a composite picture of disease severity is highly desirable, although it is currently unavailable. However, spirometric classification is useful in predicting outcomes such as health status and mortality, and should be evaluated. In addition to the FEV1, the BMI and dyspnoea have proved useful in predicting outcomes such as survival and this document recommends that they be evaluated in all patients.

 

BMI is easily obtained by dividing the weight (in kg) over the height (in m2).

Values <21 kg·m-2 are associated with increased mortality.

 

Functional dyspnoea can be assessed by the Medical Research Council dyspnoea scale.

0 not troubled with breathlessness except with strenuous exercise.

1 troubled by shortness of breath when hurrying or walking up a slight hill.

2 walks slower than people of the same age due to breathlessness or has to stop for breath when walking at own pace on the level.

3 stops for breath after walking ~100 m or after a few minutes on the level.

4 too breathless to leave the house or breathless when dressing or undressing.

 

Symptoms, Signs, and X-ray Findings

COPD is thought to begin early in life, though significant symptoms and dis­ability usually do not occur until middle age. Mild ventilatory abnormalities may be discernible long before the onset of significant clinical symptoms. A mild “smoker’s cough” is often present many years before onset of exertional dyspnea.

Gradually progressive exertional dyspnea is the most common presenting com­plaint. Patients may date the onset of dyspnea to an acute respiratory illness, but the acute infection may only unmask a preexisting subclinical chronic respiratory disorder. Cough, wheezing, recurrent respiratory infections, or, occasionally, weakness, weight loss, or lack of libido may also be initial manifestations. Rarely, initial complaints are related to congestive heart failure secondary to cor pulmo­nale, patients with such complaints apparently ignoring their cough and dyspnea prior to the onset of dependent edema and severe cyanosis.

Cough and sputum production are extremely variable. The patient may admit only to “clearing his chest” on awakening in the morning or after smoking the first cigarette of the day. Other patients may have severe disabling cough. Sputum varies from a few ml of clear viscid mucus to large bronchiectasis-like quantities of purulent material.

Wheezing also varies in character and intensity. Asthma-like episodes may oc­cur with acute infections. A mild chronic wheeze that is most obvious on reclining may be noted. Many patients deny having any wheeze.

The physical findings in COPD are notoriously variable, especially in early cases. A consistent abnormality is obstruction to expiratory air flow manifested by a slowing of forced expiration. To demonstrate this, the patient is asked to take a deep breath and then empty his lungs as quickly and completely as possible. Forced expiration is normally virtually complete in < 4 seconds. This test, which should be part of every routine physical examination, may be abnormal even though the patient does not complain of dyspnea.

Other findings, including bronchi, diminished vesicular breath sounds, tachy­cardia, distant heart tones, and decreased diaphragmatic motion, are not consis­tently present. The typical findings of gross pulmonary hyperinflation, prolonged expiration during quiet breathing, depressed diaphragm, pursed-lip breathing, stooped posture, calloused elbows from repeated assumption of the “tripod posi­tion,” and marked use of accessory muscles of respiration are seen only in later stages of COPD. A barrel-chested appearance is an unreliable finding since it is ofteoted in elderly patients without significant respiratory problems. Late in the disease, there may be frank cyanosis from hypoxemia, a plethoric appearance associated with secondary erythrocytosis, and, in patients with severe cor pulmo­nale, signs of congestive heart failure. Mild, chronic, dependent edema is quite common and does not necessarily indicate heart failure. It may result from pro­longed sitting, elevated intrathoracic pressures, and renal retention of salt second­ary to blood gas abnormalities even in the absence of cor pulmonale. X-ray findings are also variable. In early stages of the disease, the x-ray is ofteormal. Changes indicative of hyperinflation (e.g , depressed diaphragm, general­ized radiolucency of the lung fields, increased retrosternal air space, and tenting of the diaphragm at the insertions to the ribs) are common and suggestive of emphysematous disease, but are not diagnostic. They may also be found in pa dents with asthma and occasionally m healthy persons Localized radioluceno with attenuation of vascular markings is a more reliable indicator of emphysema

 

 

These radiographs of a patient with chronic obstructive pulmonary disease (COPD) reveal pulmonary hyperinflation. In the PA projection above the diaphragms are at the level of the eleventh posterior ribs and appear flat. The lateral radiograph below demonstrates the prominence of the anterior clear-space and of the AP diameter of the chest as well as the flat diaphragms.

Bullae are seen occasionally with COPD. Large bullae are generally well seen on ordinary x-rays, but small ones are more reliably detected with planograms. They may occur as part of a diffuse emphysematous process or as isolated phe­nomena and thus do not necessarily indicate a generalized lung disease.

Bronchitis itself does not have a characteristic appearance on ordinary chest x-ray, but bronchograms may reveal cylindrical dilation of bronchi on inspiration bronchial collapse on forced expiration, and enlarged mucous ducts Prank: saccular bronchiectasis is unusual and generally occurs only in patients who have had a previous severe respiratory infection.

In patients with recurrent chest infections, a variety of nondescript postinflammatory abnormalities may be noted, such as localized fibrotic changes, hone^ combing, or contraction atelectasis of a segment or lobe.

Isotopic lung scans generally demonstrate uneven ventilation and perfusion Diagnosis COPD should be suspected in any patient with chronic productive cough or exertional dyspnea of uncertain etiology, or whose physical examination reveals evidence of slowing of forced expiration. Definite diagnosis depends on (1) demonstration of physiologic evidence of airways obstruction which persists despite intensive and maximum medical management, and (2) exclusion of any specific disease (e.g., silicosis, tuberculosis, or upper airway neoplasm) as a cause of this physiologic abnormality.

Spirometric testing reveals characteristic obstruction to expiratory air flow with slowing of forced expiration as manifested by a reduced 1-second forced expiratory volume (FEV₁) and a low maximum mid-expiratory flow. Slowing of forced expiration is also evident on flow-volume curves. The vital capacity (VC) and forced vital capacity (FVC) are somewhat impaired in patients with severe disease but are better maintained than the measures of the speed of expiration. For this reason, the FEV₁/VC and FEV₁/FVC ratios are regularly reduced to < 60% with clinically significant COPD. This degree of abnormality should persist despite prolonged, maximal therapy before a diagnosis of COPD is considered confirmed

Maldistribution of ventilation and perfusion occurs in COPD and is manifested m several ways. An excessive physiologic dead space ventilation indicates that there are areas of the lung in which ventilation is high relative to blood flow (a high ventilation/perfusion ratio), resulting in “wasted” ventilation. Physiologic shunting indicates the presence of alveoli with reduced ventilation in relation to blood flow (a low ventilation/perfusion ratio) which allows some of the pulmonary blood flow to reach the left heart without becoming fully oxygenated, resulting in hypoxemia. In late stages of the disease, overall alveolar underventilation with hypercapnia occurs, aggravating any hypoxemia present due to physiologic shunting. Chronic hypercapnia is usually well compensated, and pH levels are close to normal.

The pattern of physiologic abnormality in an individual case depends to some extent on the relative severity of intrinsic bronchial disease and anatomic emphy­sema. Diffusing capacity is regularly reduced in patients with severe anatomic emphysema, but is more variable in patients with airways obstruction associated with predominant intrinsic bronchial disease. In patients with severe emphysema. resting hypoxemia is usually mild and hypercapnia does not occur until terminal stages of the illness. In these patients, cardiac output may be quite low, but frank pulmonary hypertension and cor pulmonale are usually late developments. In patients with airways obstruction associated primarily with an intrinsic bronchial disorder, severe hypoxemia and hypercapnia may be noted relatively early. Such patients usually have a well-maintained cardiac output and tend to develop severe pulmonary hypertension with chronic cor pulmonale. The residual volume (RV) and total lung capacity (TLC) are markedly elevated in emphysematous patients, while pulmonary hyperinflation may be relatively slight in bronchitic COPD, but the ratio of RV to TLC tends to be elevated in both types of disease.

Detailed lung function measurements help to determine the severity of emphy­sema and intrinsic bronchial disease in an individual case, but are rarely needed for ordinary clinical evaluation. With severe emphysema, pressure-volume curves show a characteristic loss of recoil and increased compliance. Airways resistance measurements made in the body plethysmograph tend to reflect the severity of intrinsic bronchial narrowing.

In a few cases with severe emphysema but little bronchitis or with severe ob­structive bronchitis but little, if any, emphysema, it is possible to distinguish emphysematous type (Type A) disease from bronchial type (Type B) disease on the basis of clinical and physiologic findings (see table 1). Unfortunately, most patients appear to have a “mixed” syndrome.

Specific parenchymal lung diseases which may lead to airways obstruction can usually be excluded by chest x-ray. Upper airway lesions (generally associated with stridor) and localized bronchial obstructions (often associated with a local­ized wheeze) must also be excluded. It is particularly important to exclude pri­mary cardiac disease with congestive failure as a cause of the patient’s respiratory insufficiency. A normal or small cardiac silhouette on chest x-ray is characteristic of COPD prior to development of frank cor pulmonale, but is most unusual in patients who are dyspneic as a result of a cardiac disorder.

Homozygotic antitrypsin deficiency should be suspected when there is a family history of obstructive airways disease, or when emphysema occurs in a woman, a relatively young man, or a nonsmoker. The diagnosis may be confirmed by mea­suring serum antitrypsin levels or by specific phenotyping.

Course and Prognosis

Some reversal of airways obstruction and considerable symptomatic improve­ment can often be obtained initially, but the long-term prognosis is less favorable in patients with persistent obstructive abnormality. After initial improvement, the FEV₁ generally falls 50 to 75 ml/yr, which is 2 to 3 times the rate of decline expected from aging alone. There is a concomitant slow progression of exertional dyspnea and disability. The course is punctuated by acute symptomatic exacerba­tions, generally related to superimposed bronchial infections.

Prognosis is closely related to the severity of expiratory slowing. When the FEV₁ exceeds 1.25 L, the 10-yr survival rate is about 50%; when the FEV, is 1 L, the average patient survives about 5 yr; when there is very severe expiratory slowing (FEV₁ about 0.5 L), survival for > 2 yr is unusual, particularly if the patient also has chronic hypercapnia or demonstrable cor pulmonale.

Treatment

Therapy does not result in cure, but provides symptomatic relief and controls potentially fatal exacerbations. It may also slow progression of the disorder, though this is unproved. Treatment is directed at alleviating conditions which cause symptoms and excessive disability (e.g., infection, bronchospasm, bronchial hypersecretion, hypoxemia, and unnecessary limitation of physical activity).

Infection: An attempt should be made to clear purulent sputum with a broad-spectrum antibiotic, the course re­peated promptly at the first sign of recurrent bronchial infection or sputum purulence. Ampicillin or cephalothin may be used to treat severe exacerbations Regular courses of a broad-spectrum antibiotic are indicated in patients with frequent infectious exacerbations.

Bronchospasm:

Corticosteroids have a very limited role in treating COPD, but a trial of these agents may be required to prove conclusively that the airways obstruction is not a result of potentially reversible bronchospasm. This is especially true when there is a past history suggesting asthma, eosinophilia, fluctuations in the severity of air­ways obstruction, or a good immediate response to inhalation of a bronchodilator. If a corticosteroid trial (e.g., prednisone 30 to 40 mg every morning for 3 wk) is undertaken, its usefulness should be documented by objective improvement w spirometric tests before long-term corticosteroid therapy is recommended, al which time the lowest maintenance dose which sustains improvement is used. In some patients, alternate-day therapy can be used for maintenance.

Bronchial secretions: Adequate systemic hydration is essential to prevent 10-spissation of secretions. In some patients bronchial hygiene may also be improved by inhalation of mist, postural drainage, and chest physical therapy, particularly following bronchodilator inhalation. Saturated solution of potassium iodide 10 drops in H20 t.i.d. is used by some physicians in an attempt to thin bronchial secretions. Despite their wide use, IPPB machines have not been shown to im­prove the patient’s ability to raise secretions or to affect favorably the overall condition of ambulatory patients with COPD.

Hypoxemia: Severe chronic hypoxemia, often associated with hypercapnia, accentuates pulmonary hypertension and leads to development of cor pulmonale in patients with COPD. Recurrent cardiac failure may develop and necessitate long-term 02 therapy. Low flow (1 to 2 L/min) 02 therapy via nasal prongs for 15 h or more/day (including sleeping hours) may be effective in reversing pulmonary hy­pertension and improving cardiac status. Around-the-clock 02 supplementation has been shown to be preferable for patients with severe chronic hypoxemia (arte­rial O2 tensions consistently < 55 mm Hg at rest) and appears to prolong survival. When instituting long-term O2 therapy, it is important to monitor the blood gas responses. No more O2 should be given than is needed to raise the arterial 02 tension to 55 mm Hg. One should also be sure that chronic 02 therapy does not lead to a progressive rise in C02 tension as a consequence of removing hypoxic ventilatory drive; in fact, this has rarely proved to be an important problem.

Even in patients without severe cor pulmonale, O2 may be needed to correct severe exertional hypoxemia when the patient is started on a graded exercise program. Use of 02 for symptomatic relief of dyspnea without verification of severe hypoxemia, however, is unjustified and potentially dangerous.

Hypercapnia: Patients with rapidly developing or worsening hypercapnia re­quire immediate hospitalization and intensive therapy, but chronic well-compen­sated hypercapnia is generally well tolerated and requires no specific therapy.

Heart failure: The most important measure for controlling heart failure second­ary to cor pulmonale is correction of excessive hypoxemia. Diuretic therapy and controlled sodium intake are important adjuncts. Digitalis must be used cau­tiously, if at all, since digitalis intoxication readily occurs in patients with COPD, probably as a result of fluctuating blood gas and electrolyte abnormalities.

Exercise tolerance: Prolonged inactivity leads to excessive disability in patients with COPD. As long as there is no severe cardiac disease, it is important to maintain a regular exercise program. This can usually be prescribed directly by the physician. If the patient is severely disabled, however, the program may be more effective if supervised by a trained physical therapist. The exercise program should have a specific meaningful goal (e.g., walking to the store, golfing) and should train those muscles needed for this specific activity. Breathing “exercises” (breathing training) may have a place in treating anxious patients who develop an excessively rapid ventilatory rate during exertion, but such exercises have not been shown to improve ventilatory capacity.

Exacerbations: Treat promptly; e.g., if sputum becomes purulent, prescribe a course of broad-spectrum antibiotics and a more intensive program of bronchodilation and bronchial hygiene (see above). Patients with increasing hypoxemia or hypercapnia should be hospitalized promptly for intensive therapy. Sedatives and hypnotics should always be avoided in patients with COPD, particularly during exacerbations, since they increase the risk of acute ventilatory failure.

 

 

BRONCHIAL ASTHMA

Development of Asthma

Airway Inflammation

Infectious agents constantly enter the body via the respiratory system. The bronchi have several protective methods against these invaders. These include:

·         recruitment of inflammatory cells from the bloodstream into the bronchial wall, where they directly attack the invading organisms and secrete inflammatory chemicals that are toxic to the organisms

·         swelling of the bronchial wall

·         mucus secretion

·         constriction of the airway.

The fundamental defect in asthma is that, for reasons that are unclear, these inflammatory actions occur in the bronchi wheo serious infection, toxin, or other inhaled threat to the body exists.

Airway inflammation in asthma is:

·                    a direct response of the immune system to a trigger

·                    a cascade of immunologic events that includes inflammatory cells and mediators

·                    an immune-mediated process that leads to inflammatory changes in the airway, including eosinophil recruitment and airway edema.

Bronchial hyperreactivity

Hyperreactivity of the airways to several stimuli is a hallmark of clinical asthma, and it appears bronchial hyperreactivity (BHR) is caused by airway inflammation. Studies have shown that the degree of BHR correlates, for instance, with the number of inflammatory cells recovered in BAL fluid from the airways of asthmatic patients.

Clinically, the degree of BHR (measured in research studies by methacholine challenge) has been shown to correlate with general asthma severity, with morning peak expiratory flow rate (PEFR), with the degree of diurnal variation of PEFR, and with the frequency of inhaled beta-agonist use (when taken by patients as needed for symptoms). The degree of BHR appears to decrease when asthma is well controlled with medication. The ultimate result and significance of BHR is the airflow obstruction that occurs when an asthmatic is exposed to a trigger.

Bronchoconstriction

Inhalation of an allergen solution by a patient with allergic asthma causes prompt and significant bronchoconstriction. After this bronchial allergen challenge, there is a rapid decline in forced expiratory volume in 1 second (FEV1) that begins within 15 minutes and generally subsides within the first hour (see figure below). This bronchial manifestation of immediate hypersensitivity has been termed an early asthmatic reaction (EAR), or the early phase response. After this phase resolves (spontaneously or with a beta-agonist, if needed), the FEV1 reaches a level that is at or close to the pre-challenge baseline.

In about 50% of patients, there can be a spontaneous return of bronchoconstriction that occurs several hours after the allergen challenge (and after the EAR has resolved) (see figure above). This late phase response usually occurs 6-24 hours after exposure to the allergen and is termed the late asthmatic response (LAR). This late decline in FEV1 may be less severe than during the EAR but is generally more prolonged, lasting several hours.

The EAR results from binding of inhaled allergen to mast cell membrane-bound IgE with subsequent release of mediators (e.g., histamine, leukotrienes, and prostaglandins). Among these mediators, the cysteinyl leukotrienes appear to account for a significant part of the early bronchoconstrictor response.

CLINICAL SYMPTOMS

Inquiry

Complaints

Common symptoms of asthma include wheezing, chest tightness, dyspnea and cough. The characteristics of these symptoms, which are variable, often paroxysmal and provoked by allergic or nonallergic stimuli such as cold air and irritants, are useful in diagnosis. Nocturnal occurrence is common. Measuring the patient’s response to a therapeutic trial may be helpful in diagnosis. Nonpulmonary symptoms that suggest a  predisposition to allergy—rhinitis, conjunctivitis and eczema—are also common in, but not specific to, asthma patients. In patients with symptoms that are persistent or that do not respond to simple treatment, objective confirmation of variable airflow obstruction is required.

Breathlessness

Breathlessness is the most common and troublesome symptom of COPD. It is subjective and is defi ned as an abnormal awareness of, or diffi culty with, breathing (Bourke and Brewis, 1998). There are various terms used to describe types of breathlessness.

Cough and Sputum Production

In most patients with COPD, a productive cough often precedes the onset of breathlessness. The cough is usually caused by either irritation of the airway nerves due to release of compounds from infl ammatory cells or by the presence of increased sputum production. Usually cough and sputum production in individuals who smoke is reversed once they stop. The cough is usually worse in the morning and is associated with chest tightness, which is usually relieved by expectorating. Sputum in such patients will usually be white and in smokers grey.

However, not all patients with COPD will have a cough and produce sputum routinely, except when they develop an exacerbation of COPD, which may become mucopurulent, yellow or green. Excessive production of sputum (more than an eggcup full) and frequent infective episodes may indicate a diagnosis of bronchiectasis and referral to a respiratory consultant for further investigations should be made.

Any patient with haemoptysis should be referred for a chest X-ray and a consultant’s opinion. Haemoptysis can develop as a result of a number of reasons, such as a pulmonary embolism, tuberculosis, pneumonia, infective bronchitis, left ventricular failure or mitral stenosis

Wheeze

Wheeze is caused by the sound generated by turbulent airfl ow through the airways. It is usually associated with asthma, particularly in patients with  atopy and exposure to a specifi c allergen. In some patients with COPD wheeze may be evident during an exacerbation as a result of bronchial constriction. COPD patients may experience wheeze post exertion or when going out in the cold air or during windy conditions. However, unlike patients with asthma, patients with COPD are rarely disturbed at night with a wheeze.

OTHER SYMPTOMS

Chest Pain

Chest pain may be a feature of COPD related to intercostal muscular skeletal strain through coughing or intercostal muscle ischaemia. Other causes such as pleurisy, tumours or ischaemic heart disease should be excluded.

Ankle Oedema

Ankle oedema is often present during an exacerbation, particularly in severe COPD, usually as a result of the development of right-sided heart failure, therwise known as cor pulmonale (explained further in the section ‘Complications of COPD’).

Anorexia

Loss of appetite is relatively common in patients with COPD, particularly during an exacerbation. This is due to increased breathlessness, cough and sputum production, which makes eating diffi cult and requires a great deal of effort. Loss of taste is also often common in these patients as a result of medication, in particular antibiotics and nebuliser therapy.

Weight Loss

Weight loss is a common symptom in patients with advanced or end-stage COPD, particularly those predominantly with emphysema. This is often due to an increase in the number of exacerbations per year and reduction in appetite. However, it is also as a result of a combination of factors, not just reduced calorie intake, but also the increased work of breathing due to their increased breathlessness. Insuffi cient calories are consumed to match the energy demands or metabolic rate required to sustain a steady weight. Other diagnoses such as lung cancer may also need to be investigated, especially if associated with rapid weight loss and other symptoms, such as cough and haemoptysis.

A low body mass index (BMI) and loss of lean muscle mass are common in COPD, especially in patients with emphysema. Weight loss is a poor prognostic sign and a low BMI increases the risk of death from COPD.

Fatigue and Depression

Fatigue is a familiar symptom in patients with a chronic condition, particularly in COPD. In advanced COPD breathlessness is a contributing factor in that the least exertion results in patients struggling to breathe. Various studies have revealed a strong correlation between fatigue, breathlessness and physical activity (Small and Lamb, 1999; Woo, 2000). This eventually leads to frustration, increased dependence and social isolation, which can result in clinical depression.

Disability

All symptoms such as breathlessness, excessive coughing, frequent exacerbations, fatigue and depression can have a huge impact on the patient’s quality of life and daily activities of living, such as washing and dressing, household chores or shopping. These things are taken for granted when fi t and healthy, but for patients with a chronic disease such as COPD, the simplest of tasks can take several hours to complete. The assessment of such disabilities is important to measure in order to determine the impact that the disease has on the patient’s everyday life.

 

History

Provocative factors in asthma

Aeroallergens

Aeroallergens are ubiquitous, although quantitative and qualitative differences depend on geographic location, climate, degree of urbanization and specific conditions in the home, school and workplace. Almost all adults appear to have T lymphocytes that are sensitized to at least some aeroallergens; thus, development of allergic disease may depend on quantitative differences in T cells.

Several lines of evidence link aeroallergens to asthma:

• A total of 60% of adults and 80% of children with asthma have positive skin-prick tests for environmental allergens, and allergen-bronchial challenge tests are positive only in those with allergen-specific positive skin tests.

• Allergen sensitization is a risk factor for severe, acute asthma, especially if the patient is exposed to high concentrations of the specific allergen.

• In general, severity of symptoms and of bronchial responsiveness correlates with degree of sensitivity to allergens; in some patients, allergy does not play an important

role.

• Symptoms, PEF and bronchial responsiveness usually improve when allergens to which the person is sensitized are avoided. Aeroallergens, which are carried on inhalable particles, are proteins that vary in molecular weight from 14 to 78 kilodaltons. Outdoor allergens arise from pollen or mold spores; indoor allergen sources include several species of dust mites, cats, dogs and other mammals, cockroaches and indoor mold spores. The molecular structure and functional properties of common and important indoor allergens, based on the World Health Organization’s nomenclature, have recently been summarized. Recombinant allergens with immunoreactivity comparable to that of the natural allergens are being produced and evaluated for allergen standardization, for diagnostic testing and for immunotherapy with specific epitopes and naked DNA vaccines. Infants are exposed and become sensitized to aeroallergens as well as food allergens in utero.4,5 In people who are genetically predisposed to allergy, antenatal factors, including maternal and, thus, fetal exposure to allergens and materno–placento– fetal immunologic interactions are important in determining whether the predisposition results in allergic disease.

 Exposure to low concentrations of indoor allergens in early childhood is associated with a low incidence of sensitization, but very low concentrations may be sufficient to sensitize children who are predisposed and have a family history of allergy, presumably after intrauterine priming.

 

Respiratory infections

Viral respiratory infection is a well known provocative factor for episodes of asthma. As well, specific agents, including respiratory syncytial virus (RSV), adenovirus, mycoplasma and pertussis, can provoke episodes of wheezing illness and, in a few cases, prolonged bronchial hyperresponsiveness. Recent studies using polymerase chain reaction (PCR) have implicated human rhinoviruses (HRV) as important agents in all age groups, and 1 study using this technique suggested a high prevalence of chronic Chlamydia infection in asthmatic children. How viruses or other agents provoke asthma is not clear. There is evidence of increased IgE production during viral infection. A recent study23 using a human B-cell culture system found that HRV-induced, double-stranded RNA activates an antiviral protein kinase that can induce Ig class switching to IgE, suggesting a mechanism for viral provocation of allergy and asthma.

This is consistent with a study of experimental HRV infection in asthmatic adults, which resulted in augmented eosinophilic inflammation (assessed in sputum) and enhanced bronchial responsiveness. In another controlled study of experimental HRV infection in people with allergic rhinitis (but no asthma) and a nonallergic control group, there was a significant increase in bronchial responsiveness to histamine in the allergic group. Rhinovirus infection of cultured human tracheal epithelium, confirmed by PCR, resulted in increased expression (upregulation) of messenger RNA for intercellular adhesion molecule-1 (ICAM-1) mRNA (the major HRV receptor on epithelial cells) and increased secretion of IL-1b, which itself up-regulates ICAM-1. Because ICAM-1 has important eosinophil attractant properties, this may be an important way in which the bronchial airway inflammatory response may be increased by HRV infection in asthma. RSV infection accompanying bronchiolitis is associated with persistent bronchial  hyperresponsiveness in some children, but its role in causing asthma is unclear. Recent animal studies suggest that RSV infection in mice followed by aeroallergen exposure results in pulmonary inflammation with eosinophilic infiltration; in guinea pigs, prior sensitization to allergen followed by infection with RSV results in much more severe mucosal damage.

Viruses are of greatest importance in causing wheezing illness in children under the age of 3 years. Reports from several centres now confirm that 20% or more of infants

in this age group respond to viral infections with recurring wheezing, which resolves in later childhood. These infants have reduced lung function before the onset of viral infection, have apparently normal immune responses to viral infection and do not have risk factors for asthma (i.e., increased IgE levels, bronchial hyperresponsiveness or a family history of asthma). They may have narrower intrapulmonary airways thaormal infants. A second group, about 10% of wheezy infants, also wheeze with virus infections, have some or all of the risk factors for asthma and have recurring wheeze (asthma) in later childhood. There is a great need to develop tests that will accurately differentiate these 2 populations.

 

Occupational and irritant-induced asthma

Occupational asthma (OA), defined as asthma induced by exposure to a specific agent in the workplace,32 is the most common occupational lung disease in developed countries. Occupational exposure has been estimated to cause 5%–15% of adult-onset asthma. The prevalence of OA due to agents with high molecular weight is generally < 5%; prevalence due to low molecular weight agents is 5%–10%. In 1 series, reactive airways dysfunction syndrome (RADS) or irritant-induced asthma accounted for 17% of 154 consecutive cases of OA. Many agents can cause OA. Those that cause immunologically mediated OA include a broad spectrum of protein-

derived as well as natural and synthetic chemicals used in various workplaces. Extensive lists of causative agents and workplaces have been published and a computerized database is available. These agents can be classified according to whether their pathogenic mechanism is immunologically mediated. An occupational cause should be suspected for all new cases of asthma in adults. A detailed occupational history of past and current exposure to possible causal agents in the workplace, work processes and specific job duties should be obtained. Information can be requested from the work site, including material safety data sheets. Walk-through visits of the workplace may be necessary. Industrial hygiene data and employee health records can also be obtained. Temporal associations are not sufficient to diagnose work-related asthma, and objective tests are necessary to confirm the diagnosis. Workers with asthma symptoms should not be told to leave their job until the diagnosis is proven because part of the diagnostic work-up of OA may involve a trial return to the work site by the worker. Challenge testing with the specific suspected agent has been used to confirm the work relationship. These tests can be falsely negative if a wrong agent is used for testing or if the patient has been away from work for too long. Another method to confirm the work relationship is serial monitoring of PEF for a period at work and a similar period away from work. Computerized peak-flow meters are helpful in overcoming some of the problems of PEF monitoring.  When the results of PEF monitoring suggest OA and specific inhalation challenges in the laboratory are not possible or negative, it is advisable to confirm OA by serial spirometry throughout a work shift. Combining PEF monitoring with serial assessments of nonallergic bronchial responsiveness can provide further objective evidence. Identification of those with OA is important because progressive deterioration and permanent disability may occur if exposure continues after onset of symptoms. Early removal from exposure may be associated with disappearance of symptoms and airway hyperresponsiveness. The ideal treatment is the permanent removal of patients with OA from exposure to the causal agent; some workers who have continued in the same job after diagnosis have died. Any patient with OA who remains in the same job should have respiratory protection and close medical follow-up. Worsening of asthma should lead to immediate removal from exposure. Irritant-induced asthma is caused by single or multiple exposures to high concentrations of an irritant vapour, fume or smoke in previously normal people. The term “reactive airways dysfunction syndrome” or RADS is used when the condition is caused by a single exposure. A patient’s pre-existing asthma may be aggravated by exposure to low levels of irritants, such as fumes, vapours or dust. However, the presence of asthma before being exposed to a sensitizing agent in the workplace does not preclude the development of true OA. People with asthma should not be exposed to concentrations of irritant higher than permissible (the airborne concentration to which nearly all workers may be exposed repeatedly without ill effects), although even this level may not be safe in those with airway hyperresponsiveness. For further information, readers should consult the full text of the Canadian Thoracic Society Guidelines on occupational asthma.

 

Indoor and outdoor respiratory irritants

Outdoor air pollution has been linked to acute exacerbations of asthma. Currently, the air pollutants of most concern are inhalable particulates ground-level ozone, acid aerosol, sulfur dioxide and nitrogen dioxide. Of these, inhalable particulates appear to be the single greatest hazard. Recent studies have shown strong associations between ambient concentrations of inhalable particulates and emergency room visits,55 admission to hospital and doctor visits for asthma.56–58 An increase in respiratory symptoms and a decline in PEF have also been observed in asthmatic children following increases in particle concentration. The role of inhaled particulate pollution in exacerbating asthma is based on epidemiologic studies, as no human study using controlled exposure is available. However, such studies have shown that ozone increases airway responsiveness and inflammation, and sulfur dioxide causes transient bronchoconstriction in people with asthma. Observation of the association of inhaled particulates with a range of adverse effects in people with asthma in a variety of settings strengthens the argument for a causal effect. In eastern Canada and the United States, increases in particulate concentration occur in association with increases in acid aerosol and ozone concentrations. Increased concentrations of that mixture of pollutants have also been associated with a greater number of admissions to hospital for asthma. Although the adverse effects of particulates on people with asthma clearly do not depend on the presence of acid aerosols, increases in acid aerosol concentrations in some settings contribute independently to increased respiratory symptoms. Increases in ozone concentration have also been associated with more emergency room visits and admissions to hospital for asthma, although ozone was present in combination with particulates and acid aerosols. Increases in ozone concentration have also been associated with worsening of asthma symptoms and decreased lung function in people with asthma independent of acid aerosols and particulates. Studies on humans using controlled exposure have demonstrated that people with asthma are much more susceptible than those without asthma to the bronchoconstricting effects of sulfur dioxide. However, the effects of exposure to acid aerosol and nitrogen dioxide have been contradictory. Ozone exposure causes predictable acute decreases in vital capacity under controlled conditions, but people with asthma are not more likely than healthy subjects to experience these effects. People with asthma exposed to ozone may experience more adverse effects following exposure to allergens. A similar situation occurs with exposure to nitrogen dioxide. Indoors, the most important respiratory irritant is environmental tobacco smoke (ETS). Asthmatic children of smoking mothers have more severe asthma than those whose mothers are nonsmokers, and when parents of an asthmatic child give up smoking, the child’s condition improves. Exposure to ETS is associated with increased frequency and severity of exacerbations of asthma and the development of asthma in predisposed infants and young children. The effects of ETS exposure may occur in utero. In the Canadian climate, exposure to ETS represents an important risk to respiratory health. Products of indoor combustion, such as nitrogen dioxide from gas stoves and wood smoke, may increase respiratory symptoms in people with asthma,84 but evidence for this is not conclusive. Formaldehyde and other volatile organic compounds detectable in indoor air are irritating to the eyes and the upper respiratory tract. Preventing respiratory effects of irritants consists of reducing exposure. During periods of increased outdoor pollution, patients can minimize exposure by remaining indoors or reducing exercise outdoors. Reduction of indoor pollutants can be achieved by avoiding exposure to cigarette smoke, by ensuring adequate venting of gas stoves and ensuring that wood stoves are air tight. Pregnant and breastfeeding mothers should be encouraged to give up smoking. Smoking parents or caregivers of asthmatic children should also be encouraged to give up smoking. Various types of indoor air cleaners are available, but, although several have been shown to reduce levels of irritants significantly, health benefits have yet to be demonstrated consistently. Human experimental studies have shown that bronchoconstriction resulting from controlled exposure to air pollutants in people with asthma can be prevented by use of an inhaled bronchodilator. Because continued exposure to respiratory irritants following the use of an inhaled bronchodilator will allow the inflammatory effects of irritant exposure to continue, preventing or reducing exposure should be the primary management approach. Recent studies have focused on the relationship between air pollution and airway inflammation. For example, there is a greater influx of neutrophils and eosiniophils in the nasal mucosa of atopic people whose nasal mucosa are challenged by a specific allergen in the presence of ozone than in air. People with asthma are also at higher risk of developing ozone-induced respiratory tract injury or inflammation characterized by increased neutrophils than people without asthma. In addition, ozone exposure results in increased inflammation in the lower airways of allergic people with asthma, demonstrated by an increase in both neutrophils and eosinophils. These results may explain the increased asthma morbidity associated with episodes of ozone pollution. Pre-exposure to a number of air pollutants, alone or in combination, will result in increased bronchial responsiveness to specific allergen in allergic asthmatic patients. Pre-exposure to ozone has been shown to increase specific airway reactivity of asthmatic patients who are allergic to grass pollen, although in at least one case these results could not be reproduced. A similar outcome was obtained with pre-exposure to nitrogen dioxide alone or mixed with sulfur dioxide. These results may depend on the pre-exposure status of the patient with asthma, i.e., the presence of eosinophilic inflammation in the airway before exposure to the pollutant, which then enhances the inflammation with an influx of eosinophils and generation of pro-inflammatory chemokines. There is now extensive evidence demonstrating adjuvant effects of air pollutants on the formation of specific IgE antibodies and cytokines in both animals and man. Experiments in rats showed that exposure to nitrogen oxide enhances immune responsiveness and the severity of pulmonary inflammation following antigen challenge. This adjuvant effect of air pollution has been particularly well documented with diesel exhaust particle emissions, which have been shown to enhance specific IgE antibody production, increase cytokine production and increase the gene expression of Th2 cytokines.  Several reports have documented enhanced production of specific IgE antibody and cytokines in cultures of lymphoid cells from mice or rats pretreated with diesel exhaust particles, and in vivo animal studies have demonstrated increased IgE-specific antibody production after intranasal pretreatment with diesel exhaust particles. These studies were extended to demonstrate that intratracheal immunization with antigen in the presence of diesel exhaust particles enhanced local IgE antibody production and also increased infiltration of eosinophils and the production of Th2 cytokines locally in the lungs compared with either antigen or diesel exhaust particles alone. These results mimic the nature of inflammation in allergic asthma.  These various studies strongly suggest that air pollution can modulate or enhance airway inflammation associated with allergic and asthmatic diseases; however, no studies have demonstrated the effect of medications used to treat asthma. Management of the adverse effects of respiratory  irritants on people with asthma consists primarily of preventing or reducing exposure. Exposure to outdoor pollutants may be reduced by remaining indoors, minimizing outdoor physical activity and breathing through the nose exposure. Reduction in indoor exposure can be achieved by avoiding cigarette smoke, assuring adequate venting of gas stoves and ensuring that wood stoves are air tight. Although some air cleaners can remove both particulate and gaseous indoor airborne pollutants, their effectiveness in

preventing adverse effects in people with asthma is not known. Finally, although bronchoconstriction resulting from controlled exposure to air pollutants in people with asthma can be averted by the use of inhaled bronchodilators, this is unlikely to prevent the inflammatory effects of the pollution and may aggravate them by masking symptoms. Preventing or reducing exposure should be the primary management approach.

 

Frequent Chest Infections

Patients with COPD, particularly when severe or end stage, may present with frequent chest infections, especially in the winter. Symptoms of a chest infection consist of increased breathlessness, usually with a productive cough of  yellow or green sputum. Wheeze may be evident in some patients at rest. Patients generally feel unwell, lethargic and have little appetite.

 

Essentials of Diagnosis:

• Recurrent acute attacks of dyspnea, cough, and mucoid sputum, usually accompanied by wheezing.

• Prolonged expiration with generalized wheezing and musical rales.

• Bronchial obstruction reversible by drugs

 

 

Clinical Findings

Symptoms and Signs:

 Asthma is characterized by recurrent attacks of dyspnea, cough, and expectoration of tenacious mucoid sputum, and usually wheezing. Symptoms may be mild and may occur only in association with respiratory infection, or they may occur in various degrees of severity to the point of being life-threatening.

Classic allergic (atopic) asthma usually begins in childhood and becomes progressively more severe throughout life, although spontaneous remissions may occur in adulthood. Hay fever often accompanies atopic asthma.

The acute attack is characterized by dyspnea usually associated with expiratory wheezing that may be heard without a stethoscope. Cough may be present but is usually not the predominant symptom. There is a small group of patients with asthma in whom paroxysmal cough may be the predominant symptom.

When asthma becomes prolonged, with severe intractable wheezing, it is known as status asthmaticus.

Appearance of a patient during attack of asthma

 

Evaluation of asthma severity

There is no agreement about how best to assess overall asthma severity. Assessment of asthma severity before or without treatment usually takes into account 3 factors, including 2 considered in the diagnosis:  symptoms, physiologic indicators of airway disease and asthma morbidity. Thus, some algorithm based on frequency and severity of symptoms (including the need for inhaled β2- agonist rescue therapy), degree of airflow obstruction and indices of morbidity (admissions to hospital, need for intubation, emergency room visits, time away from work or school, etc.) can be used to classify asthma severity (Table 1). Because asthma is controllable, the factors that define its severity before treatment become markers of its control in

the treated patient. The amount of anti-inflammatory medication required to control symptoms is often added to the severity algorithm. However, a case has been made that the primary measure of asthma severity in the treated patient should be the minimum anti-inflammatory medication required  to achieve ideal control

Laboratory Findings: The sputum is characteristically tenacious and mucoid, containing “plugs” and “spirals.” Eosinophils are seen microscopically. The differential blood count may show eosinophilia. In severe, acute bronchospasm, arterial hypoxemia may be present as a result of disturbed perfusion /ventilation relationships, alveolar hypoventilation, or functional right-to-left shunts.

 

X-Ray Findings: Chest films usually show no abnormalities. Reversible hyperexpansion may occur in severe paroxysms, or hyperexpansion may persist in long-standing cases. Transient, migratory pulmonary infiltrations may be present. Severe attacks are sometimes complicated by pneumothorax

 

Treatment

Medications used to treat asthma are generally divided  into 2 main categories: relievers and controllers. Relievers are best represented by the inhaled short-acting β2-agonists. These quick-acting bronchodilators are used to relieve acute intercurrent asthma symptoms, only on demand and at the minimum required dose and frequency.

Inhaled ipratropium bromide is less effective, but is occasionally used as a reliever medication in patients intolerant of short-acting β2-agonists. Controllers (or preventers) include anti-inflammatory medications, such as inhaled (and oral) glucocorticosteroids, leukotriene-receptor antagonists, and anti-allergic or inhaled nonsteroidal agents, such as cromoglycate and nedocromil. These agents are  generally taken regularly to control asthma and prevent exacerbations. Inhaled

glucocorticosteroids are the most effective agents in this category.

The controller group also includes some bronchodilators that are taken regularly in addition to inhaled glucocorticosteroids to help achieve and maintain asthma control.

These include the long-acting inhaled β2-agonists salmeterol and formoterol, which are the first choice in this category, as well as theophylline and ipratropium. The β2-agonists and ipratropium are considered of no significant benefit in reducing airway inflammation.

There is some evidence that theophylline may have immunomodulatory effects.

Asthma medications should be used at the minimum dose and frequency required to maintain acceptable asthma control; they should not be used as a substitute for proper control of the environment.

 

Diagnosis and evaluation of asthma in adults

Basic Recommendations

• Objective measurements are needed to confirm the diagnosis of asthma and to assess its severity in all

symptomatic patients using:

Spirometry: A 12% (preferably 15%) or greater (at least 180 mL) improvement in FEV1 from the baseline 15 minutes after use of an inhaled short-acting β2-agonist, a 20% (250 mL) improvement after 10–14 days of inhaled glucocorticosteroid or ingested prednisone when symptoms are stable or a 20% (250 mL) or greater

“spontaneous variability” is considered significant.

Peak expiratory flow (PEF): When spirometry and methacholine testing are unavailable, variable airflow obstruction (i.e., ideally 20% or greater diurnal variability) can be documented by home-measured PEF , although this method is not as sensitive or reliable as FEV1.

Airway hyperresponsiveness: Measurement of airway responsiveness to methacholine in specialized  pulmonary function laboratories may help to diagnose asthma.

• Appropriate allergy assessment is warranted in patients with asthma  and must be interpreted in light of the patient’s history.

• The primary measure of asthma severity in the treated patient should be the minimum therapy required

to achieve acceptable control Three main features must be considered in the diagnosis of asthma: symptoms, variable airflow obstruction and airway inflammation.  Airway inflammation is not yet readily tested in routine clinical practice and will not be considered further here. However, skin testing may be an adjunct to diagnosis and is discussed in this section.

Usage of bronchodilators

 

Variable airflow obstruction

Objective measurements are needed to confirm the diagnosis of asthma in all patients and to assess its  severity. Objective documentation of variable airflow obstruction can be obtained through measurement of FEV1, PEF or hyperresponsiveness to methacholine inhalation challenge.

Complex nebulizer

 

Forced expiratory volume in 1 second

Variable airflow obstruction can be illustrated by improvement in FEV1 15 minutes after an inhaled β2-agonist

or after a 7- to 14-day course of inhaled glucocorticosteroid or ingested prednisone. A 12% or greater improvement in FEV1 (i.e., at least 180 mL) from the baseline after administration of a β2-agonist is considered significant (i.e., outside the 95% confidence interval (CI) for repeatability in people without asthma). However, there are no data to confirm that a bronchodilator response outside this 95% CI is indicative of asthma, and some suggest basing diagnosis on a greater than 15% increase in FEV1.

Because there is greater variability in FEV1 over a longer time interval (days or weeks v. minutes), longer-term changes in FEV1, either without any specific therapeutic intervention or after glucocorticosteroids, must be greater than 20% (at least 250 mL). A trial of glucocorticosteroid involves maximizing the patient’s response to a bronchodilator and obtaining a baseline FEV1, then carrying out a follow-up measurement after a 2-week course of prednisone (taken at the rate of 30 to 40 mg/d) to determine significant response.

 

Peak expiratory flow

Home measurement of PEF may also be used to document variable airflow obstruction. Variable airflow  bstruction is confirmed when the 95% CI of the mean percentage difference between the highest and lowest of 4 PEF values (morning and afternoon, before and after using a bronchodilator) is > 12%. However, some recommend a 20% variability to confirm the diagnosis of asthma. The importance of appropriate technique and the limitations of PEF are discussed further under “Home monitoring.”

 

Airway hyperresponsiveness

In patients with normal airflow while resting, excessive using a methacholine inhalation challenge.8 This test

should be done when symptoms are present or have occurred within a few days. Usually the test is available only in specialized centres, which may limit its utility. This test should be made available to primary care  physicians who see most patients with mild asthma and where the measurement of responsiveness is most useful.9 Tests for airway responsiveness may give normal results in patients with glucocorticosteroid-

responsive cough due to eosinophilic bronchitis.

 

 

 

PNEUMONIA

Aetiology and pathogenesis. All authors who studied the aetiology of lobar pneumonia (pleuropneumonia, crupous pneumonia), discovered Frenkel pneumococci (mostly types I and II, less frequently types III and IV) in about 95 per cent of cases. Fridlaender diplobacillus, Pfeiffer’s bacillus, streptococcus, staphylococcus, etc. are found less fre­quently.

Lobar pneumonia occurs mostly after severe overcooling. The main portal of infection is bronchogenic, less frequently lymphogenic and haematogenic. Congestion in the lungs in cardiac failure, chronic and acute diseases of the upper airways, avitaminosis, overstrain and other factors promote the onset of pneumonia. Acute lobar pneumonia is relatively frequent in patients who had pneumonia in their past history (it re 30—40 per cent of cases which is another evidence of the  character of the disease).

Clinical picture. The onset of the disease. Typical acute N pneumonia begins abruptly with shaking chills, severe headache, and (to 39-40 °C). The chills usually persist for 1-3 hours, then pain »pp in the affected side; sometimes it may arise below the costal arch in domen to simulate acute appendicitis, hepatic colics, etc. (this usually curs in inflammation of the lower lobe of the lung, when the diaphie pleura becomes involved in the process). Cough is first dry and in 1 i\ rusty sputum is expectorated. The patient’s general condition is grave.

General examination shows hyperaemia of the cheeks, more pronounced on the affected side, dyspnoea, cyanosis, often herpes on the lips, nose; the affected side of the chest lags behind in the respiratory act. fremitus is slightly exaggerated over the affected lobe. Sounds ov» lungs are quite varied and depend on the distribution of the procctij stage of the disease, and other factors. At the onset of the disease, slm ed percussion sound can be heard over the affected lobe, often with panic effect because liquid and air are simultaneously contained ii alveoli; the vesicular breathing is decreased while bronchophony is hit I ed; the so-called initial crepitation (crepitus indux) is present.

Lobes of the lungs

 

The height of the disease (classified by pathologists as the red ami hepatization stages) is characterized by the grave general condition, ll] be explained not only by the size of the affected area of the lung which does not take part in respiration but also by general toxicosis. Respiration is accelerated and superficial (30—40 per min) and tachycardia is characteristic. Dullness is heard over the affected lnh( the lung; bronchial respiration is revealed by auscultation; vocal fremutus and bronchophony are exaggerated. Vocal fremitus is in some cases till absent or enfeebled (in combination with pleurisy with effusion, ami in massive acute lobar pneumonia, in which the inflammatory exudate in large bronchi); bronchial breathing is inaudible.

 

Classification of pneumonia:

community-acquired pneumonias;

Pneumonia in immunocompromised host

Nosocomial pneumonia

Pneumonia due to aspiration

Community-acquired pneumonia has become a major health problem throughout the world. Each year in the United States, an estimated 4 million cases occur. About 20% of these cases require hospitalization, the condition resulting in more than 65 million days of restricted activity overall. Mortality rates range from 1% to 5% in death. Many experts divide therapy for community-acquired pneumonia into two categories: inpatient and outpatient.

Problems in establishing a cause The etiology of community-acquired pneumonia is a long- and often-debated topic. Some researchers imply that outpatients contract different causative agents than do inpatients, while other investigators do not make major distinctions between the two categories. Other experts have attempted to elucidate the causes according to patient age. Even after examination of virtually every study completed on community-acquired pneumonia, it is extremely difficult to posit any useful probability of cause on the basis of age or outpatient versus inpatient setting.

The difficulty arises from a simple fact: in most patients with community-acquired pneumonia (about 98% of those treated as outpatients and 50% to 60% of those treated as inpatients), the causative organism is not known. Even in studies at academic centers where every effort is made to culture samples from all conceivable sites, the success rate in determining a cause is only about 50%. In most cases with an “established” cause, testing has been done on expectorated sputum, and this source of sample material always has the potential of contamination with upper-airway organisms. Correlation is not high between findings in expectorated sputum and findings in specimens from lower in the respiratory tract, obtained by bronchoscopy with a protected brush or by fine-needle or transtracheal aspiration.

A variety of organisms can cause community-acquired pneumonia. A review of studies during the past 20 years that included more than 100 subjects (total, >4,900 patients) reveals that the following are the most common pathogens(1): Streptococcus pneumoniae (9% to 75%; mean, 33%), Haemophilus influenzae (0 to 50%; mean, 10%), Legionella species (0 to 50%; mean, 7%), and Chlamydia pneumoniae (0 to 20%; mean, 5%) (1,3,5,8). Other organisms reported, io particular order, were Mycoplasma pneumoniae, other gram-positive organisms, gram-negative organisms, anaerobes, mycobacteria, fungi, and viruses. The incidence of so-called “atypical” (legionellal, chlamydial, and mycoplasmal) pneumonias is particularly difficult to ascertain, because diagnosis of these infections is usually made by serologic testing. This method indicates only whether there has been exposure to these organisms and an immunologic response; it does not necessarily establish that they are causative agents of the pneumonia under scrutiny.

Despite all the contradictory statistics on etiology, most investigators agree that S pneumoniae is the leading cause of community-acquired pneumonia in both inpatients and outpatients.

 

PNEUMOCOCCAL PNEUMONIA

Essentials of Diagnosis

• Sudden onset of shaking chills, fever, chest pain, and cough with rust-colored sputum.

• X-rays show infiltration, often lobar in distribu- tion, but sometimes patchy.

• Pneumococci are present in the sputum and often in the blood.

• Leukocytosis.

General Considerations

Pneumonia is an inflammatory process in lung parenchyma most commonly caused by infection. The consolidation of pneumonia must be differentiated from pulmonary infarction, atelectasis with bronchial obstruction, and congestive heart failure, but it may coexist with any of these conditions. The pneumococcus accounts for 50-80% of community-acquired bacterial pneumonias; types 1-9 and 12 are most commonly found in adults, whereas types 6, 14, 19, and 23 are most common in children. These bacteria frequently are in the normal flora of the respiratory tract. The development of pneumonia must therefore usually be attributed to an impairment of natural resis- tance. Conditions leading to aspiration of secretions include suppression of the cough or epiglottic reflex, impairment of upward migration of mucous sheets (propelled by cilia), and impairment of alveolar phagocyte function. Among conditions that predis- pose to pneumonia are viral respiratory diseases, mal- nutrition, exposure to cold, noxious gases, alcohol intoxication, depression of cerebral functions by drugs, and cardiac failure. Pulmonary consolidation may be in one or more lobes or may be patchy in distribution.

Clinical Findings

A. Symptoms and Signs: The onset is usually sudden, with shaking chills, “stabbing” chest pain (exaggerated by respiration but sometimes referred to the shoulder, abdomen, or flank), high fever, cough and “rusty” sputum, and occasionally vomiting. A history of recent upper respiratory illness can often be elicited.

The patient appears severely ill, with marked tachypnea (30-40/min) but no orthopnea. Respi- rations are grunting, nares flaring, and the patient often lies on the affected side in an attempt to splint the chest. Herpes simplex facial lesions are often present.

Initially, chest excursion is diminished on the involved side, breath sounds are suppressed, and fine inspiratory rales are heard. Later, the classic signs (absent breath sounds, dullness, etc) of consolidation appear. A pleural friction rub or abdominal distention may be present. During resolution of the pneumonia, the signs of consolidation are replaced by rales. Physical findings are often inconclusive, and repeated x-ray examination is helpful.

B. Laboratory Findings: Blood cultures are positive for pneumococci in 15-25% of cases early in the disease. In peripheral blood, leukocytosis (20-35 thousand/^L) is the rule, and a low white blood cell count carries a poorer prognosis.

Sputum must be examined by Gram’s stain and by culture. In the smears, the presence of many squamous epithelial cells suggests heavy contamination with saliva, and such specimens are of no value. Typical sputum from pneumococcal pneumonia contains many red and white cells (PMNs) and many pneumococci. If good sputum specimens are not obtainable, a trans- tracheal aspirate may reveal the causative agent, but this procedure is not without risk. A microscopic “quellung” reaction with pooled antiserum rapidly identifies pneumococci in fresh sputum.

C. X-Ray Findings (picture 1): Initially, there may be only a vague haziness across the involved part of the lung field. Later typical consolidation is well defined either in lobar or in patchy distribution. Fluid shadows in the costophrenic angles may appear before pleural exudate can be detected by physical examination. During reso lution of the consolidation, which may require 8-10 weeks, areas of radiolucency may appear, suggesting ‘ ‘pseudocavitation.”

 

Pulmonary infiltration of the right lower lung lobe

Relaxation of diaphragm in pneumonia

 

 

This chest x-ray in a patient with a cough and fever showed a white area (yellow circle) in the right lower lung. This is pneumonia

 

 

 

The patchy infiltrates bilaterally with the right greater than the left containing air bronchograms are characteristic of a bilateral pneumonic process which extends into the alveolar spaces.

 

Clinical Findings

A. Symptoms and Signs: The onset is usually insidious, with low-grade fever, cough, expectoration, and dyspnea that may become marked and lead to cyanosis. Physical findings are extremely variable and may not be impressive against a background of cardiac or pulmonary disease. The signs listed under Other Bacterial Pneumonias may also be present.

B. Laboratory Findings: The appearance of a greenish or yellowish (purulent) sputum should suggest a complicating pneumonia. Smears and cul- tures reveal a mixed flora, often including anaerobes. Predominant types should be noted. Leukocytosis is often absent in the aged and debilitated patient present- ing with a mixed infection.

C. X-Ray Findings: X-ray (Picture 3) shows patchy, irregular infiltrations, most commonly posterior and basal (in bedridden patients). Abscess formation may be observed. Careful interpretation will avoid confusion with shadows due to preexisting heart or lung disease.

Hypostatic pneumonia

 

Differential Diagnosis

Mixed bacterial pneumonias must be differ- entiated from tuberculosis, carcinoma, and other spe- cific mycotic, bacterial, and viral pulmonary infec- tions (to which they may be secondary).

Treatment

Clear the airway and correct hypoxia. Unless a probably significant etiologic agent can be identified, give one of the new cephalosporins (eg, cefotaxime, 12 g/d intravenously) as initial therapy. This will be modified according to clinical and laboratory results.

Prognosis

The prognosis depends upon the nature and sever- ity of the underlying pulmonary disease and varies with the predominating organism.

 

ASPIRATION PNEUMONIA

Aspiration pneumonia is an especially severe type of pneumonia, often with a high mortality rate. It results from the aspiration of gastric contents in addition to aspiration of upper respiratory flora in secretions. Important predisposing factors include impairment of the swallowing mechanism (eg, esopha- geal disease), inadequate cough reflex (eg, anesthesia, postoperative state, central nervous system disease, drug abuse), and impaired gastric emptying (eg, pyloric obstruction). Pulmonary injury is due in large part to the low pH (< 2.5) of gastric secretions.

Scattered areas of pulmonary edema and bron- chospasm occur, and the x-ray appearance (pictures 4-5) may be confused with that of pulmonary emboli, atelectasis, bronchopneumonia, and congestive heart failure.

Removal of aspirated material by catheter suction or bronchoscopy may be attempted, but this usually fails to remove all aspirate completely. Corticosteroids (eg, prednisone, 100 mg orally on the first or second day) may reduce the intensity of the inflammatory reaction to acidic gastric secretion, but the value of corticosteroids in the treatment of aspiration pneumo- nia is not proved, and they increase the risk of superinfection. Some aspiration pneumonias have no bacterial component, but in many others a mixed bacterial flora is involved. Antimicrobial drugs directed against the latter (eg, penicillin G plus an aminoglycoside or the best available cephalosporin) are sometimes adminis- tered without waiting for evidence of progressive pul- monary infection. In doing so, however, there is a risk of favoring the development of resistant mi- croorganisms. Therefore, administration of antimi- crobials should not continue without laboratory and clinical evidence of microbial infection. Assisted ventilation and supplementary oxygen are beneficial.

Abscess is forming after aspiration

 

 

Right sided aspiration pneumonia

Infection in the immunocompromised host

Viral Pneumonias

Viruses are a common cause of serious infections of the lower respiratory tract among immunocompromised patients. Pathogens most commonly implicated are the herpesviruses–herpes simplex, varicella-zoster, and cytomegalovirus. These viruses belong to the family Herpesviridae, which consists of large, enveloped, double-stranded DNA viruses.

Herpesviruses vary widely in their ability to infect different types of cells. Further, they share the common ability to establish lifelong latent infection. This latter aspect is of particular concern for seropositive immunosuppressed persons, whose immune systems may be unable to contain the virus in its latent form.

Other viruses that cause significant lower respiratory tract disease in immunocompromised patients include adenoviruses and measles virus.

Epidemiologic, etiologic, and clinical characteristics       
Immunocompromised patients are at particular risk for virus pneumonia. These include patients who are receiving cancer chemotherapy, those who are neutropenic, those infected with HIV, burn victims, those with congenital cell-mediated immunodeficiency, and those who are severely debilitated or malnourished as a result of prolonged hospitalization. Although the lung is often involved in disseminated HSV infection, disseminated disease seldom occurs among those with mucocutaneous HSV infections. Visceral dissemination develops in fewer than 10% of virus -seropositive transplant recipients with infection.

HSV pneumonia develops by two principal mechanisms. First, the presence of focal or multifocal infiltrates correlates with antecedent upper airway infection with virus. This pattern is most likely due to direct extension of viral infection from the upper to the lower respiratory tract, aspiration of infectious secretions, or reactivation of dormant HSV in vagal ganglia. Tracheitis or esophagitis and oral mucocutaneous lesions often precede development of pulmonary disease. Second, diffuse interstitial infiltrates may develop following viremia secondary to dissemination of HSV from genital or oral lesions or transfusion of HSV-infected blood. Early dissemination also may be reflected by other organ dysfunction, such as elevated liver enzyme levels.

The spectrum of respiratory diseases due to HSV infection ranges from oropharyngitis to membranous tracheobronchitis and diffuse or localized pneumonia. Usually the trachea and large bronchi are involved in creating a thick inflammatory membrane that can ultimately cause significant resistance to ventilation. Community-acquired pneumonia caused by HSV is uncommon, occurring usually only after a prolonged and complicated hospital stay.

Dyspnea and cough are the most common symptoms of HSV pneumonia. Fever, tachypnea, intractable wheezing, chest pain, and hemoptysis also occur. Cutaneous, genital, or oral lesions may herald pulmonary or disseminated disease.

Focal lesions on chest film begin as small nodules that are best seen in the periphery, away from normal vascular markings. As the disease progresses, the nodules may coalesce to form extensive infiltrates. HSV pneumonia may initially present as a focal or segmental pneumonia that has spread from upper airway lesions. However, it can ultimately extend to other areas of the lung, producing diffuse infiltrates similar to the pattern seen with viremic HSV infection.

Diagnosis
The diagnosis of virus pneumonia should be based on clinical suspicion, radiographic findings (picture 6), isolation of HSV from the lungs, and histologic findings of a necrotizing or hemorrhagic pneumonia. Since virus can be isolated from oropharyngeal secretions in 2% to 25% of normal hosts, positive sputum cultures are often difficult to interpret. The use of tracheal aspirates to bypass the upper respiratory tract can yield samples with significantly improved specificity. Bronchoscopy is especially useful for direct sampling of bronchial mucosal lesions and for obtaining bronchial brushings, washings, and biopsy specimens for histologic and cytologic examination. Scrapings from the base of ulcerated lesions can be examined with Wright or Giemsa stain for multinucleated giant cells and intranuclear inclusions. Specimens also can be examined by immunofluorescent staining with polyclonal- or monoclonal-specific antibodies or by electron microscopy. Appropriate viral cultures of mucosal lesions, blood, and respiratory secretions should always be obtained in cases of suspected herpetic pneumonia. Serologic assays are of little diagnostic use.

A-normal chest X –ray; B-right sided viral pneumonia

 

 

TREATMENT

Antibiotics. The Infectious Diseases Society of America recommends selecting from among the macrolides erythromycin, clarithromycin (Biaxin), and azithromycin (Zithromax); the fluoroquinolones levofloxacin (Levaquin), trovafloxacin mesylate (Trovan), grepafloxacin (Raxar), sparfloxacin (Zagam), and any other fluoroquinolone with enhanced activity against S pneumoniae; and (in patients between the ages of 17 and 40) doxycycline.

Duration of therapy
The preferred duration of therapy for community-acquired pneumonia is an unresolved issue, and surprisingly, applicable prospective studies are not available. The Infectious Diseases Society of America recommends 7 to 10 days. However, one study found that clinical outcomes were as good with a 3- to 5-day course of azithromycin as with the usual 7- to 10-day course of comparable antibiotics. Outcome research is urgently needed, because both cost and resistance could be minimized by using shorter courses of antibiotic therapy.

Antibiotic resistance

Development of bacterial resistance has been a significant problem related to antibiotic use. The frequency of resistance among community-acquired pathogens is increasing and has been linked to inappropriate use of antibiotics, such as the following:

To treat viral infections

To treat resistant organisms

For longer periods thaecessary

To treat a particular organism with a much-wider-spectrum agent thaeeded

Unnecessary use of antibiotics for viral illnesses is common and has led to increasing rates of antibiotic resistance among S pneumoniae and other community-acquired pathogens. In addition, boundaries between community and hospital environments are blurring, with potential negative consequences regarding resistance. Resistance genes occur in both pathogenic and commensal organisms to which people are exposed continually through food, the environment, and animals. The multitude of genetic mechanisms available for evolution and reassortment of antibiotic resistance genes virtually ensures that genes useful to survival of bacteria are rapidly disseminated.

Resistance to different antibiotics may vary by hospital and by locale, so the pattern of resistance in a geographic area of practice must be known to make a rational selection among antibiotics. Information on resistance patterns can be obtained from each hospital’s microbiology department and each state’s board of health.

Surveillance studies show almost exponential increases in penicillin-resistant S pneumoniae over the past 3 years in the United States. This trend is also true worldwide. If a location has considerable (eg, more than 5% to 10%) resistance to S pneumoniae, use of another antibiotic should be considered. High-level resistance to penicillin is associated with high-level resistance to macrolides, cephalosporins, and doxycycline as well. In contrast, to date, high-level resistance to the newer fluoroquinolones is less than 1%, and cross-resistance between these agents and penicillin has not, as yet, been recognized.

Minimizing resistance       
Theoretically, choosing doses of antibiotics on the basis of pharmacodynamics should increase eradication of bacteria and thus minimize development of resistance. Preventing antibiotic resistance through rapid DNA-based testing is an emerging and potentially promising biotechnologic tool. Additional new techniques under way to combat resistance include development of products that block bacterial adherence to tissues, design of drugs to fit model chemicals into the crystal structures of the catalytic sites of key enzymes from bacteria, and use of other highly sophisticated molecular biology tools.

More general solutions to the problem of increasing antibiotic resistance include intensive education of healthcare providers, enhanced education of patients, institution of mandatory surveillance programs, and funding of appropriate research.

Preventive measures

Virtually all experts on community-acquired pneumonia recommend use of polyvalent pneumococcal vaccine (Pneumovax 23, Pnu-Imune 23) in patients considered at increased risk. Some authors question the usefulness of pneumococcal vaccine, particularly in the elderly, but case-control and cohort studies have documented its efficacy. Prospective studies evaluating the impact of immunization on disease incidence, antibiotic resistance, and overall treatment cost are under way.

 

Clinical, instrumental and laboratory examinations of patients with chronic gastritis, stomach and duodenal peptic ulcer. Main symptoms and syndromes

 

 

 

Physiology of Gastric secretion. Determination of the gastric acid-secretion function. Determination of the gastric pepsin-secretion function.

The gastric epithelial lining consists of rugae that contain microscopic gastric pits, each branching into four or five gastric glands made up of highly specialized epithelial cells. The makeup of gastric glands varies with their anatomic location. Glands within the gastric cardia comprise <5% of the gastric gland area and contain mucous and endocrine cells. The majority of gastric glands (75%) are found within the oxyntic mucosa and contain mucous neck, parietal, chief, endocrine, and enterochromaffin cells. Pyloric glands contain mucous and endocrine cells (including gastrin cells) and are found in the antrum.

The parietal cell, also known as the oxyntic cell, is usually found in the neck, or isthmus, or the oxyntic gland. The resting, or unstimulated, parietal cell has prominent cytoplasmic tubulovesicles and intracellular canaliculi containing short microvilli along its apical surface. H+, K+-ATPase is expressed in the tubulovesicle membrane; upon cell stimulation, this membrane, along with apical membranes, transforms into a dense network of apical intracellular canaliculi containing long microvilli. Acid secretion, a process requiring high energy, occurs at the apical canalicular surface. Numerous mitochondria (30 to 40% of total cell volume) generate the energy required for secretion.

Gastroduodenal Mucosal Defense.  The gastric epithelium is under a constant assault by a series of endogenous noxious factors including HCl, pepsinogen/pepsin, and bile salts. In addition, a steady flow of exogenous substances such as medications, alcohol, and bacteria encounter the gastric mucosa. A highly intricate biologic system is in place to provide defense from mucosal injury and to repair any injury that may occur.

The mucosal defense system can be envisioned as a three-level barrier, composed of preepithelial, epithelial, and subepithelial elements. The first line of defense is a mucus-bicarbonate layer, which serves as a physicochemical barrier to multiple molecules including hydrogen ions. Mucus is secreted in a regulated fashion by gastroduodenal surface epithelial cells. It consists primarily of water (95%) and a mixture of lipids and glycoproteins. Mucin is the constituent glycoprotein that, in combination with phospholipids (also secreted by gastric mucous cells), forms a hydrophobic surface with fatty acids that extend into the lumen from the cell membrane. The mucous gel functions as a nonstirred water layer impeding diffusion of ions and molecules such as pepsin. Bicarbonate, secreted by surface epithelial cells of the gastroduodenal mucosa into the mucous gel, forms a pH gradient ranging from 1 to 2 at the gastric luminal surface and reaching 6 to 7 along the epithelial cell surface. Bicarbonate secretion is stimulated by calcium, prostaglandins, cholinergic input, and luminal acidification.

Surface epithelial cells provide the next line of defense through several factors, including mucus production, epithelial cell ionic transporters that maintain intracellular pH and bicarbonate production, and intracellular tight junctions. If the preepithelial barrier were breached, gastric epithelial cells bordering a site of injury can migrate to restore a damaged region (restitution). This process occurs independent of cell division and requires uninterrupted blood flow and an alkaline pH in the surrounding environment. Several growth factors including epidermal growth factor (EGF), transforming growth factor (TGF) a, and basic fibroblast growth factor (FGF) modulate the process of restitution. Larger defects that are not effectively repaired by restitution require cell proliferation. Epithelial cell regeneration is regulated by prostaglandins and growth factors such as EGF and TGF-a. In tandem with epithelial cell renewal, formation of new vessels (angiogenesis) within the injured microvascular bed occurs. Both FGF and vascular endothelial growth factor (VEGF) are important in regulating angiogenesis in the gastric mucosa.

An elaborate microvascular system within the gastric submucosal layer is the key component of the subepithelial defense/repair system. A rich submucosal circulatory bed provides HCO3-, which neutralizes the acid generated by parietal cell secretion of HCl. Moreover, this microcirculatory bed provides an adequate supply of micronutrients and oxygen while removing toxic metabolic by-products.

Prostaglandins play a central role in gastric epithelial defense/repair. The gastric mucosa contains abundant levels of prostaglandins. These metabolites of arachidonic acid regulate the release of mucosal bicarbonate and mucus, inhibit parietal cell secretion, and are important in maintaining mucosal blood flow and epithelial cell restitution. Prostaglandins are derived from esterified arachidonic acid, which is formed from phospholipids (cell membrane) by the action of phospholipase A2. A key enzyme that controls the rate-limiting step in prostaglandin synthesis is cyclooxygenase (COX), which is present in two isoforms (COX-1, COX-2), each having distinct characteristics regarding structure, tissue distribution, and expression. COX-1 is expressed in a host of tissues including the stomach, platelets, kidneys, and endothelial cells. This isoform is expressed in a constitutive manner and plays an important role in maintaining the integrity of renal function, platelet aggregation, and gastrointestinal mucosal integrity. In contrast, the expression of COX-2 is inducible by inflammatory stimuli, and it is expressed in macrophages, leukocytes, fibroblasts, and synovial cells. The beneficial effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on tissue inflammation are due to inhibition of COX-2; the toxicity of these drugs (e.g., gastrointestinal mucosal ulceration and renal dysfunction) is related to inhibition of the COX-1 isoform. The highly COX-2-selective NSAIDs have the potential to provide the beneficial effect of decreasing tissue inflammation while minimizing toxicity in the gastrointestinal tract.

Hydrochloric acid and pepsinogen are the two principal gastric secretory products capable of inducing mucosal injury. Acid secretion should be viewed as occurring under basal and stimulated conditions. Basal acid production occurs in a circadian pattern, with highest levels occurring during the night and lowest levels during the morning hours. Cholinergic input via the vagus nerve and histaminergic input from local gastric sources are the principal contributors to basal acid secretion. Stimulated gastric acid secretion occurs primarily in three phases based on the site where the signal originates (cephalic, gastric, and intestinal). Sight, smell, and taste of food are the components of the cephalic phase, which stimulates gastric secretion via the vagus nerve. The gastric phase is activated once food enters the stomach. This component of secretion is driven by nutrients (amino acids and amines) that directly stimulate the G cell to release gastrin, which in turn activates the parietal cell via direct and indirect mechanisms. Distention of the stomach wall also leads to gastrin release and acid production. The last phase of gastric acid secretion is initiated as food enters the intestine and is mediated by luminal distention and nutrient assimilation. A series of pathways that inhibit gastric acid production are also set into motion during these phases. The gastrointestinal hormone somatostatin is released from endocrine cells found in the gastric mucosa (D cells) in response to HCl. Somatostatin can inhibit acid production by both direct (parietal cell) and indirect mechanisms [decreased histamine release from enterochromaffin-like (ECL) cells and gastrin release from G cells]. Additional neural (central and peripheral) and hormonal (secretin, cholecystokinin) factors play a role in counterbalancing acid secretion. Under physiologic circumstances, these phases are occurring simultaneously.

The acid-secreting parietal cell is located in the oxyntic gland, adjacent to other cellular elements (ECL cell, D cell) important in the gastric secretory process. This unique cell also secretes intrinsic factor. The parietal cell expresses receptors for several stimulants of acid secretion including histamine (H2), gastrin (cholecystokinin B/gastrin receptor) and acetylcholine (muscarinic, M3). Each of these are G protein-linked, seven transmembrane-spanning receptors. Binding of histamine to the H2 receptor leads to activation of adenylate cyclase and an increase in cyclic AMP. Activation of the gastrin and muscarinic receptors results in activation of the protein kinase C/phosphoinositide signaling pathway. Each of these signaling pathways in turn regulates a series of downstream kinase cascades, which control the acid-secreting pump, H+, K+-ATPase. The discovery that different ligands and their corresponding receptors lead to activation of different signaling pathways explains the potentiation of acid secretion that occurs when histamine and gastrin or acetylcholine are combined. More importantly, this observation explains why blocking one receptor type (H2) decreases acid secretion stimulated by agents that activate a different pathway (gastrin, acetylcholine). Parietal cells also express receptors for ligands that inhibit acid production (prostaglandins, somatostatin, and EGF).

The enzyme H+, K+-ATPase is responsible for generating the large concentration of H+. It is a membrane-bound protein that consists of two subunits, a and b. The active catalytic site is found within the a subunit; the function of the b subunit is unclear. This enzyme uses the chemical energy of ATP to transfer H+ ions from parietal cell cytoplasm to the secretory canaliculi in exchange for K+. The H+,K+-ATPase is located within the secretory canaliculus and ionsecretory cytoplasmic tubulovesicles. The tubulovesicles are impermeable to K+, which leads to an inactive pump in this location. The distribution of pumps between the nonsecretory vesicles and the secretory canaliculus varies according to parietal cell. Under resting conditions, only 5% of pumps are within the secretory canaliculus, whereas upon parietal cell stimulation, tubulovesicles are immediately transferred to the secretory canalicular membrane, where 60 to 70% of the pumps are activated. Proton pumps are recycled back to the inactive state in cytoplasmic vesicles once parietal cell activation ceases.

The chief cell, found primarily in the gastric fundus, synthesizes and secretes pepsinogen, the inactive precursor of the proteolytic enzyme pepsin. The acid environment within the stomach leads to cleavage of the inactive precursor to pepsin and provides the low pH (<2.0) required for pepsin activity. Pepsin activity is significantly diminished at a pH of 4 and irreversibly inactivated and denatured at a pH of >7. Many of the secretagogues that stimulate acid secretion also stimulate pepsinogen release. The precise role of pepsin in the pathogenesis of PUD remains to be established.

Tongue in chronic gastritis

 

SECRETORY STUDIES

There are many methods of secretory studies of stomach function by gastric intubation: the acid output is measured in response to pentagastrin, to broth, histamine, insuline.

The acid output is measured in response to pentagastrin, a syntheric pentapeptide which exerts the biological effects of gastrin.  Preparation consists of an overnight fast. H₂-receptor antagonist drugs must be stopped for at least 48 hours before the test and omeprasole seven days before. The fasting contents of the stomach are aspirated and their volume measured; then the secretions are collected continuously for one hour. This is termed the ‘basal acid output’. Pentagastrin is then injected subcutaneously and the gastric secretions are collected for a further hour. The acid output in this hour is termed the ‘maximal acid output’.

3. Bacteriological and immunological investigation in the diseases of alimentary tract.

X-ray examination is less informative in gastritis

 

DIAGNOSIS FOR H.PYLORI

Tests for H. pylori can be divided into two groups: invasive tests, which require upper gastrointestinal endoscopy and are based on the analysis of gastric biopsy specimens, and noninvasive tests.

. Endoscopic examination in chronic gastritis: the devise, the principle of examination and the appearance of stomach mucosa in gastritis (hyperemia, erosions)

 

Invasive tests are preferred for (1) the initial management of dyspeptic patients, because the decision of whether or not to eradicate H. pylori depends on ulcer disease status, and (2) follow-up after treatment of patients with gastric ulceration to be certain that the ulcer was not malignant. Follow-up endoscopy should be performed at least 4 weeks after cessation of all anti-Helicobacter drugs, since at earlier points the H. pylori load may be low and tests may be falsely negative. The most convenient endoscopy-based test is the biopsy urease test, in which two antral biopsy specimens are put into a gel containing urea and an indicator. The presence of H. pylori urease elicits a color change, which often takes place within minutes but can require up to 24 h. Histologic examination of biopsy specimens is accurate, provided that a special stain (e.g., a modified Giemsa or silver stain) permitting optimal visualization of H. pylori is used. Histologic study yields additional information, including the degree and pattern of inflammation, atrophy, metaplasia, and dysplasia, although these details are rarely of clinical use. Microbiologic culture is most specific but may be insensitive due to difficulty with H. pylori isolation. Once cultured, the identity of H. pylori can be confirmed by its typical appearance on Gram’s stain and its positive reactions in oxidase, catalase, and urease tests. Antibiotic sensitivities also can be determined. Specimens containing H. heilmanii are only weakly positive in the biopsy urease test. The diagnosis is based on visualization of the characteristic long, tight spiral bacteria in histologic sections.

The simplest tests for H. pylori infection are serologic, involving the assessment of specific IgG levels in serum. The best of these tests are as accurate as other diagnostic methods, but many commercial tests, especially rapid office tests, perform poorly. In quantitative tests, a defined drop in antibody titer between matched serum samples taken before and 6 months after treatment (no sooner because of the slow decline in antibody titer) accurately indicates that H. pylori infection has been eradicated. The other major noninvasive tests are the 13C and 14C urea breath tests. In these simple tests, the patient drinks a labeled urea solution and then blows into a tube. The urea is labeled with either the nonradioactive isotope 13C or a minute dose of the radioactive isotope 14C (which exposes the patient to less radiation than a standard chest x-ray). If H. pylori urease is present, the urea is hydrolyzed and labeled carbon dioxide is detected in breath samples. Unlike serologic tests, urea breath tests can be used to assess the outcome of treatment 1 month after its completion and thus may replace endoscopy for this purpose in the follow-up of duodenal ulcer patients. As for endoscopic tests, all anti-Helicobacter drugs should be avoided in this period or the test may be falsely negative.

Chronic diarrhea in a tropical environment is most often caused by infectious agents including G. lamblia, Yersinia enterocolitica, C. difficile, Cryptosporidium parvum, and Cyclospora cayetanensis, among other organisms. Tropical sprue should not be entertained as a possible diagnosis until the presence of cysts and trophozoites has been excluded in three stool samples.

CLINICAL FEATURES History  Abdominal pain is common to many gastrointestinal disorders, including DU and GU, but has a poor predictive value for the presence of either DU or GU. Up to 10% of patients with NSAID-induced mucosal disease can present with a complication (bleeding, perforation, and obstruction) without antecedent symptoms. Despite this poor correlation, a careful history and physical examination are essential components of the approach to a patient suspected of having peptic ulcers.

 

Epigastric pain described as a burning or gnawing discomfort can be present in both DU and GU. The discomfort is also described as an ill-defined, aching sensation or as hunger pain. The typical pain pattern in DU occurs 90 min to 3 h after a meal and is frequently relieved by antacids or food. Pain that awakes the patient from sleep (between midnight and 3 A.M.) is the most discriminating symptom, with two-thirds of DU patients describing this complaint. Unfortunately, this symptom is also present in one-third of patients with NUD. The pain pattern in GU patients may be different from that in DU patients, where discomfort may actually be precipitated by food. Nausea and weight loss occur more commonly in GU patients. In the United States, endoscopy detects ulcers in <30% of patients who have dyspepsia. Despite this, 40% of these individuals with typical ulcer symptoms had an ulcer crater, and 40% had gastroduodenitis on endoscopic examination.

The mechanism for development of abdominal pain in ulcer patients is unknown. Several possible explanations include acid-induced activation of chemical receptors in the duodenum, enhanced duodenal sensitivity to bile acids and pepsin, or altered gastroduodenal motility.

Variation in the intensity or distribution of the abdominal pain, as well as the onset of associated symptoms such as nausea and/or vomiting, may be indicative of an ulcer complication. Dyspepsia that becomes constant, is no longer relieved by food or antacids, or radiates to the back may indicate a penetrating ulcer (pancreas). Sudden onset of severe, generalized abdominal pain may indicate perforation. Pain worsening with meals, nausea, and vomiting of undigested food suggest gastric outlet obstruction. Tarry stools or coffee ground emesis indicate bleeding.

 Criteria for diagnosis of the gastritis.

 A-gastritis.

 B-gastritis.

 C-gastritis.

The term gastritis should be reserved for histologically documented inflammation of the gastric mucosa. Gastritis is not the mucosal erythema seen during endoscopy and is not interchangeable with “dyspepsia.” The etiologic factors leading to gastritis are broad and heterogeneous. Gastritis has been classified based on time course (acute vs. chronic), histologic features, and anatomic distribution or proposed pathogenic mechanism .

The correlation between the histologic findings of gastritis, the clinical picture of abdominal pain or dyspepsia, and endoscopic findings noted on gross inspection of the gastric mucosa is poor. Therefore, there is no typical clinical manifestation of gastritis.

Acute Gastritis. The most common causes of acute gastritis are infectious. Acute infection with H. pylori induces gastritis. However, H. pylori acute gastritis has not been extensively studied. Reported as presenting with sudden onset of epigastric pain, nausea, and vomiting, limited mucosal histologic studies demonstrate a marked infiltrate of neutrophils with edema and hyperemia. If not treated, this picture will evolve into one of chronic gastritis. Hypochlorhydria lasting for up to 1 year may follow acute H. pylori infection.

The highly acidic gastric environment may be one reason why infectious processes of the stomach are rare. Bacterial infection of the stomach or phlegmonous gastritis is a rare potentially life-threatening disorder, characterized by marked and diffuse acute inflammatory infiltrates of the entire gastric wall, at times accompanied by necrosis. Elderly individuals, alcoholics, and AIDS patients may be affected. Potential iatrogenic causes include polypectomy and mucosal injection with India ink. Organisms associated with this entity include streptococci, staphylococci, Escherichia coli, Proteus, and Haemophilus. Failure of supportive measures and antibiotics may result in gastrectomy.

Chronic Gastritis. Chronic gastritis is identified histologically by an inflammatory cell infiltrate consisting primarily of lymphocytes and plasma cells, with very scant neutrophil involvement. Distribution of the inflammation may be patchy, initially involving superficial and glandular portions of the gastric mucosa. This picture may progress to more severe glandular destruction, with atrophy and metaplasia. Chronic gastritis has been classified according to histologic characteristics. These include superficial atrophic changes and gastric atrophy.

The early phase of chronic gastritis is superficial gastritis. The inflammatory changes are limited to the lamina propria of the surface mucosa, with edema and cellular infiltrates separating intact gastric glands. Additional findings may include decreased mucus in the mucous cells and decreased mitotic figures in the glandular cells. The next stage is atrophic gastritis. The inflammatory infiltrate extends deeper into the mucosa, with progressive distortion and destruction of the glands. The final stage of chronic gastritis is gastric atrophy. Glandular structures are lost; there is a paucity of inflammatory infiltrates. Endoscopically the mucosa may be substantially thin, permitting clear visualization of the underlying blood vessels.   

 

Video: chronic gastritis

 

Gastric glands may undergo morphologic transformation in chronic gastritis. Intestinal metaplasia denotes the conversion of gastric glands to a small intestinal phenotype with small-bowel mucosal glands containing goblet cells. The metaplastic changes may vary in distribution from patchy to fairly extensive gastric involvement. Intestinal metaplasia is an important predisposing factor for gastric cancer.

Chronic gastritis is also classified according to the predominant site of involvement. Type A refers to the body-predominant form (autoimmune) and type B is the central-predominant form (H. pylori-related). This classification is artificial in view of the difficulty in distinguishing these two entities. The term AB gastritis has been used to refer to a mixed antral/body picture.

Type A Gastritis. The less common of the two forms involves primarily the fundus and body, with antral sparing. Traditionally, this form of gastritis has been associated with pernicious anemia in the presence of circulating antibodies against parietal cells and intrinsic factor; thus it is also called autoimmune gastritis. H. pylori infection can lead to a similar distribution of gastritis. The characteristics of an autoimmune picture are not always present.

Antibodies to parietal cells have been detected in >90% of patients with pernicious anemia and in up to 50% of patients with type A gastritis. Anti-parietal cell antibodies are cytotoxic for gastric mucous cells. The parietal cell antibody is directed against H+,K+-ATPase. T cells are also implicated in the injury pattern of this form of gastritis.

Parietal cell antibodies and atrophic gastritis are observed in family members of patients with pernicious anemia. These antibodies are observed in up to 20% of individuals over age 60 and in ~20% of patients with vitiligo and Addison’s disease. About half of patients with pernicious anemia have antibodies to thyroid antigens, and about 30% of patients with thyroid disease have circulating anti-parietal cell antibodies. Anti-intrinsic factor antibodies are more specific than parietal cell antibodies for type A gastritis, being present in ~40% of patients with pernicious anemia. Another parameter consistent with this form of gastritis being autoimmune in origin is the higher incidence of specific familial histocompatibility haplotypes such as HLA-B8 and -DR3.

The parietal cell-containing gastric gland is preferentially targeted in this form of gastritis, and achlorhydria results. Parietal cells are the source of intrinsic factor, lack of which will lead to vitamin B12 deficiency and its sequelae (megaloblastic anemia, neurologic dysfunction).

Gastric acid plays an important role in feedback inhibition of gastrin release from G cells. Achlorhydria, coupled with relative sparing of the antral mucosa (site of G cells), leads to hypergastrinemia. Gastrin levels can be markedly elevated (>500 pg/mL) in patients with pernicious anemia. ECL cell hyperplasia with frank development of gastric carcinoid tumors may result from gastrin trophic effects. The role of gastrin in carcinoid development is confirmed by the observation that antrectomy leads to regression of these lesions. Hypergastrinemia and achlorhydria may also be seen in non-pernicious anemia-associated type A gastritis.

Type B gastritis. Type B, or antral-predominant, gastritis is the more common form of chronic gastritis. H. pylori infection is the cause of this entity. Although described as “antral-predominant,” this is likely a misnomer in view of studies documenting the progression of the inflammatory process towards the body and fundus of infected individuals. The conversion to a pan-gastritis is time-dependent-estimated to require 15 to 20 years. This form of gastritis increases with age, being present in up to 100% of people over age 70. Histology improves after H. pylori eradication. The number of H. pylori organisms decreases dramatically with progression to gastric atrophy, and the degree of inflammation correlates with the level of these organisms. Early on, with antral-predominant findings, the quantity of H. pylori is highest and a dense chronic inflammatory infiltrate of the lamina propria is noted accompanied by epithelial cell infiltration with polymorphonuclear leukocytes.

Multifocal atrophic gastritis, gastric atrophy with subsequent metaplasia, has been observed in chronic H. pylori-induced gastritis. This may ultimately lead to development of gastric adenocarcinoma. H. pylori infection is now considered an independent risk factor for gastric cancer. Worldwide epidemiologic studies have documented a higher incidence of H. pylori infection in patients with adenocarcinoma of the stomach as compared to control subjects. Seropositivity for H. pylori is associated with a three- to sixfold increased risk of gastric cancer. This risk may be as high as ninefold after adjusting for the inaccuracy of serologic testing in the elderly. The mechanism by which H. pylori infection leads to cancer is unknown. However, eradication of H. pylori as a general preventative measure for gastric cancer is not recommended.

Infection with H. pylori is also associated with development of a low grade B cell lymphoma, gastric MALT lymphoma. The chronic T cell stimulation caused by the infection leads to production of cytokines that promote the B cell tumor. Tumor growth remains dependent upon the presence of H. pylori in that its eradication is often associated with complete regression of the tumor. The tumor may take more than a year to regress after treating the infection. Such patients should be followed by EUS every 2 to 3 months. If the tumor is stable or decreasing in size, no other therapy is necessary. If the tumor grows, it may have become a high-grade B cell lymphoma. When the tumor becomes a high-grade aggressive lymphoma histologically, it loses responsiveness to H. pylori eradication.

H.pylori

 

 

 

 

 

Physical Examination Epigastric tenderness is the most frequent finding in patients with GU or DU. Pain may be found to the right of the midline in 20% of patients. Unfortunately, the predictive value of this finding is rather low. Physical examination is critically important for discovering evidence of ulcer complication. Tachycardia and orthostasis suggest dehydration secondary to vomiting or active gastrointestinal blood loss. A severely tender, boardlike abdomen suggests a perforation. Presence of a succussion splash indicates retained fluid in the stomach, suggesting gastric outlet obstruction.

 

Diagnostic Evaluation. In view of the poor predictive value of abdominal pain for the presence of a gastroduodenal ulcer and the multiple disease processes that can mimic this disease, the clinician is often confronted with having to establish the presence of an ulcer. Documentation of an ulcer requires either a radiographic (barium study) or an endoscopic procedure.

Barium examination of the stomach and duodenum reveals an ulcer, 1 cm in diameter (arrow), in the duodenal bulb with radiating folds.

Barium studies of the proximal gastrointestinal tract are still commonly used as a first test for documenting an ulcer. The sensitivity of older single-contrast barium meals for detecting a DU is as high as 80%, with a double-contrast study providing detection rates as high as 90%. Sensitivity for detection is decreased in small ulcers (<0.5 cm), presence of previous scarring, or in postoperative patients. A DU appears as a well-demarcated crater, most often seen in the bulb. A GU may represent benign or malignant disease. Typically, a benign GU also appears as a discrete crater with radiating mucosal folds originating from the ulcer margin. Ulcers >3 cm in size or those associated with a mass are more often malignant. Unfortunately, up to 8% of GUs that appear to be benign by radiographic appearance are malignant by endoscopy or surgery. Radiographic studies that show a GU must be followed by endoscopy and biopsy.

Endoscopy provides the most sensitive and specific approach for examining the upper gastrointestinal tract. In addition to permitting direct visualization of the mucosa, endoscopy facilitates photographic documentation of a mucosal defect and tissue biopsy to rule out malignancy (GU) or H. pylori. Endoscopic examination is particularly helpful in identifying lesions too small to detect by radiographic examination, for evaluation of atypical radiographic abnormalities, or to determine if an ulcer is a source of blood loss.

 

 

 

 

 

Treatment in chronic gastritis is aimed at the sequelae and not the underlying inflammation. Patients with pernicious anemia will require parenteral vitamin B12 supplementation on a long-term basis. Eradication of H. pylori is not routinely recommended unless PUD or a low-grade MALT lymphoma is present.

Miscellaneous Forms of Gastritis. Lymphocytic gastritis is characterized histologically by intense infiltration of the surface epithelium with lymphocytes. The infiltrative process is primarily in the body of the stomach and consists of mature T cells and plasmacytes. The etiology of this form of chronic gastritis is unknown. It has been described in patients with celiac sprue, but whether there is a common factor associating these two entities is unknown. No specific symptoms suggest lymphocytic gastritis. A subgroup of patients has thickened folds noted on endoscopy. These folds are often capped by small nodules that contain a central depression or erosion; this form of the disease is called varioliform gastritis. H. pylori probably plays no significant role in lymphocytic gastritis. Therapy with glucocorticoids or sodium cromoglycate has obtained unclear results.

 

Marked eosinophilic infiltration involving any layer of the stomach (mucosa, muscularis propria, and serosa) is characteristic of eosinophilic gastritis. Affected individuals will often have circulating eosinophilia with clinical manifestation of systemic allergy. Involvement may range from isolated gastric disease to diffuse eosinophilic gastroenteritis. Antral involvement predominates, with prominent edematous folds being observed on endoscopy. These prominent antral folds can lead to outlet obstruction. Patients can present with epigastric discomfort, nausea, and vomiting. Treatment with glucocorticoids has been successful.

Several systemic disorders may be associated with granulomatous gastritis. Gastric involvement has been observed in Crohn’s disease. Involvement may range from granulomatous infiltrates noted only on gastric biopsies to frank ulceration and stricture formation. Gastric Crohn’s disease usually occurs in the presence of small-intestinal disease. Several rare infectious processes can lead to granulomatous gastritis, including histoplasmosis, candidiasis, syphilis, and tuberculosis. Other unusual causes of this form of gastritis include sarcoidosis, idiopathic granulomatous gastritis, and eosinophilic granulomas involving the stomach. Establishing the specific etiologic agent in this form of gastritis can be difficult, at times requiring repeat endoscopy with biopsy and cytology. Occasionally, a surgically obtained full-thickness biopsy of the stomach may be required to exclude malignancy.

Treatment of the ulcer diseases.

Before the discovery of H. pylori, the therapy of PUD disease was centered on the old dictum by Schwartz of “no acid, no ulcer.” Although acid secretion is still important in the pathogenesis of PUD, eradication of H. pylori and therapy/prevention of NSAID-induced disease is the mainstay.

 

 

 

 

Acid Neutralizing/Inhibitory Drugs

Antacids  Before we understood the important role of histamine in stimulating parietal cell activity, neutralization of secreted acid with antacids constituted the main form of therapy for peptic ulcers. They are now rarely, if ever, used as the primary therapeutic agent but instead are often used by patients for symptomatic relief of dyspepsia. The most commonly used agents are mixtures of aluminum hydroxide and magnesium hydroxide. Aluminum hydroxide can produce constipation and phosphate depletion; magnesium hydroxide may cause loose stools. Many of the commonly used antacids (e.g., Maalox, Mylanta) have a combination of both aluminum and magnesium hydroxide in order to avoid these side effects. The magnesium-containing preparation should not be used in chronic renal failure patients because of possible hypermagnesemia, and aluminum may cause chronic neurotoxicity in these patients.

Calcium carbonate and sodium bicarbonate are potent antacids with varying levels of potential problems. The long-term use of calcium carbonate (converts to calcium chloride in the stomach) can lead to milk-alkali syndrome (hypercalcemia, hyperphosphatemia with possible renal calcinosis and progression to renal insufficiency). Sodium bicarbonate may induce systemic alkalosis.

H2 Receptor antagonists  Four of these agents are presently available (cimetidine, ranitidine, famotidine, and nizatidine), and their structures share homology with histamine. Although each has different potency, all will significantly inhibit basal and stimulated acid secretion to comparable levels when used at therapeutic doses. Moreover, similar ulcer-healing rates are achieved with each drug when used at the correct dosage. Presently, this class of drug is often used for treatment of active ulcers (4 to 6 weeks) in combination with antibiotics directed at eradicating H. pylori.

Cimetidine was the first H2 receptor antagonist used for the treatment of acid peptic disorders. The initial recommended dosing profile for cimetidine was 300 mg four times per day. Subsequent studies have documented the efficacy of using 800 mg at bedtime for treatment of active ulcer, with healing rates approaching 80% at 4 weeks. Cimetidine may have weak antiandrogenic side effects resulting in reversible gynecomastia and impotence, primarily in patients receiving high doses for prolonged periods of time (months to years, as in ZES). In view of cimetidine’s ability to inhibit cytochrome P450, careful monitoring of drugs such as warfarin, phenytoin, and theophylline is indicated with long-term usage. Other rare reversible adverse effects reported with cimetidine include confusion and elevated levels of serum aminotransferases, creatinine, and serum prolactin. Ranitidine, famotidine, and nizatidine are more potent H2 receptor antagonists than cimetidine. Each can be used once a day at bedtime. Comparable nighttime dosing regimens are ranitidine, 300 mg, famotidine, 40 mg, and nizatidine, 300 mg.

Additional rare, reversible systemic toxicities reported with H2 receptor antagonists include pancytopenia, neutropenia, anemia, and thrombocytopenia, with a prevalence rate varying from 0.01 to 0.2%. Cimetidine and rantidine (to a lesser extent) can bind to hepatic cytochrome P450, whereas the newer agents, famotidine and nizatidine, do not.

Proton pump (H+,K+-ATPase) inhibitors  Omeprazole, lansoprazole, and the newest additions, rabeprazole and pantoprazole, are substituted benzimidazole derivatives that covalently bind and irreversibly inhibit H+,K+-ATPase. These are the most potent acid inhibitory agents available. Omeprazole and lansoprazole are the proton pump inhibitors (PPIs) that have been used for the longest time. Both are acid labile and are administered as enteric-coated granules in a sustained-release capsule that dissolves within the small intestine at a pH of 6. These agents are lipophilic compounds; upon entering the parietal cell, they are protonated and trapped within the acid environment of the tubulovesicular and canalicular system. These agents potently inhibit all phases of gastric acid secretion. Onset of action is rapid, with a maximum acid inhibitory effect between 2 and 6 h after administration and duration of inhibition lasting up to 72 to 96 h. With repeated daily dosing, progressive acid inhibitory effects are observed, with basal and secretagogue-stimulated acid production being inhibited by >95% after 1 week of therapy. The half-life of PPIs is approximately 18 h, thus it can take between 2 and 5 days for gastric acid secretion to return to normal levels once these drugs have been discontinued. Because the pumps need to be activated for these agents to be effective, their efficacy is maximized if they are administered before a meal (e.g., in the morning before breakfast). Standard dosing for omeprazole and lansoprazole is 20 mg and 30 mg once per day, respectively. Mild to moderate hypergastrinemia has been observed in patients taking these drugs. Carcinoid tumors developed in some animals given the drugs preclinically; however, extensive experience has failed to demonstrate gastric carcinoid tumor development in humans. Serum gastrin levels return to normal levels within 1 to 2 weeks after drug cessation. As with any agent that leads to significant hypochlorhydria, PPIs may interfere with absorption of drugs such as ketoconazole, ampicillin, iron, and digoxin. Hepatic cytochrome P450 can be inhibited by these agents, but the overall clinical significance of this observation is not definitely established. Caution should be taken when using warfarin, diazepam, and phenytoin concomitantly with PPIs.

Cytoprotective Agents: Sucralfate  Sucralfate is a complex sucrose salt in which the hydroxyl groups have been substituted by aluminum hydroxide and sulfate. This compound is insoluble in water and becomes a viscous paste within the stomach and duodenum, binding primarily to sites of active ulceration. Sucralfate may act by several mechanisms. In the gastric environment, aluminum hydroxide dissociates, leaving the polar sulfate anion, which can bind to positively charged tissue proteins found within the ulcer bed, and providing a physicochemical barrier impeding further tissue injury by acid and pepsin. Sucralfate may also induce a trophic effect by binding growth factors such as EGF, enhance prostaglandin synthesis, stimulate mucous and bicarbonate secretion, and enhance mucosal defense and repair. Toxicity from this drug is rare, with constipation being the most common one reported (2 to 3%). It should be avoided in patients with chronic renal insufficiency to prevent aluminum-induced neurotoxicity. Hypophosphatemia and gastric bezoar formation have also been rarely reported. Standard dosing of sucralfate is 1 g four times per day.

Bismuth-containing preparations  Sir William Osler considered bismuth-containing compounds the drug of choice for treating PUD. The resurgence in the use of these agents is due to their effect against H. pylori. Colloidal bismuth subcitrate (CBS) and bismuth subsalicylate (BSS, Pepto-Bismol) are the most widely used preparations. The mechanism by which these agents induce ulcer healing is unclear. Potential mechanisms include ulcer coating; prevention of further pepsin/HCl-induced damage; binding of pepsin; and stimulation of prostaglandins, bicarbonate, and mucous secretion. Adverse effects with short-term usage are rare with bismuth compounds. Long-term usage with high doses, especially with the avidly absorbed CBS, may lead to neurotoxicity. These compounds are commonly used as one of the agents in an anti-H. pylori regimen.

Prostaglandin analogues  In view of their central role in maintaining mucosal integrity and repair, stable prostaglandin analogues were developed for the treatment of PUD. The prostaglandin E1 derivative misoprostal is the only agent of this class approved by the U.S. Food and Drug Administration for clinical use in the prevention of NSAID-induced gastroduodenal mucosal injury. The mechanism by which this rapidly absorbed drug provides its therapeutic effect is through enhancement of mucosal defense and repair. Prostaglandin analogues enhance mucous bicarbonate secretion, stimulate mucosal blood flow, and decrease mucosal cell turnover. The most common toxicity noted with this drug is diarrhea (10 to 30% incidence). Other major toxicities include uterine bleeding and contractions; misoprostal is contraindicated in women who may be pregnant, and women of childbearing age must be made clearly aware of this potential drug toxicity. The standard therapeutic dose is 200 ug four times per day.

Miscellaneous drugs. A number of drugs aimed at treating acid peptic disorders have been developed over the years. In view of their limited utilization in the United States, if any, they will only be listed briefly. Anticholinergics, designed to inhibit activation of the muscarinic receptor in parietal cells, met with limited success due to their relatively weak acid-inhibiting effect and significant side effects (dry eyes, dry mouth, urinary retention). Tricyclic antidepressants have been suggested by some, but again the toxicity of these agents in comparison to the safe, effective drugs already described, precludes their utility. Finally, the licorice extract carbenoxolone has aldosterone-like side effects with fluid retention and hypokalemia, making it an undesirable therapeutic option.