Respiratory disease 5

Chronic obstructive pulmonary diseas

Chronic obstructive pulmonary disease (COPD) refers broadly to a group of conditions that cause irreversible respiratory impairment by increasing obstruction to airflow through the bronchi of the lungs. This condition occurs most commonly in current or former regular cigarette smokers and is present in moderate to severe form in 80 million people worldwide. In 2005 the World Health Organization reported that 5 percent of all deaths around the world were due to COPD.

COPD typically has two components which may be present to varying degrees: chronic obstructive bronchitis and pulmonary emphysema. Individuals who predominantly have emphysema experience symptoms that differ in detail from those who predominantly have chronic bronchitis; however, both disorders contribute to shortness of breath during exercise and to general disability.

 

Chronic bronchitis

The chronic cough and sputum production of chronic bronchitis were once dismissed as nothing more than “smoker's cough,” without serious implications. But the striking increase in mortality from chronic bronchitis and emphysema that occurred after World War II in all Western countries indicated that the long-term consequences of chronic bronchitis could be serious. This common condition is characteristically produced by cigarette smoking. After about 15 years of smoking, significant quantities of mucus are coughed up in the morning, due to an increase in size and number of mucous glands lining the large airways. The increase in mucous cells and the development of chronic bronchitis may be enhanced by breathing polluted air (particularly in areas of uncontrolled coal burning). The changes are not confined to large airways, though these produce the dominant symptom of chronic sputum production. Changes in smaller bronchioles lead to obliteration and inflammation around their walls. All these changes together, if severe enough, can lead to disturbances in the distribution of ventilation and perfusion in the lung, causing a fall in arterial oxygen tension and a rise in carbon dioxide tension. By the time this occurs, the ventilatory ability of the patient, as measured by the velocity of a single forced expiration, is severely compromised; in a cigarette smoker, ventilatory ability has usually been declining rapidly for some years. It is not clear what determines the severity of these changes. Some people can smoke for decades without evidence of significant airway changes, whereas others may experience severe respiratory compromise after 15 years or less of exposure.

 

Pulmonary emphysema

This irreversible disease consists of destruction of alveolar walls. It occurs in two forms, centrilobular emphysema, in which the destruction begins at the centre of the lobule, and panlobular (or panacinar) emphysema, in which alveolar destruction occurs in all alveoli within the lobule simultaneously. In advanced cases of either type, this distinction can be difficult to make. Centrilobular emphysema is the form most commonly seen in cigarette smokers, and some observers believe it is confined to smokers. It is more common in the upper lobes of the lung (for unknown reasons). By the time the disease has developed, some impairment of ventilatory ability has probably occurred. Panacinar emphysema may also occur in smokers, but it is the type of emphysema characteristically found in the lower lobes of patients with a deficiency in the antiproteolytic enzyme known as alpha-1 antitrypsin. Like centrilobular emphysema, panacinar emphysema causes ventilatory limitation and eventually blood gas changes. Other types of emphysema, of less importance than the two major varieties, may develop along the dividing walls of the lung (septal emphysema) or in association with scars from other lesions.

A major step forward in understanding the development of emphysema followed the identification, in Sweden, of families with an inherited deficiency of alpha-1 antitrypsin, an enzyme essential for lung integrity. Members of affected families who smoked cigarettes commonly developed panacinar emphysema in the lower lobes, unassociated with chronic bronchitis but leading to ventilatory impairment and disability. Intense investigation of this major clue led to the “protease-antiprotease” theory of emphysema. It is postulated that cigarette smoking either increases the concentration of protease enzymes released in the lung (probably from white blood cells) or impairs the lung's defenses against these enzymes or both. Although many details of the essential biochemical steps at the cellular level remain to be clarified, this represents a major step forward in understanding a disease whose genesis was once ascribed to overinflation of the lung (like overdistending a bicycle tire).

Chronic bronchitis and emphysema are distinct processes. Both may follow cigarette smoking, however, and they commonly occur together, so determination of the extent of each during life is not easy. In general, significant emphysema is more likely if ventilatory impairment is constant, gas transfer in the lung (usually measured with carbon monoxide) is reduced, and the lung volumes are abnormal. Development of high-resolution computerized tomography has greatly improved the accuracy of detection of emphysema. Some people with emphysema suffer severe incapacity before the age of 60; thus, emphysema is not a disease of the elderly only. An accurate diagnosis can be made from pulmonary function tests, careful radiological examination, and a detailed history. The physical examination of the chest reveals evidence of airflow obstruction and overinflation of the lung, but the extent of lung destruction cannot be reliably gauged from these signs, and therefore laboratory tests are required. (For more information about the methods of detection of lung diseases, see above Methods of investigation.)

The prime symptom of emphysema, which is always accompanied by a loss of elasticity of the lung, is shortness of breath, initially on exercise only, and associated with loss of normal ventilatory ability and increased obstruction to expiratory airflow. The expiratory airflow from a maximum inspiration is measured by the “forced expiratory volume in one second,” or FEV1, and is a predictor of survival of emphysema. Chronic hypoxemia (lowered oxygen tension) often occurs in severe emphysema and leads to the development of increased blood pressure in the pulmonary circulation, which in turn leads to failure of the right ventricle of the heart. The symptoms and signs of right ventricular failure include swelling of the ankles (edema) and engorgement of the neck veins. These are portents of advanced lung disease in this condition. The hypoxemia may also lead to an increase in total hemoglobin content and in the number of circulating red blood cells, as well as to psychological depression, irritability, loss of appetite, and loss of weight. Thus, the advanced syndrome of chronic obstructive lung disease may cause such shortness of breath that the afflicted person has difficulty walking, talking, and dressing, as well as numerous other symptoms.

The slight fall in ventilation that normally accompanies sleep may exacerbate the failure of lung function in chronic obstructive lung disease, leading to a further fall in arterial oxygen tension and an increase in pulmonary arterial pressure.

Unusual forms of emphysema also occur. In one form the disease appears to be unilateral, involving one lung only and causing few symptoms. Unilateral emphysema is believed to result from a severe bronchiolitis in childhood that prevented normal maturation of the lung on that side. “Congenital lobar emphysema” of infants is usually a misnomer, since there is no alveolar destruction. It is most commonly caused by overinflation of a lung lobe due to developmental malformation of cartilage in the wall of the major bronchus. Such lobes may have to be surgically removed to relieve the condition. Bullous emphysema can occur in one or both lungs and is characterized by the presence of one or several abnormally large air spaces surrounded by relatively normal lung tissue. This disease most commonly occurs between the ages of 15 and 30 and usually is not recognized until a bullous air space leaks into the pleural space, causing a pneumothorax.

 

Lung cancer

Up to the time of World War II, cancer of the lung was a relatively rare condition. The increase in its incidence in Europe after World War II was at first ascribed to better diagnostic methods, but by 1956 it had become clear that the rate of increase was too great to be accounted for in this way. At that time the first epidemiological studies began to indicate that a long history of cigarette smoking was associated with a great increase in risk of death from lung cancer. By 1965 cancer of the lung and bronchus accounted for 43 percent of all cancers in the United States in men, an incidence nearly three times greater than that of the second most common cancer (of the prostate gland) in men, which accounted for 16.7 percent of cancers. In 1964 Smoking and Health: Report of the Advisory Committee to the Surgeon General of the Public Health Service (United States) concluded categorically that cigarette smoking is causally related to lung cancer in men. Since then, many further studies in diverse countries have confirmed this conclusion.

The incidence of lung cancer in women began to rise in 1960 and continued rising through the mid-1980s. This is believed to be explained by the later development of heavy cigarette smoking in women compared with men, since women greatly increased their cigarette consumption during World War II. By 1988 there was evidence suggesting that the peak incidence of lung cancer due to cigarette smoking in men may have been passed. The incidence of lung cancer mortality in women, however, is increasing.

The reason for the carcinogenicity of tobacco smoke is not known. Tobacco smoke contains more than 60 carcinogenic compounds, including harmful nitrosamines and polycyclic aromatic hydrocarbons. In addition to its single-agent effects, cigarette smoking greatly potentiates the cancer-causing proclivity of asbestos fibres, increases the risk of lung cancer due to inhalation of radon daughters (products of the radioactive decay of radon gas), and possibly also increases the risk of lung cancer due to arsenic exposure. People who do not smoke but who live or work with smokers and who therefore are exposed to secondhand tobacco smoke have an increased risk for lung cancer.

Because lung cancer is characterized by different types of tumours, because it may be located in different parts of the lung, and because it may spread beyond the lungs at an early stage, the first symptoms noted by the patient vary. These symptoms may include a persistent cough, blood staining of the sputum, a pneumonia that does not resolve fully with antibiotics, or shortness of breath due to a pleural effusion. A physician may discover distant metastases in bone tissues or in the brain that cause symptoms unrelated to the lung. Lymph nodes may be involved early, and enlargement of the lymph nodes in the neck may lead to a chest examination and the discovery of a tumour. In some cases a small tumour metastasis in the skin, abnormal mental function or behaviour, jaundice from liver dysfunction, or sensory changes in the legs from peripheral neuropathy (damage to nerves outside the central nervous system) may be the first sign of the disease. In other cases, only a general feeling of malaise, unusual fatigue, or seemingly minor symptoms may serve as the first indication. In addition, some affected individuals experience clubbing (swelling) of the fingers and toes, an unusual sign that may disappear after surgical removal of the tumour. Lung cancer may develop in an individual who already has chronic bronchitis and who therefore has had a cough for many years.The diagnosis often depends on securing tissue for histological examination, although in some cases this entails removal of the entire neoplasm before a definitive diagnosis can be made.

Survival from lung cancer has improved only slightly since the mid-1970s, when the U.S. government greatly increased funding for cancer research in an effort to find a cure for the disease. Early detection with routine chest radiographs has been attempted, and large-scale trials of routine sputum examination for the detection of malignant cells have been conducted, but neither screening method has been shown thus far to affect long-term mortality. Attention has been turned to prevention by every means possible. Foremost among them are efforts to inform the public of the risk and to limit the advertising of cigarettes. Steps have been taken to reduce asbestos exposure, both in the workplace and in public and private buildings, and to control air pollution. The magnitude of the contribution of air pollution to the incidence of lung cancer is not known with certainty.

Persons exposed to radon are at risk for lung cancer. The hazard from exposure was formerly thought to be confined to uranium miners, who, by virtue of their work underground, encounter high levels of these radioactive materials. However, significant levels of radon have been detected in houses built over natural sources, and, with increasingly efficient insulation of houses, radon may reach concentrations high enough to place the occupants at risk for lung cancer. Major regional variations in the natural distribution of radon occur, and it is not yet possible to quantify precisely the actual magnitude of the risk. In some regions of the world (such as the Salzburg region of Austria), levels are high enough that radon exposure is believed to account for the majority of cases of lung cancer in nonsmokers.

Workers exposed to arsenic in metal-smelting operations, and the community around the factories from which arsenic is emitted, have an increased risk for lung cancer. Arsenic is widely used in the electronics industry in the manufacture of various products, including microchips and semiconductors, and careful surveillance of this industry has helped prevent future disease.

Some types of lung cancer are unrelated to cigarette smoking. Alveolar cell cancer is a slowly spreading condition that affects men and women in equal proportion and is not related to cigarette smoking. Pulmonary adenocarcinoma of the lung also has a more equal sex incidence than other types; although its incidence is increased in smokers, it may also be caused by other factors.

It is common to feel intuitively that one should be able to apportion cases of lung cancer among discrete causes, on a percentage basis. But in multifactorial disease, this is not possible. Although the incidence of lung cancer would probably be far lower without cigarette smoking, the contribution of neither this factor nor any of the other factors mentioned can be precisely quantified. Treatment of most forms of lung cancer may involve chemotherapy, radiation therapy, or surgery (see Lung cancer: Treatment).

 

Occupational lung disease

Respiratory disease 3

Diseases of the mediastinum and diaphragm

The mediastinum comprises the fibrous membrane in the centre of the thoracic cavity, together with the many important structures situated within it. Enlargement of lymph glands in this region is common, particularly in the presence of lung tumours or as part of a generalized enlargement of lymphatic tissue in disease. Primary tumours of mediastinal structures may arise from the thymus gland or the lower part of the thyroid gland; noninvasive cysts of different kinds are also found in the mediastinum.

The diaphragm may be incompletely formed, leading to herniation of abdominal viscera through it. In adult life an important disease involving the diaphragm is bilateral diaphragmatic paralysis. This leads to a severe reduction in vital capacity, especially when the subject is recumbent. In many cases the cause of the paralysis cannot be determined. Paralysis of the diaphragm on one side is more common and better tolerated than bilateral paralysis, although some shortness of breath on exertion is often present. The function of the diaphragm may be compromised when the lung is highly overinflated, as occurs in emphysema; diaphragmatic fatigue may limit the exercise capability of affected persons.

Although these divisions provide a general outline of the ways in which diseases may affect the lung, they are by no means rigid. It is common for more than one part of the system to be involved in any particular disease process, and disease in one region frequently leads to involvement of other parts.

 

Major diseases of the respiratory system

Viral infections of the respiratory system

A wide variety of viruses are responsible for acute respiratory disease. The common cold—frequently of viral origin—can cause inflammation of the trachea and laryngitis, and such inflammation may extend to involve the lower bronchial tree. After such episodes the ciliary lining of the bronchial tree may be damaged, but the repair process is usually rapid.

Infections with rhinoviruses and adenoviruses are especially important in children, in whom they cause a febrile (fever-associated) illness, occasionally with severe bronchiolar involvement. Although recovery is usually rapid, in some infections with respiratory syncytial virus an extensive bronchiolitis develops that may be severe enough to threaten life. In epidemics of these diseases, occasional cases occur in which the course is complicated by inflammation of the pericardium—the membrane enclosing the heart—or by a pleural effusion.

Influenza and parainfluenza viruses are capable of causing severe illness. The influenza virus attacks many systems of the body simultaneously, but the primary site of viral replication appears to be the alveolar cells of the lung. There the virus multiplies many times over within a 24-hour period, and the pulmonary involvement may begin in the parenchyma and cause considerable consolidation and inflammation of lung tissue. Severe tracheitis, bronchitis, and bronchiolitis often occur at the same time. Another form of the disorder is that described as viral pneumonia, in which a distinguishing feature is the presence of patchy areas of atelectasis, or partial collapse of lung tissue, without extensive involvement of the bronchial tree. All these conditions are more dangerous in small children and in the elderly, and the lung that is the seat of a severe attack of influenza may quickly become secondarily infected.

It was secondary bacterial infection that accounted for the high mortality in the influenza epidemic of 1918–19, one of the worst human catastrophes on record. Today this epidemic is more precisely called a pandemic because it affected populations around the world. It has been estimated that more than 20,000,000 people worldwide died during the outbreak; of the 20,000,000 people who suffered from the illness in the United States, approximately 850,000 died. It was a characteristic of this pandemic that young people were severely affected. The high mortality resulted from the lack of antibiotics for treating the secondary bacterial infection; widespread malnutrition probably also contributed to the death rate.

There are three immunologically distinct types of influenza virus, designated A, B, and C; parainfluenza viruses are designated by the letter D. Types A, B, and D cause epidemic disease. Within type A there are known to be at least four distinct strains. The “Asian” strain of type A was responsible for the 1957 influenza epidemic. Epidemic influenza tends to occur in two- or three-year cycles; careful study has allowed predictions to be made of their future occurrence. Although infected individuals develop lasting immunity to a particular strain following an attack of influenza, the immunity is highly specific as to type, and no protection is afforded against even closely related strains. Artificial immunization with high- potency vaccines is of value in protecting against previous strains, and the vaccines have been shown to ameliorate the infection in the general population. Their use is particularly indicated in elderly people whose cardiac or lung function is already compromised.

Psittacosis and ornithosis, primarily infections of birds and particularly common among parakeets and parrots, are transmitted to human beings by inhalation of dust particles from the droppings of infected birds. The onset of psittacosis may be quite severe, with headache, insomnia, and even delirium. Gastrointestinal symptoms such as vomiting and pain are frequent, and a cough productive of clear sputum usually develops after a few days. Mild attacks are often unrecognized and dismissed as due to influenza. Recovery is usually complete, but convalescence may be slow. A pandemic of this disease in 1929 was caused by the shipment of 5,000 parrots into Argentina from Brazil for auction. Many of the birds died, and there was considerable human mortality. Mandatory isolation of imported birds for observation has largely controlled this disease in many countries around the world.

Chickenpox (varicella), particularly when it occurs in adults, may affect the lung. Acute lesions may occur in the lung parenchyma, leading to a transient but significant fall in arterial oxygen tension (hypoxemia), occasionally necessitating oxygen therapy. Recovery may be slow but is usually complete, although shadows may remain on a chest radiograph as a result of it.

Whooping cough occurs in epidemic form among children and appears to be linked to the later development of the chronic infective process known as bronchiectasis, which occurs as a result of bronchial damage. In Western countries, both whooping cough and measles (which causes an acute bronchiolitis) have been largely controlled by effective vaccines, although whooping cough sometimes occurs in adults many years after vaccination. In some developing countries, where these vaccines are not consistently available, whooping cough and measles can still be major causes of mortality in children. Mortality is worsened by malnutrition, which reduces resistance to acute respiratory diseases and is present in many children of developing countries.

The reparative processes in the lung after any viral attack may be quite slow. Apparent clinical recovery may occur relatively quickly and radiographs may show no remaining shadows, yet repair and restitution of the alveolar wall may take several additional weeks. Sometimes a cough persists for two or three months after systemic symptoms have resolved, reflecting continued healing of the bronchi. However, the occurrence of a severe viral infection in childhood may impair subsequent development of the lung or even set the stage for chronic respiratory disease in later life.

 

Bacterial infections of the respiratory system

Pneumonia

Before effective antibiotics became available, pneumonia was the respiratory disease responsible for the greatest mortality and consequently was one of the most-feared diseases. Because it frequently led to the death of severely disabled elderly people, it was also known as the “old man's friend.” The most common form of the disease, streptococcal pneumonia (sometimes called pneumococcal pneumonia), is caused by a streptococcus called Streptococcus pneumoniae. This form of pneumonia begins abruptly with a high fever and severe malaise followed by natural resolution in survivors after several days or longer. In some cases, infection is followed by complications, such as a lung abscess, pleurisy, or heart failure. Prompt antibiotic therapy controls the acute process within 24 hours in most instances; however, some deaths occur despite appropriate antibiotic therapy. Emergence of antibiotic-resistant S. pneumoniae strains is a growing concern. Streptococcal pneumonia may also occur as a complication of an acute attack of influenza because susceptibility to infection by streptococci is increased. In addition, the much-lowered mortality of influenza can be explained by antibiotics effective against streptococci. Staphylococcal pneumonia occurs as an acute illness in small children and may lead to rapid destruction of lung tissue with abscess formation; however, if the acute state is survived, as it usually is with chemotherapy, the lung recovers fully. This type of pneumonia may also occur as a complication of preexisting lung disease of any kind and may follow aspiration of stomach contents into the lung. The development of antibiotic-resistant staphylococci, such as methicillin-resistant Staphylococcus aureus (MRSA), has meant that this form of pneumonia may be a problem in the hospital environment, complicating other lung diseases or occurring postoperatively.

Pneumonia due to infection with Klebsiella pneumoniae may be difficult to treat and characteristically may occur as a repetitive series of episodes of pneumonia, each running a rather long course with slow resolution.

The organism Hemophilus influenzae is commonly isolated from the sputum of patients with chronic bronchitis during acute exacerbations of infection and is an important cause of pneumonia in adults.

Mycoplasma, identified in 1944 as responsible for a group of pneumonias previously thought to be of viral origin, is a member of a group of organisms known as the pleuropneumonia-like organisms and has also been termed the “Eaton agent” after the scientist who first described it. Mycoplasma pneumoniae is the single most common cause of pneumonia in school-age children and young adults. The infection produces soft patchy shadows on the chest radiograph and relatively few signs on physical examination. A nonproductive cough and a fever occur for a few days. Familial spread is common, and disease occurs in epidemic form in young healthy people brought together in clusters, as in military recruit camps and colleges, where a number of outbreaks have been documented. It is not usually a life-threatening disease, but in rare cases it may progress to cause acute respiratory distress syndrome.

In all these bacterial pneumonias, the diagnosis may be made from the characteristic radiographic pattern, together with isolation from the sputum of the bacterium primarily responsible.

 

Legionnaires disease

In July 1976 an outbreak of severe pneumonia occurred among U.S. veterans attending a convention of the American Legion in Philadelphia. Of the 147 persons admitted to hospitals, 29 died. Identification of the organism responsible (subsequently named Legionella pneumophila) constituted a classic medical detective story. The bacterium had evaded detection before because it does not stain with the usual stains used in sputum examination. Today it is known that this bacterium may grow in air-conditioning systems or on shower heads, and it has been shown to be responsible for sporadic but severe outbreaks of pneumonia, particularly but not exclusively in older people. Fortunately, the bacterium is sensitive to erythromycin and other antibiotics.

 

Pneumonia in immunocompromised persons

For some years prior to 1980, it had been known that if the immune system was compromised by immunosuppressive drugs (given, for example, before organ transplantation to reduce the rate of rejection), the patient was at risk for developing pneumonia from organisms or viruses not normally pathogenic. Patients with AIDS may develop pneumonia from cytomegalovirus or Pneumocystis infections, capable of causing invasive pneumonic lesions in the setting of reduced immunity. Such infections are a major cause of illness in these patients, are difficult to treat, and may prove fatal. Infections with fungi such as Candida also occur. The diagnosis and management of these cases has become a challenging and time-consuming responsibility for respiratory specialists in locations with large numbers of AIDS cases.

 

Tuberculosis

Of all the lung diseases caused by bacteria, pulmonary tuberculosis is historically by far the most important. Particular features of this dreaded condition include the severe general debilitation and weakness that it may cause; the insidious nature of the onset of its initial symptoms, which may not be pulmonary in nature; the familial tendency; the long-drawn-out course of the disease and the distressing nature of many of its manifestations, particularly severe hemorrhage from the lung and from tuberculous involvement of the brain (meningitis), or involvement of the adrenal gland leading to adrenal insufficiency (Addison disease); and, above all, the general inefficacy of medical treatment before effective antibiotic therapy became available. Antibiotics have greatly reduced the mortality from pulmonary tuberculosis in all developed countries, but the decline in mortality began well before their introduction, and it is clear that improved diet and housing were responsible for this. With antibiotic therapy, however, the bacilli quickly disappear from the sputum and the spread of infection is quickly controlled.

In its classic form, tuberculosis first causes pulmonary inflammation at the apices (upper portions) of the lungs, and it may progress slowly to form a chronic cavity in this region. Secondary infection of the cavity may occur and may be difficult to eradicate. When still active, pulmonary tuberculosis is a constant threat to the patient, because blood-borne spread may occur at any time. Diffuse spread of tuberculosis in the lung (known as miliary tuberculosis) may occur at the onset of the disease. The chest radiograph reveals many small and diffuse shadows. The exact sequence of events that leads to this disseminated form of disease is not understood, but prompt treatment is required to prevent spread to the brain and other organs. Pulmonary tuberculosis remains an important disease.

Treatment of tuberculosis is based on whether an individual has tuberculosis infection or tuberculosis disease. Treatment of the former is aimed at preventing disease and often involves only one drug, whereas treatment of the latter is aimed at fighting the disease and involves regimens that employ multiple drugs. Streptomycin was the first clinically successful antituberculous drug; however, it is only occasionally used today. Most cases of tuberculosis infection are treated with isoniazid (isonicotinic hydrazide). Treatment often lasts for a period of six to nine months. In the case of active tuberculosis disease, the combination of isoniazid, rifampin, pyrazinamide, and ethambutol is often used for a period of six months to a year. There is no one “best” regimen preferable to all others since tubercle bacilli can acquire resistance to most of the antituberculous drugs. The development of resistance to antibiotics is often delayed by the concomitant use of two or more drugs, by continuous treatment without significant interruption until all bacterial growth has ceased, and by the use of bed rest and resectional surgery in a few selected cases. Surgery may be indicated when a chronic cavity has developed.

The major problem in treating pulmonary tuberculosis is ensuring continued medication and supervision. This may be very difficult in developing countries and in isolated regions of the world. Although the death rate from respiratory tuberculosis in the Western world has fallen greatly since 1900, it remains a serious and difficult problem in many tropical countries and in any population with inadequate medical care and poor diet and hygiene. In addition, pulmonary tuberculosis has reappeared in the West in persons with AIDS, in whom treatment is complicated by diminished immunity.

 

Q fever

Q fever is an infection with the pathogenic bacteria Coxiella burnetii. The disease was first described in Queensland, Australia; areas in which Q fever is known to be endemic include Australia, the western United States, Africa, England, and the Mediterranean countries. Animal infection is widespread and involves a large variety of domestic farm animals, particularly cattle and sheep, and some wild animals. Transmission is believed to occur between mammals through ticks and mice. Human disease, which is uncommon, is probably acquired through inhalation of infected material. Laboratory workers and employees in slaughterhouses are particularly at risk. Q fever is usually a mild and self-limited disease, requiring only symptomatic treatment.

 

Allergic lung diseases

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Respiratory disease 2

Lung transplantation

Early attempts at transplanting a single lung in patients with severe bilateral lung disease were not successful, but from the late 1970s bilateral lung transplantation had some striking results. Persons severely disabled by cystic fibrosis, emphysema, sarcoidosis, pulmonary fibrosis, or severe primary pulmonary hypertension can achieve nearly normal lung function several months after the procedure. Because transplantation offers the only hope for persons with severe lung disease, who may be relatively young, the techniques are being pursued aggressively in specialized centres. Availability of donor lungs is sharply limited by the number of suitable donors; for example, many people who die of severe head injuries, which presumably would leave the lungs intact, often have also suffered lung injury or lung infection. With proper selection of donor organs and proper transplantation technique, survival at one year has been reported at 90 percent.

Many recipients of single or double lung transplantation develop bronchiolitis obliterans beginning several months or years after surgery. This complication is thought to represent gradual immunologic rejection of the transplanted tissue despite the use of immunosuppressant drugs. Brochiolitis obliterans and the constant risk of serious infection brought about by the use of immunosuppressant drugs limit survival to approximately 40 to 60 percent five years after surgery.
 

Morphological classification of respiratory disease

The main divisions of the respiratory system serve as a basis for the morphological description of respiratory system diseases. The upper airway consists of the nose, nasopharynx, and larynx. Below these structures lies the trachea. Thereafter the airway divides into two major airways, right and left, and then into progressively smaller tubes until finally the terminal bronchioles, which are about one millimetre in diameter, are reached. On average, 16 generations of division occur between the trachea and the terminal bronchioles. Although there is only one airway at the beginning—the trachea—there are about 650,000 terminal bronchioles. The cross-sectional area of the bronchial tree increases with increasing subdivision. The end of each terminal bronchiole opens into an acinus, so called because the structure resembles a cluster of grapes, and from this point onward the gas-exchanging portion of the lung is reached. The alveoli, or air sacs, which are divided into groups or lobules by fibrous partitions, or septa, are small hexagonal structures forming a blind end to the acinus. The wall of the acinus consists of blood capillaries, and the remaining structures are extremely thin, only providing supporting tissue for the rich capillary bed that constitutes the parenchyma, or the essential tissue of the lung itself. The parenchyma is the gas-exchanging tissue of the lung and has a surface area roughly comparable to that of a tennis court. Blood is distributed to the lung through the branching pulmonary artery, which subdivides with the bronchial tree and accompanies the smaller bronchioles into the region of the acinus to supply the capillaries of the alveolar wall. Oxygenated blood from the acini is collected into pulmonary veins, which run at some little distance from the bronchioles. An interstitial space exists around the alveoli and around the bronchioles and blood vessels, and this connects the lymph nodes (the small masses of lymphatic tissue that occur along the course of the lymph vessels) situated in the midline of the thoracic cavity and extending in a chain up into the neck and down into the abdomen.

Each lung is covered by a protective membrane, or pleura, which consists of a visceral layer that lines the outer surface of the lung and a parietal layer that lines the inside of the chest wall. The space between these two layers, called the intrapleural space, normally contains no air and only a few millilitres of fluid for lubrication purposes, as during breathing one layer must slide on another. The pleurae may become involved by inflammation or neoplastic disease, in which case an effusion of fluid may occur between the two layers.

From this general description, diseases of the respiratory system may be grouped into the following categories.

 
Diseases of the upper airwayThe nasal sinuses are frequently the site of both acute and chronic infections. In common with the palate and the nasopharynx, they are also the site of malignant neoplastic changes. Cancer of the larynx is much more common in smokers than in nonsmokers.

The occurrence of upper airway obstruction (particularly common in people who snore) has been documented in sleep laboratory studies. Sleep apnea, which sometimes involves upper airway obstruction, is characterized by cessation of breathing for up to a minute and by a marked fall in blood oxygen levels, thus arousing an affected individual from sleep. Sleep apnea affects approximately 4 percent of adults. It is not confined to the very obese, although it forms part of the syndrome of severe obesity in which sleep disturbance is common, and it is associated with the daytime somnolence known as the pickwickian syndrome, after Charles Dickens's description of the fat boy in The Pickwick Papers. Sleep apnea is sometimes caused by relaxation of muscles around the pharynx and obstruction of the airway by the palate and tongue. It is related to narrow anatomical dimensions in this area but is also more likely to occur if alcohol is ingested shortly before sleep. Sleep apnea may cause a rise in systemic blood pressure, and pickwickian syndrome may affect one's performance at work and ability to do other tasks carried out during the day. In severe cases, sleep apnea leads to right ventricular heart failure.

 

Diseases of the major bronchi

The major bronchi can become the seat of chronic inflammation, as in chronic bronchitis or bronchiectasis. The latter disease may be caused by the familial disease cystic fibrosis (see below Bronchiectasis). The major bronchi may also be the site of development of malignant disease.

 

Diseases of the smaller bronchi and bronchioles

It is in the smaller bronchi that major obstruction commonly occurs in asthma: these bronchi contain smooth muscle in their walls, and the muscle may contract, causing airway obstruction. The small radicles of the bronchial tree, the bronchioles, are commonly involved in infective processes such as viral infections; they are also the primary site of deposition of inhaled dust and particles. Because of the large cross-sectional area of this part of the airway, considerable disease may be present in the bronchioles without affecting the expiratory flow rate. The bronchioles are occasionally the site of a primary noninfective bronchiolitis in persons with rheumatoid arthritis or other systemic inflammatory diseases.

 

Diseases of the alveolar ducts and alveoli

These structures are the site of primary involvement in many infections, including pneumonia, and it is on the parenchyma of the lung that the main effects of blockage of a pulmonary artery (pulmonary embolism) occur. The capillary bed surrounding the alveoli is subject to damage, and fluid may leak through the alveolar capillaries to accumulate in the lungs (pulmonary edema). The capillary bed is also extensively damaged in the condition known generally as acute respiratory distress syndrome; the exact mechanism of the damage is not yet fully understood. The alveolar walls themselves may undergo diffuse interstitial thickening, a characteristic of diseases grouped under the heading of “diffuse interstitial fibrosis”; interstitial thickening may also occur as a manifestation of collagen diseases such as scleroderma. One of the common forms of emphysema, in which alveolar destruction occurs, entails early loss of tissue at the point where the bronchiole ends in the acinus, resulting in a punched-out lesion in the centriacinar region. This form of emphysema is the one that most commonly develops after years of cigarette smoking.

The lung parenchyma is the site of the discrete aggregations of cells, usually giant cells, that form the granulomas characteristic of the generalized disease known as sarcoidosis, and it is in the lung parenchyma that nodules caused by the inhalation of silica particles are found.

 

Diseases of the pleura

The pleura may be involved in inflammatory or neoplastic processes, either of which may lead to fluid accumulation (pleural effusion) between the two layers. The pleural membranes of the lungs may become perforated and spontaneously rupture, usually over a small collection of congenital blebs, or cysts at the apex of the lung. This causes spontaneous pneumothorax, a partial or occasionally complete collapse of the lung. In the majority of cases, a pneumothorax resolves slowly of its own accord, although pleural suction may be needed to expedite recovery. If repetitive attacks occur, the blebs may be removed surgically, and the pleural membrane of the affected lung may be sealed to the pleural membrane of the inner wall of the thorax to prevent a recurrence.

The most common disease of the pleura is caused by inflammation and is referred to as pleurisy. A pleurisy with an effusion may be the presenting symptom of pulmonary tuberculosis, and pleurisy may accompany any kind of pneumonia. When a pleural effusion in a person with bacterial pneumonia becomes infected, pus accumulates in the pleural cavity (empyema). This complication—dreaded before the widespread availability of antibiotics in the mid-20th century and after the outbreaks of antibiotic-resistant microorganisms in the late 20th and early 21st centuries—requires drainage of the pleural space. In severe instances of empyema, video-assisted thoracic surgery is performed to evacuate viscous or semisolid infected material from the space.

Mesothelioma, a cancer of the pleura, may occur many years after inhalation of asbestos fibres (see below Asbestosis and mesothelioma). The cancerous cells of the pleura can eventually metastasize and invade nearby and distant tissues, including tissues of the neck and head.

Respiratory disease 1

Respiratory disease

Introduction

any of the diseases and disorders that affect human respiration

Diseases of the respiratory system may affect any of the structures and organs that have to do with breathing, including the nasal cavities, the pharynx (or throat), the larynx, the trachea (or windpipe), the bronchi and bronchioles, the tissues of the lungs, and the respiratory muscles of the chest cage.

 

 

• During normal breathing, inhaled air travels through two main channels (primary bronchi) that …

The respiratory tract is the site of an exceptionally large range of disorders for three main reasons: 1) it is exposed to the environment and therefore may be affected by inhaled organisms, dusts, or gases; 2) it possesses a large network of capillaries through which the entire output of the heartblood vessels are likely to affect the lung; and 3) it may be the site of “sensitivity” or allergic phenomena that may profoundly has to pass, which means that diseases that affect the small affect function.

This article discusses the signs and symptoms of respiratory disease, the natural defenses of the human respiratory system, the methods of detecting respiratory disease, and the different diseases of the respiratory system. For more information about the anatomy of the human respiratory system and the process of respiration, see human respiratory system.

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Colorado tick fever

also called  Mountain Fever

acute, febrile viral infection usually transmitted to humans by the bite of the tick Dermacentor andersoni. The virus is classified as an orbivirus of the family Reoviridae, a grouping of viruses that is characterized by the lack of a lipid envelope and the presence of two protein coats. D. andersoni requires a vertebrate host for a part of its life cycle. The main mammalian reservoir of the virus is the golden-mantled ground squirrel, Citellus lateralis. The carrier tick is found chiefly in the western parts of the United States, notably in Colorado, and is most active in the late spring and summer.

A few days following tick exposure, the fever onset is abrupt, often with intolerance to light, headache, and prostrating weakness. Aching soon becomes generalized, especially in the muscles and joints. Abdominal pain and vomiting occur occasionally. The first attack lasts about two days. After a complete remission of all signs and symptoms lasting also about two days, there is in most cases a second attack that may be even more acute than the first. Except for the rare development of brain inflammation (encephalitis) in young children, however, recovery is usually uncomplicated, and there is lifelong immunity.

paralysis

Paralysis

Introduction

also called  palsy 

loss or impairment of voluntary muscular movement caused by structural abnormalities of nervous or muscular tissue or by metabolic disturbances in neuromuscular function. Paralysis can affect the legs and lower part of the body (paraplegia) or both arms and both legs (quadriplegia). Sometimes the muscles of the lower face, arm, and leg on only one side of the body are involved (hemiplegia).

Most diseases that cause paralysis can be divided into two main groups depending on whether they entail structural alterations in nervous or muscular tissue, or lead to metabolic disturbances in neuromuscular function. Some act systemically and affect one of the three elements in the motor system (upper neuron, lower neuron, or muscle) more or less extensively and exclusively. More often, however, one element or neighbouring portions of two of the three elements are involved over a limited extent by a single focal lesion.

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Lyme disease

tick-borne bacterial disease that was first conclusively identified in 1975 and is named for the town in Connecticut, U.S., in which it was first observed. The disease has been identified in every region of the United States and in Europe, Asia, Africa, and Australia. Lyme disease is caused by the spirochete (corkscrew-shaped bacterium) Borrelia burgdorferi. The spirochete is transmitted to the human bloodstream by the bite of various species of ticks. In the northeastern United States, the carrier tick is usually Ixodes dammini; in the West, I. pacificus; and in Europe, I. ricinus. Ticks pick up the spirochete by sucking the blood of deer or other infected animals. I. dammini mainly feeds on white-tailed deer and white-footed mice, especially in areas of tall grass, and is most active in summer. The larval and nymphal stages of this tick are more likely to bite humans than are the adult and are therefore more likely to cause human cases of the disease. In humans the disease progresses in three stages. The first and mildest stage is characterized by a circular rash in a bull's-eye pattern that appears anywhere from a few days to a month after the tick bite. The rash is often accompanied by such flulike symptoms as headache, fatigue, chills, loss of appetite, fever, and aching joints or muscles. The majority of persons who contract Lyme disease experience only these first-stage symptoms and never become seriously ill. A minority, however, will go on to the second stage of the disease, which begins two weeks to three months after infection. This stage is indicated by arthritic pain that migrates from joint to joint and by disturbances of memory, vision, movement, or other neurological symptoms. The third stage of Lyme disease, which generally begins within two years of the bite, is marked by crippling arthritis and by neurological symptoms that resemble those of multiple sclerosis. Symptoms vary widely, however, and some persons experience facial paralysis, meningitis, memory loss, mood swings, and an inability to concentrate. Because Lyme disease often mimics other disorders, its diagnosis is sometimes difficult, especially when there is no record of the distinctive rash. Early treatment of Lyme disease with antibiotics is important in order to prevent progression of the disease to a more serious stage. More powerful antibiotics are used in the latter case, though symptoms may recur periodically thereafter.

Nervous system disease 1

Nervous system disease

Introduction

any of the diseases or disorders that affect the functioning of the human nervous system. Everything that humans sense, consider, and effect and all the unlearned reflexes of the body depend on the functioning of the nervous system. The skeleton and muscles support and transport the body, and the digestive system, heart, and lungs provide nutrients; but the nervous system contains the epitome of the human—the mind—and commands all perception, thought, and action. Disturbance or malfunction of the functions of the nervous system causes changes felt throughout the body. Although many brain diseases cause disorders of thought or mood, this article discusses only diseases of the nervous system that have organic causes. For a discussion of psychological disorders, see mental disorders.

The first part of this article describes the neurological examination—the medical history, the physical examination of the patient, and the diagnostic tests and procedures that can be employed to provide a physician with information about a possible neurological disorder. Next the principles used in localizing a disease within the nervous system are explained. The third part of this article provides an overview of pathological processes. Finally, an account is presented of the diseases of the nervous system, using a general classification based upon the primary or major site of the disease.

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Digestive system disease 1

Digestive system disease

Introduction
 any of the diseases that affect the human digestive tract. Such disorders may affect the esophagus, stomach, small intestine, large intestine (colon), pancreas, liver, or biliary tract. A prevalent disorder of the digestive system is gastroesophageal reflux disease (i.e., the passage of gastric contents into the esophagus), which causes heartburn on a regular basis in some individuals. Cirrhosis of the liver primarily results from excessive alcohol consumption, but it may also develop after infection with the hepatitis C virus. Other common diseases of the digestive system include peptic ulcers, colorectal cancer, and gallstones. Many disorders of the digestive system can be prevented by a diet low in fats and high in fruits and vegetables, limited alcohol consumption, and periodic medical examinations. This article discusses the common infections, inflammations, ulcers, and cancers that affect each organ of the digestive tract. For a detailed discussion of the anatomy and physiology of the digestive system, see digestive system, human.

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Peritonitis

Peritonitis

inflammation of the peritoneum, the membrane that lines the abdominal wall and then folds in to enclose the abdominal organs. The condition is marked by an accumulation of cells, pus, and other bodily fluids, such as serum and fibrin, in the peritoneal cavity (between the two folds of the peritoneal membrane) and by abdominal pain and distension, vomiting, and fever.

Peritonitis may be acute or chronic, generalized or localized. Acute peritonitis is usually caused by inflammation elsewhere in the body and may be due to a number of causes, such as bacterial invasion from an infected structure, blood or other fluids from a ruptured organ. A perforated gastrointestinal tract, notably a ruptured appendix, is a common cause of peritonitis.

Treatment of peritonitis is directed toward control of the source of inflammation. Surgery is often necessary to remove the source of infection, such as the appendix, or to repair a perforation. If localized abscesses have developed in the peritoneal cavity, antibiotic therapy and drainage are necessary.

Fluke or trematode

Fluke

also called  blood fluke  or  trematode

any member of the invertebrate class Trematoda (phylum Platyhelminthes), a group of parasitic flatworms that probably evolved from free-living forms millions of years ago. There are more than 10,000 species of flukes. They occur worldwide and range in size from about 5 millimetres (0.2 inch) to several centimetres; most do not exceed 100 millimetres (4 inches) in length.

Flukes parasitize members of all vertebrate classes but most commonly parasitize fish, frogs, and turtles; they also parasitize humans, domestic animals, and invertebrates such as mollusks and crustaceans. Some are external parasites (ectoparasites); some attach themselves to internal organs (endoparasites); others are semi-external, attaching themselves to the lining of the mouth, to the gills, or to the cloaca (the end of the digestive tract). Some attack a single host, while others require two or more hosts.

The symmetrical body of a fluke is covered with a noncellular cuticle. Most are flattened and leaflike or ribbonlike, although some are stout and circular in cross section. Muscular suckers on the ventral (bottom) surface, hooks, and spines are used for attachment. The body is solid and filled with a spongy connective tissue (mesenchyme) that surrounds all the body organs. A circulatory system is absent. The digestive system consists of a simple sac with a mouth either at the anterior end or in the middle of the ventral surface. An anus is usually absent, but some species have one or two anal pores. The nervous system consists of a pair of anterior ganglia, or nerve centres, and usually three pairs of lengthwise nerve cords.

Most species are hermaphroditic; i.e., functional reproductive organs of both sexes occur in the same individual. In some, however, the sexes are separate. Most species pass through egg, larval, and mature stages.

Blood flukes occur in most types of vertebrates; three species attack humans: the urinary blood fluke (Schistosoma haematobium), the intestinal blood fluke (S. mansoni), and the Oriental blood fluke (S. japonicum). The human diseases caused by them are known as schistosomiasis (bilharziasis); they affect millions of persons, particularly in Africa and east Asia.

The urinary blood fluke (S. haematobium), which lives in the veins of the urinary bladder, occurs mainly in Africa, southern Europe, and the Middle East. Eggs, laid in the veins, break through the vein wall into the bladder and are voided during urination. The larval fluke develops in the body of a snail (chiefly of the genera Bulinus and Physopsis), the intermediate host. The mature larva makes its way into the body of the final host, man, through the skin or the mouth.

The intestinal blood fluke (S. mansoni), which lives in the veins around the large and small intestines, occurs primarily in Africa and in northern South America. The eggs pass from the host with the feces. The larva enters the body of a snail (any of several genera), the intermediate host, and returns to a human host through the skin.

The Oriental blood fluke, which occurs primarily in China, Japan, Taiwan, the East Indies, and the Philippine Islands, differs from S. mansoni and S. haematobium in that it may attack vertebrates other than man, including various domestic animals, rats, and mice. Snails of the genus Oncomelania are the intermediate host. The adult occurs in the veins of the small intestine. Some eggs are carried in the bloodstream to various organs and may cause a variety of symptoms, including enlargement of the liver. Human hosts may die from severe infestations.

Flukes of detrimental economic significance to man include the widely occurring giant liver fluke of cattle (Fasciola hepatica) and the Chinese, or Oriental, liver fluke (Opisthorchis sinensis, or Clonorchis sinensis). F. hepatica causes the highly destructive “liver rot” in sheep and other domestic animals. Man may become infested with this fluke by eating uncooked vegetables.

The Chinese liver fluke infests a variety of mammals, including man. In addition to the snail as an intermediate host, the Chinese liver fluke infests fish as a second intermediate host before passing to the final host. The cat liver fluke, Opisthorchis felineus, which may also infest man as the final host, also requires a freshwater snail (Bithynia leachii) and a carp as its secondary intermediate hosts.

Beriberi )disease )

Beriberi

nutritional disorder caused by a deficiency of thiamin (vitamin B₁) and characterized by impairment of the nerves and heart. General symptoms include loss of appetite and overall

lassitude, digestive irregularities, and a feeling of numbness and weakness in the limbs and extremities. (The term beriberi is derived from the Sinhalese word meaning “extreme weakness.”) In the form known as dry beriberi, there is a gradual degeneration of the long nerves, first of the legs and then of the arms, with associated atrophy of muscle and loss of reflexes. In wet beriberi, a more acute form, there is edema (overabundance of fluid in the tissues) resulting largely from cardiac failure and poor circulation. In infants breast-fed by mothers who are deficient in thiamin, beriberi may lead to rapidly progressive heart failure.

The cardiac symptoms, in both infants and adults, generally respond promptly and dramatically to the administration of thiamin. When neurological involvement is present, the response to thiamin is much more gradual; in severe cases, the structural lesions of the nerve cells may be irreversible.

Thiamin normally plays an essential role as a coenzyme in the metabolism of carbohydrates; in its absence, pyruvic acid and lactic acid (products of carbohydrate digestion) accumulate in the tissues, where they are believed to be responsible for most of the neurological and cardiac manifestations.

Thiamin occurs widely in food but may be lost in the course of processing, particularly in the milling of grains. In East Asian countries, where polished white rice is a dietary staple, beriberi has been a long-standing problem. The history of the recognition, the cause, and the cure of beriberi is dramatic and is well documented in medical literature. In the 1880s the Japanese navy reported that beriberi had been eradicated among its sailors as a result of adding extra meat, fish, and vegetables to their regular diet. Before that time, almost half of the sailors were likely to develop beriberi, and many died of it. In 1897 Christiaan Eijkman, working in the Dutch East Indies (now Indonesia), found that a beriberi-like disease could be produced in chickens by feeding them a diet of polished rice. British researchers William Fletcher, Henry Fraser, and A.T. Stanton later confirmed that beriberi in humans was also related to the consumption of polished white rice. In 1912 Casimir Funk demonstrated that beriberi-like symptoms induced in pigeons could be cured by feeding them white rice that was supplemented with a concentrate made from rice polishings. Following this discovery he proposed that this, as well as several other conditions, were due to diets that were deficient in specific factors that he called “vitamines,” later called vitamins.

The prevention of beriberi is accomplished by eating a well-balanced diet, since thiamin is present in most raw and untreated foods. The incidence of beriberi in Asia has markedly decreased because an improved standard of living has allowed a more varied diet and partly because of the gradual popular acceptance of partially dehusked, parboiled, and enriched rice—forms that contain higher concentrations of thiamin. In Western countries, thiamin deficiency is encountered almost solely in cases of chronic alcoholism.

Immune System 1

Mechanisms of the immune system

Nonspecific, innate immunity

Most microorganisms encountered in daily life are repelled before they cause detectable signs and symptoms of disease. These potential pathogens, which include viruses, bacteria, fungi, protozoans, and worms, are quite diverse, and therefore a nonspecific defense system that diverts all types of this varied microscopic horde equally is quite useful to an organism. The innate immune system provides this kind of nonspecific protection through a number of defense mechanisms, which include physical barriers such as the skin, chemical barriers such as antimicrobial proteins that harm or destroy invaders, and cells that attack foreign cells and body cells harbouring infectious agents. The details of how these mechanisms operate to protect the body are described in the following sections.

 

External barriers to infection

The skin and the mucous membrane linings of the respiratory, gastrointestinal, and genitourinary tracts provide the first line of defense against invasion by microbes or parasites.

 

Skin

Human skin has a tough outer layer of cells that produce keratin. This layer of cells, which is constantly renewed from below, serves as a mechanical barrier to infection. In addition, glands in the skin secrete oily substances that include fatty acids, such as oleic acid, that can kill some bacteria; skin glands also secrete lysozyme, an enzyme (also present in tears and saliva) that can break down the outer wall of certain bacteria. Victims of severe burns often fall prey to infections from normally harmless bacteria, illustrating the importance of intact, healthy skin to a healthy immune system.

 

Mucous membranes

Like the outer layer of the skin but much softer, the mucous membrane linings of the respiratory, gastrointestinal, and genitourinary tracts provide a mechanical barrier of cells that are constantly being renewed. The lining of the respiratory tract has cells that secrete mucus (phlegm), which traps small particles. Other cells in the wall of the respiratory tract have small hairlike projections called cilia, which steadily beat in a sweeping movement that propels the mucus and any trapped particles up and out of the throat and nose. Also present in the mucus are protective antibodies, which are products of specific immunity. Cells in the lining of the gastrointestinal tract secrete mucus that, in addition to aiding the passage of food, can trap potentially harmful particles or prevent them from attaching to cells that make up the lining of the gut. Protective antibodies are secreted by cells underlying the gastrointestinal lining. Furthermore, the stomach lining secretes hydrochloric acid that is strong enough to kill many microbes.

 

Chemical barriers to infection

Some microbes penetrate the body's protective barriers and enter the internal tissues. There they encounter a variety of chemical substances that may prevent their growth. These substances include chemicals whose protective effects are incidental to their primary function in the body, chemicals whose principal function is to harm or destroy invaders, and chemicals produced by naturally occurring bacteria.

 

Chemicals with incidental protective effects

Some of the chemicals involved in normal body processes are not directly involved in defending the body against disease. Nevertheless, they do help repel invaders. For example, chemicals that inhibit the potentially damaging digestive enzymes released from body cells which have died in the natural course of events also can inhibit similar enzymes produced by bacteria, thereby limiting bacterial growth. Another substance that provides protection against microbes incidentally to its primary cellular role is the blood protein transferrin. The normal function of transferrin is to bind molecules of iron that are absorbed into the bloodstream through the gut and to deliver the iron to cells, which require the mineral to grow. The protective benefit transferrin confers results from the fact that bacteria, like cells, need free iron to grow. When bound to transferrin, however, iron is unavailable to the invading microbes, and their growth is stemmed.

 

Antimicrobial proteins

Complement

A number of proteins contribute directly to the body's nonspecific defense system by helping to destroy invading microorganisms. One group of such proteins is termed complement because it works with other defense mechanisms of the body, complementing their efforts to eradicate invaders. Many microorganisms can activate complement in ways that do not involve specific immunity. Once activated, complement proteins work together to lyse, or break apart, harmful infectious organisms that do not have protective coats. Other microorganisms can evade these mechanisms but fall prey to scavenger cells, which engulf and destroy infectious agents, and to the mechanisms of the specific immune response. Complement cooperates with both nonspecific and specific defense systems and is described more fully under Antibody-mediated immune mechanisms.

 

Interferons

Another group of proteins that provide protection are the interferons, which inhibit the replication of many—but not all—viruses. Cells that have been infected with a virus produce interferon, which sends a signal to other cells of the body to resist viral growth. When first discovered in 1957, interferon was thought to be a single substance, but since then several types have been discovered, each produced by a different type of cell. Alpha interferon is produced by white blood cells other than lymphocytes, beta interferon by fibroblasts, and gamma interferon by lymphocytes. All interferons inhibit viral replication by interfering with the transcription of viral nucleic acid. Interferons exert additional inhibitory effects by regulating the extent to which lymphocytes and other cells express certain important molecules on their surface membranes and by stimulating the activity of natural killer cells, which are described below.

 

Proteins from naturally occurring bacteria

In the small and large intestines the growth of invading bacteria can be inhibited by naturally gut-dwelling bacteria that do not cause disease. These gut-dwelling microorganisms secrete a variety of proteins that enhance their own survival by inhibiting the growth of the invading bacterial species.

 

Cellular defenses

 

 

• Time-lapse photography of a macrophage (the light-coloured, globular structure) consuming bacteria.

If an infectious agent is not successfully repelled by the chemical and physical barriers described above, it will encounter cells whose function is to eliminate foreign substances that enter the body. These cells are the nonspecific effector cells of the innate immune response. They include scavenger cells—i.e., various cells that attack infectious agents directly—and natural killer cells, which attack cells of the body that harbour infectious organisms. Some of these cells destroy infectious agents by engulfing and destroying them through the process of phagocytosis, while other cells resort to alternative means. As is true of other components of innate immunity, these cells interact with components of acquired immunity to fight infection.

 

Scavenger cells

All higher animals and many lower ones have scavenger cells—primarily leukocytes (white blood cells)—that destroy infectious agents. Most vertebrates, including all birds and mammals, possess two main kinds of scavenger cells. Their importance was first recognized in 1884 by the Russian biologist Élie Metchnikoff, who named them microphages and macrophages, after Greek words meaning “little eaters” and “big eaters.”

 

Granulocytes

Microphages are now called either granulocytes, because of the numerous chemical-containing granules found in their cytoplasm, or polymorphonuclear leukocytes, because of the oddly shaped nucleus these cells contain. Some granules contain digestive enzymes capable of breaking down proteins, while others contain bacteriocidal (bacteria-killing) proteins. There are three classes of granulocytes—neutrophils, eosinophils, and basophils—which are distinguished according to the shape of the nucleus and the way in which the granules in the cytoplasm are stained by dye. The differences in staining characteristics reflect differences in the chemical makeup of the granules. Neutrophils are the most common type of granulocyte, making up about 60 to 70 percent of all white blood cells. These granulocytes ingest and destroy microorganisms, especially bacteria. Less common are the eosinophils, which are particularly effective at damaging the cells that make up the cuticle (body wall) of larger parasites. Fewer still are the basophils, which release heparin (a substance that inhibits blood coagulation), histamine, and other substances that play a role in some allergic reactions (see immune system disorder: Allergies). Very similar in structure and function to basophils are the tissue cells called mast cells, which also contribute to immune responses.

Granulocytes, which have a life span of only a few days, are continuously produced from stem (i.e., precursor) cells in the bone marrow. They enter the bloodstream and circulate for a few hours, after which they leave the circulation and die. Granulocytes are mobile and are attracted to foreign materials by chemical signals, some of which are produced by the invading microorganisms themselves, others by damaged tissues, and still others by the interaction between microbes and proteins in the blood plasma. Some microorganisms produce toxins that poison granulocytes and thus escape phagocytosis; other microbes are indigestible and are not killed when ingested. By themselves, then, granulocytes are of limited effectiveness and require reinforcement by the mechanisms of specific immunity.

 

Macrophages

 

 

• The destruction of bacteria by a macrophage, one of the principal phagocytic (cell-engulfing) …

The other main type of scavenger cell is the macrophage, the mature form of the monocyte. Like granulocytes, monocytes are produced by stem cells in the bone marrow and circulate through the blood, though in lesser numbers. But, unlike granulocytes, monocytes undergo differentiation, becoming macrophages that settle in many tissues, especially the lymphoid tissues (e.g., spleen and lymph nodes) and the liver, which serve as filters for trapping microbes and other foreign particles that arrive through the blood or the lymph. Macrophages live longer than granulocytes and, although effective as scavengers, basically provide a different function. Compared with granulocytes, macrophages move relatively sluggishly. They are attracted by different stimuli and usually arrive at sites of invasion later than granulocytes. Macrophages recognize and ingest foreign particles by mechanisms that are basically similar to those of granulocytes, although the digestive process is slower and not as complete. This aspect is of great importance for the role that macrophages play in stimulating specific immune responses—something in which granulocytes play no part (see Activation of T and B lymphocytes).

 

Natural killer (NK) cells

Natural killer cells do not attack invading organisms directly but instead destroy the body's own cells that have either become cancerous or been infected with a virus. NK cells were first recognized in 1975, when researchers observed cells in the blood and lymphoid tissues that were neither the scavengers described above nor ordinary lymphocytes but which nevertheless were capable of killing cells. Although similar in outward appearance to lymphocytes, NK cells contain granules that harbour cytotoxic chemicals. NK cells recognize dividing cells by a mechanism that does not depend on specific immunity. They then bind to these dividing cells and insert their granules through the outer membrane and into the cytoplasm. This causes the dividing cells to leak and die. It is not certain whether NK cells belong to a distinct lineage or are a special form of lymphocyte. It is known that they are stimulated by gamma interferon. Their main biological role may be to regulate the growth of stem cells in the bone marrow and elsewhere.

 

Nonspecific responses to infection

The body has a number of nonspecific methods of fighting infection that are called early induced responses. They include the acute-phase response and the inflammation response, which can eliminate infection or hold it in check until specific, acquired immune responses have time to develop. Nonspecific immune responses occur more rapidly than acquired immune responses do, but they do not provide lasting immunity to specific pathogens.

Nonadaptive immune responses rely on a number of chemical signals, collectively called cytokines, to carry out their effects. These cytokines include members of the family of proteins called interleukins, which induce fever and the acute-phase response, and tumour necrosis factor-alpha, which initiates the inflammatory response.

 

Acute-phase response

When the body is invaded by a pathogen, macrophages release the protein signals interleukin-1 (IL-1) and interleukin-6 (IL-6) to help fight the infection. One of their effects is to raise the temperature of the body, causing the fever that often accompanies infection. (The interleukins increase body temperature by acting on the temperature-regulating hypothalamus in the brain and by affecting energy mobilization by fat and muscle cells.) Fever is believed to be helpful in eliminating infections because most bacteria grow optimally at temperatures lower than normal body temperature. But fever is only part of the more general innate defense mechanism called the acute-phase response. In addition to raising body temperature, the interleukins stimulate liver cells to secrete increased amounts of several different proteins into the bloodstream. These proteins, collectively called acute-phase proteins, bind to bacteria and, by doing so, activate complement proteins that destroy the pathogen. The acute-phase proteins act similarly to antibodies but are more democratic—that is, they do not distinguish between pathogens as antibodies do but instead attack a wide range of microorganisms equally. Another effect the interleukins have is to increase the number of circulating neutrophils and eosinophils, which help fight infection.

 

Inflammatory response

Infection often results in tissue damage, which may trigger an inflammatory response. The signs of inflammation include pain, swelling, redness, and fever, which are induced by chemicals released by macrophages. These substances promote blood flow to the area, increase the permeability of capillaries, and induce coagulation. The increased blood flow is responsible for redness, and the leakiness of the capillaries allows cells and fluids to enter tissues, causing pain and swelling. These effects bring more phagocytic cells to the area to help eliminate the pathogens. The first cells to arrive, usually within an hour, are neutrophils and eosinophils, followed a few hours later by macrophages. Macrophages not only engulf pathogens but also help the healing process by disposing of cellular debris which accumulates from destroyed tissue cells and neutrophils that self-destruct after ingesting microorganisms. If infection persists, components of specific immunity—antibodies and T cells—arrive at the site to fight the infection.

 

Specific, acquired immunity

It has been known for centuries that persons who have contracted certain diseases and survived generally do not catch those illnesses again. The Greek historian Thucydides recorded that, when the plague was raging in Athens during the 5th century BC, the sick and dying would have received no nursing at all had it not been for the devotion of those who had already recovered from the disease; it was known that no one ever caught the plague a second time. The same applies, with rare exceptions, to many other diseases, such as smallpox, chicken pox, measles, and mumps. Yet having had measles does not prevent a child from contracting chicken pox, or vice versa. The protection acquired by experiencing one of these infections is specific for that infection; in other words, it is due to specific, acquired immunity, also called adaptive immunity.

There are other infectious conditions, such as the common cold, influenza, pneumonia, and diarrheal diseases, that can be caught again and again; these seem to contradict the notion of specific immunity. But the reason such illnesses can recur is that many different infectious agents produce similar symptoms (and thus the same disease). For example, more than 100 viruses can cause the cluster of symptoms known as the common cold. Consequently, even though infection with a particular agent does protect against reinfection by that same pathogen, it does not confer protection from other pathogens that have not been encountered.

Acquired immunity is dependent on the specialized white blood cells known as lymphocytes. This section describes the various ways in which lymphocytes operate to confer specific immunity. Although pioneer studies were begun in the late 19th century, most of the knowledge of specific immunity has been gained since the 1960s, and new insights are continually being obtained.

 

The nature of lymphocytes

General characteristics

Location in the lymphatic system

 

 

• The human lymphatic system, showing the lymphatic vessels and lymphoid organs.

Lymphocytes are the cells responsible for the body's ability to distinguish and react to an almost infinite number of different foreign substances, including those of which microbes are composed. Lymphocytes are mainly a dormant population, awaiting the appropriate signals to be stirred to action. The inactive lymphocytes are small, round cells filled largely by a nucleus. Although they have only a small amount of cytoplasm compared with other cells, each lymphocyte has sufficient cytoplasmic organelles (small functional units such as mitochondria, the endoplasmic reticulum, and a Golgi apparatus) to keep the cell alive. Lymphocytes move only sluggishly on their own, but they can travel swiftly around the body when carried along in the blood or lymph. At any one time an adult human has approximately 2 × 10¹² lymphocytes, about 1 percent of which are in the bloodstream. The majority are concentrated in various tissues scattered throughout the body, particularly the bone marrow, spleen, thymus, lymph nodes, tonsils, and lining of the intestines, which make up the lymphatic system (see illustration). Organs or tissues containing such concentrations of lymphocytes are termed lymphoid. The lymphocytes in lymphoid structures are free to move, although they are not lying loose; rather, they are confined within a delicate network of lymph capillaries located in connective tissues that channel the lymphocytes so that they come into contact with other cells, especially macrophages, that line the meshes of the network. This ensures that the lymphocytes interact with each other and with foreign materials trapped by the macrophages in an ordered manner.

 

T and B cells

Lymphocytes originate from stem cells in the bone marrow; these stem cells divide continuously, releasing immature lymphocytes into the bloodstream. Some of these cells travel to the thymus, where they multiply and differentiate into T lymphocytes, or T cells. The T stands for thymus-derived, referring to the fact that these cells mature in the thymus. Once they have left the thymus, T cells enter the bloodstream and circulate to and within the rest of the lymphoid organs, where they can multiply further in response to appropriate stimulation. About half of all lymphocytes are T cells.

Some lymphocytes remain in the bone marrow, where they differentiate and then pass directly to the lymphoid organs. They are termed B lymphocytes, or B cells, and they, like T cells, can mature and multiply further in the lymphoid organs when suitably stimulated. Although it is appropriate to refer to them as B cells in humans and other mammals, because they are bone-marrow derived, the B actually stands for the bursa of Fabricius, a lymphoid organ found only in birds, the organisms in which B cells were first discovered.

B and T cells both recognize and help eliminate foreign molecules (antigens), such as those that are part of invading organisms, but they do so in different ways. B cells secrete antibodies, proteins that bind to antigens. Since antibodies circulate through the humours (i.e., body fluids), the protection afforded by B cells is called humoral immunity. T cells, in contrast, do not produce antibodies but instead directly attack invaders. Because this second type of acquired immunity depends on the direct involvement of cells rather than antibodies, it is called cell-mediated immunity. T cells recognize only infectious agents that have entered into cells of the body, whereas B cells and antibodies interact with invaders that remain outside the body's cells. These two types of specific, acquired immunity, however, are not as distinct as might be inferred from this description, since T cells also play a major role in regulating the function of B cells. In many cases an immune response involves both humoral and cell-mediated assaults on the foreign substance. Furthermore, both classes of lymphocytes can activate or enhance a variety of nonspecific immune responses.

 

Ability to recognize foreign molecules

Receptor molecules

Lymphocytes are distinguished from other cells by their capacity to recognize foreign molecules. Recognition is accomplished by means of receptor molecules. A receptor molecule is a special protein whose shape is complementary to a portion of a foreign molecule. This complementarity of shape allows the receptor and the foreign molecule to conform to each other in a fashion roughly analogous to the way a key fits into a lock.

Receptor molecules are either attached to the surface of the lymphocyte or secreted into fluids of the body. B and T lymphocytes both have receptor molecules on their cell surfaces, but only B cells manufacture and secrete large numbers of unattached receptor molecules, called antibodies. Antibodies correspond in structure to the receptor molecules on the surface of the B cell.

 

Antigens

Any foreign material—usually of a complex nature and often a protein—that binds specifically to a receptor molecule made by lymphocytes is called an antigen. Antigens include molecules found on invading microorganisms, such as viruses, bacteria, protozoans, and fungi, as well as molecules located on the surface of foreign substances, such as pollen, dust, or transplanted tissue. When an antigen binds to a receptor molecule, it may or may not evoke an immune response. Antigens that induce such a response are called immunogens. Thus, it can be said that all immunogens are antigens, but not all antigens are immunogens. For example, a simple chemical group that can combine with a lymphocyte receptor (i.e., is an antigen) but does not induce an immune response (i.e., is not an immunogen) is called a hapten. Although haptens cannot evoke an immune response by themselves, they can become immunogenic when joined to a larger, more complex molecule such as a protein, a feature that is useful in the study of immune responses.

Many antigens have a variety of distinct three-dimensional patterns on different areas of their surfaces. Each pattern is called an antigenic determinant, or epitope, and each epitope is capable of reacting with a different lymphocyte receptor. Complex antigens present an “antigenic mosaic” and can evoke responses from a variety of specific lymphocytes. Some antigenic determinants are better than others at effecting an immune response, presumably because a greater number of responsive lymphocytes are present. It is possible for two or more different substances to have an epitope in common. In these cases, immune components induced by one antigen are able to react with all other antigens carrying the same epitope. Such antigens are known as cross-reacting antigens.

T cells and B cells differ in the form of the antigen they recognize, and this affects which antigens they can detect. B cells bind to antigen on invaders that are found in circulation outside the cells of the body, while T cells detect only invaders that have somehow entered the cells of the body. Thus foreign materials that have been ingested by cells of the body or microorganisms such as viruses that penetrate cells and multiply within them are out of reach of antibodies but can be eliminated by T cells.

 

Diversity of lymphocytes

The specific immune system (in other words, the sum total of all the lymphocytes) can recognize virtually any complex molecule that nature or science has devised. This remarkable ability results from the trillions of different antigen receptors that are produced by the B and T lymphocytes. Each lymphocyte produces its own specific receptor, which is structurally organized so that it responds to a different antigen. After a cell encounters an antigen that it recognizes, it is stimulated to multiply, and the population of lymphocytes bearing that particular receptor increases.

How is it that the body has such an incredible diversity of receptors that are always ready to respond to invading molecules? To understand this, a quick review of genes and proteins will be helpful. Antigen receptor molecules are proteins, which are composed of a few polypeptide chains (i.e., chains of amino acids linked together by chemical bonds known as peptide bonds). The sequence in which the amino acids are assembled to form a particular polypeptide chain is specified by a discrete region of DNA, called a gene. But, if every polypeptide region of every antigen receptor were encoded by a different gene, the human genome (all the genetic information encoded in the DNA that is carried on the chromosomes of cells) would need to devote trillions of genes to code just for these immune system proteins. Since the entire human genome contains approximately 30,000 genes, individuals cannot inherit a gene for each particular antigen receptor component. Instead, a mechanism exists that generates an enormous variety of receptors from a limited number of genes.

What is inherited is a pool of gene segments for each type of polypeptide chain. As each lymphocyte matures, these gene segments are pieced together to form one gene for each polypeptide that makes up a specific antigen receptor. This rearrangement of alternative gene segments occurs predominantly, though not entirely, at random, so that an enormous number of combinations can result. Additional diversity is generated from the imprecise recombination of gene segments—a process called junctional diversification—through which the ends of the gene segments can be shortened or lengthened. The genetic rearrangement takes place at the stage when the lymphocytes generated from stem cells first become functional, so that each mature lymphocyte is able to make only one type of receptor. Thus, from a pool of only hundreds of genes, an unlimited variety of diverse antigen receptors can be created.

Still other mechanisms contribute to receptor diversity. Superimposed on the mechanism outlined in simplified terms above is another process, called somatic mutation. Mutation is the spontaneous occurrence of small changes in the DNA during the process of cell division. It is called somatic when it takes place in body cells (Greek soma means “body”) rather than in germ-line cells (eggs and sperm). Although somatic mutation can be a chance event in any body cell, it occurs regularly in the DNA that codes for antigen receptors in lymphocytes. Thus, when a lymphocyte is stimulated by an antigen to divide, new variants of its antigen receptor can be present on its descendant cells, and some of these variants may provide an even better fit for the antigen that was responsible for the original stimulation.

 

B-cell antigen receptors and antibodies

The antigen receptors on B lymphocytes are identical to the binding sites of antibodies that these lymphocytes manufacture once stimulated, except that the receptor molecules have an extra tail that penetrates the cell membrane and anchors them to the cell surface. Thus, a description of the structure and properties of antibodies, which are well studied, will suffice for both.

 

Basic structure of the immunoglobulin molecule

 

 

• The four-chain structure of an antibody, or immunoglobulin, molecule

Antibodies belong to the class of proteins called globulins, so named for their globular structure. Collectively, antibodies are known as immunoglobulins (abbreviated Ig). All immunoglobulins have the same basic molecular structure, consisting of four polypeptide chains. Two of the chains, which are identical in any given immunoglobulin molecule, are heavy (H) chains; the other two are identical light (L) chains. The terms heavy and light simply mean larger and smaller. Each chain is manufactured separately and is encoded by different genes. The four chains are joined in the final immunoglobulin molecule to form a flexible Y shape, which is the simplest form an antibody can take.

At the tip of each arm of the Y-shaped molecule is an area called the antigen-binding, or antibody-combining, site, which is formed by a portion of the heavy and light chains. Every immunoglobulin molecule has at least two of these sites, which are identical to one another. The antigen-binding site is what allows the antibody to recognize a specific part of the antigen (the epitope, or antigenic determinant). If the shape of the epitope corresponds to the shape of the antigen-binding site, it can fit into the site—that is, be “recognized” by the antibody. Chemical bonds called weak bonds then form to hold the antigen within the binding site.

The heavy and light chains that make up each arm of the antibody are composed of two regions, called constant (C) and variable (V). These regions are distinguished on the basis of amino acid similarity—that is, constant regions have essentially the same amino acid sequence in all antibody molecules of the same class (IgG, IgM, IgA, IgD, or IgE), but the amino acid sequences of the variable regions differ quite a lot from antibody to antibody. This makes sense, because the variable regions determine the unique shape of the antibody-binding site. The tail of the molecule, which does not bind to antigens, is composed entirely of the constant regions of heavy chains.