chronic granulomatous disease

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Chronic Granulomatous Disease

 

Definition

Chronic granulomatous disease (CGD) is an inherited disorder in which white blood cells lose their ability to destroy certain bacteria and fungi.

Description

CGD is an X-linked genetic disease, meaning the defective gene is carried on the X chromosome (one of the sex chromosomes). Females have two copies of the X chromosome, whereas males have one X and one Y. CGD also is a recessive defect meaning that both copies of the chromosome must have the defect before it can be expressed. Females who have one X chromosome without the defect do not get this disease. Males, since they only have one X chromosome, get the disease if the defect is present. Thus, CGD affects mostly males.
CGD is an immunodeficiency disorder. Patients with immunodeficiency disorders suffer frequent infections. This happens because part of their immune system isn't working properly and the infectious microorganisms are not killed as rapidly as is normal. In CGD there is a defect in the ability of the white blood cells to kill bacteria and fungi. The white blood cells affected are phagocytic cells. They are part of the non-specific immune system and move via the blood to all parts of the body where they ingest and destroy microbes. Phagocytic cells are the first line of defense against microorganisms. In this disease, the decreased ability to kill microbes that they have ingested leads to a failure to effectively combat infectious diseases. Patients with CGD are subject to certain types of recurring infection, especially those of the skin, lungs, mouth, nose, intestines, and lymph nodes. With the exception of the lymph nodes, all of these areas are considered external tissues that come into contact with microorganisms from the environment. The lymph system drains all areas of the body to eliminate destroyed microorganisms and to assist the immune system in attacking microorganisms. Infections occur in the lymph nodes as a consequence of the normal draining function.

Causes and symptoms

The genetic defect that causes CGD reduces the amount of hydrogen peroxide and superoxide that white blood cells can make. These chemicals are important for killing bacteria and fungi. Without them the white blood cells ingest the microorganisms, but cannot kill them. In some cases, the microbes then replicate inside the white blood cell eventually causing its death.
Symptoms of the disease usually appear by age two. Frequent, recurrent infections of the skin, lungs (e.g. pneumonia), mouth (e.g. gingivitis), nose, intestines and lymph nodes are a hallmark of this disease. Patients may also develop multiple, recurrent liver abscesses and bone infections (osteomyelitis).

Diagnosis

Diagnosis is made based on the observation of a pattern of recurrent infections. Blood tests of lymphocyte and antibody functions will be normal. Tests of phagocytic cells will show normal ingestion, but a greatly decreased ability to kill bacteria.

Treatment

Early, aggressive treatment of all infections is critical to the successful management of CGD. Patients are treated with antibiotics and immune serum. Antibiotics are used at the first sign of infection. Immune serum is a source of antibodies that help fight infections. Interferon gamma is an experimental treatment for CGD that has shown promising results. There is no cure for the underlying cause of chronic granulomatous disease

Prognosis

Although antibiotics can treat most infections and may help prevent others, premature death may result, typically due to repeated lung infections.

Prevention

Since CGD is a hereditary disorder, it cannot currently be prevented. Patients and their families may benefit from genetic counseling. Preventive (prophylactic) antibiotics may help keep some infections from occurring, and good hygiene, especially rigorous skin and mouth care, can help prevent infections in these areas. Avoiding crowds or other people who have infections are also effective preventive measures.

Resources

Organizations

Chronic Granulomatous Disease Association. 2616 Monterey Road, San Marino, CA 91108-1646. (818) 441-4118.
National Organization for Rare Disorders. P.O. Box 8923, New Fairfield, CT 06812-8923. (800) 999-6673. http://www.rarediseases.org.

Key terms

Immunodeficiency — A weakening of the body's immune system.
Phagocytic cells — A cell that ingests microorganisms and foreign particles.

chronic

 [kron´ik]
persisting for a long time; applied to a morbid state, designating one showing little change or extremely slow progression over a long period.
chronic airflow limitation (CAL) any pulmonary disorder occurring as a result of increased airway resistance or of decreased elastic recoil; the diseases most often associated are asthma, chronic bronchitis, and chronic pulmonary emphysema. Called also chronic obstructive pulmonary disease.

Chronic airflow limitation has the highest morbidity rate of any significant chronic pulmonary disorder in the United States and is the second most common cause of hospital admissions. It is difficult to estimate its exact incidence because most diseases of the respiratory tract are not reportable and there is some confusion in definition of terms related to diseases of this type. However, the Social Security Administration reports that CAL ranked only second to heart disease as the cause of disability in men over the age of 40. The incidence of CAL is increasing and, although not all specific causes are known, factors contributing to its development and affecting its degree of severity have been identified. Heavy cigarette smoking is probably the most important factor, and others are industrial pollution, occupational exposure to irritating inhalants, allergy, autoimmunity, genetic predisposition, and chronic infections.

Prevention is best accomplished through education of the public about the hazards of cigarette smoking and air pollution and the need for early detection and prompt treatment of respiratory disorders that could become chronic in nature. The American Lung Association is particularly interested in education of lay persons in these matters and in the prevention of all types of respiratory disorders. This agency, which has local offices distributed throughout the country, is an excellent source of information about prevention and the latest developments in the treatment of respiratory diseases.
Symptoms. This is an insidious disease that can develop into advanced lung damage almost before its victim is aware that the condition is serious. The early symptoms are shortness of breath upon exertion, a mild cough (sometimes called “smoker's cough”), which occurs most often in the morning, and easy fatigability that follows even minimal physical effort. Prompt treatment of these symptoms can forestall the more serious effects of extensive lung damage; however, the destruction of lung tissue and bronchial mucosa damage that has already occurred by the time these symptoms appear is irreversible.

As the disease progresses, the symptoms of dyspnea, weakness, and cough become more severe. The patient has difficulty expelling air from the lungs and the cough becomes more productive of thick, tenacious sputum. The patient looks anxious and drawn and may speak in short, hesitant sentences. Symptoms related to disturbances of the respiratory and circulatory systems and acid-base balance may appear as these complications develop.
Complications. Destructive involvement of respiratory structures and the resultant impairment of circulatory function can produce serious life-threatening complications. Among these are acute respiratory failure, disturbance in the acid-base balance (which can occur either as uncompensated respiratory acidosis or metabolic alkalosis), bronchopulmonary infections, cor pulmonale (the result of increased resistance in pulmonary circulation), pulmonary embolism (especially if polycythemia is severe), and peptic ulcer. blood gas analysis is helpful in evaluating effectiveness of blood gas exchange across alveolar walls. In severe chronic airflow limitation, the PaCO2 level is high while the PaO2 and the SaO2 levels are low.
Treatment and Patient Care. In general, treatment is concerned with restoring and maintaining existing lung function, relieving symptoms, and planning a program of rehabilitation tailored to accommodate the individual patient's physiologic needs, physical stamina, vocational needs, lifestyle, and personality. Specific measures of patient care are concerned with (1) initial and periodic evaluation of patient status, (2) maintenance of general health as much as possible, (3) prevention and control of infection, (4) improvement of ventilation, and (5) patient education.

Chronic airflow limitation is a disease that has no cure; its chronic nature requires an ongoing program of assessment and long-term care that is planned and revised as the patient's needs dictate. Whatever the patient care setting—acute care facility, out-patient clinic, long-term care facility, or home—the elements of care presented below are essential to the effective management of the condition.
Evaluation. Patient assessment begins with the taking of the patient's history and performing physical examination and lung function tests at the time the diagnosis is established. These measures, along with blood gas analysis at rest and after exercise, provide a baseline for periodic evaluation of the patient's status to determine the progress of the disease and the effectiveness of treatment.

When patients are informed about the purpose of the tests and therapy they are more likely to participate in the planned regimen of care and to become motivated to continue carrying out their responsibilities in the management of their illness. Those who work with the patient should clarify the goals and offer encouragement when they make progress toward those goals, no matter how slight the improvement might be. This implies, of course, that all members of the health care team have an understanding of the disease, the meaning of various test values, and the purpose of each aspect of care.
Maintenance of Health Status. It is important to communicate to these patients the concept of health status, particularly in regard to their position on the health-illness continuum. They cannot be completely disease-free or restored to their former state of health. They can, however, manage the disease symptoms for periods of time and some may even make progress toward a better state of health. For those patients who continue to deteriorate despite appropriate care, encouragement should be provided to maintain as much function as possible.

Poor appetite and the potential for dehydration are problems commonly associated with pulmonary disease. Purulent sputum, coughing, and fatigue can contribute to loss of interest in eating. Mouth breathing, increased respiratory rate, and frequent expectorating contribute to the loss of fluid.

Frequent oral hygiene and mouth care can help diminish mouth odor and unpleasant taste. A short period of rest just prior to each meal can help overcome the problem of fatigue. Meals should be spaced so that the stomach is not overloaded at any one time; five small meals, rather than three a day, can help avoid overfilling of the stomach and interference with breathing. Postural drainage and similar procedures should not be done on a full stomach, nor should they be scheduled just before a meal. Adequate hydration can be accomplished by an intake of at least 3000 ml of liquid each day. Unless contraindicated, this should include bouillon, fruit juices, and other liquids the patient finds enjoyable and refreshing.

Physical activity may be severely limited by CAL because of inadequate ventilation and decreased circulation. As with all other aspects of patient care, plans to increase exercise tolerance and promote physical activity should be designed according to the patient's cardiopulmonary status. Techniques to promote muscular relaxation and breathing control are the first step, followed by gradual increase in activity as the patient's progress and general physical condition permit.

Adequate rest is essential, but the hazards of immobility must be avoided, especially in patients who are fearful that any physical activity may precipitate an exhausting episode of coughing and dyspnea. The goal is to provide sufficient rest so that the body's natural restorative processes can work, but to avoid long periods of sleeping and lying in bed during the day.

When the patient's cardiopulmonary condition is such that bed rest is prescribed, care is taken to avoid complete physical inactivity, which will only serve to increase problems of inadequate ventilation and muscle weakness. Proper positioning is essential and should be such that the neck is extended, with the chin well off the chest. Support under the thighs while the patient is supine will release tension on abdominal muscles, thereby facilitating movement of the diaphragm for deep breathing and effective coughing. The arms and hands should also be supported on pillows and positioned away from the sides to allow for maximum lung expansion without elevation of the upper chest. A foot board is placed so as to maintain good posture, promote comfort, and ensure good muscle tone in the legs and feet.
Prevention and Control of Infection. Acute respiratory infection can be fatal in patients with chronic airflow limitation. Chronic infections inflict further damage to the respiratory structures, lead to increased debilitation, and increase the likelihood of severe complications. Both acute and chronic infections produce increased secretions in the air passages, which further restrict the flow of air.

Contact with others who have an upper respiratory infection should be avoided, as should being in large crowds during the season when such infections are common. A high level of resistance should be maintained through good personal hygiene and adequate nutrition. Vaccines to guard against influenza are recommended. Patients should be taught to watch for changes in color and amount of sputum. If a change in sputum or any other symptoms of infection appear, this should be reported.
Improvement of Ventilation. It is obvious that measures to improve ventilation in the patient with CAL are of primary importance, and perhaps that is why so many ways have been devised to facilitate the flow of air to and from the lungs. Breathing is most difficult during the expiratory phase, making it difficult to remove trapped air and secretions. In addition, the bronchial walls are weakened in patients with emphysema and are subject to collapse. Health status and physical condition at the time the technique is used will affect the choice of method and its effectiveness.

Hydration is considered especially valuable in improvement of ventilation. Inhaled air should be moist so as to thin the secretions for removal and soothe the irritated mucous membranes. This can be accomplished through the use of vaporizers and humidifiers, either for environmental humidification in the patient's room or in conjunction with oxygen therapy and the administration of aerosols. Oral intake of fluids is also important. Bronchodilators, usually in the form of aerosols, sometimes as oral medications, are usually prescribed. The aerosol method of delivery depends on the ability of the patient to breathe deeply so that the medication reaches the lower segments of the respiratory tract.

Controlled deep breathing patterns are especially helpful in emptying the lungs and providing adequate ventilation. The patient with CAL is taught to expand the lower chest and to use the accessory muscles and diaphragm to improve the breathing pattern. Performance of these breathing patterns is important because patients probably are not in the habit of breathing in the most effective manner, making optimum use of remaining pulmonary function. The patient is taught slow, controlled, and steady breathing. Respiratory effort should be concentrated on slow expiratory flow through parted or pursed lips. Pushing the air out of the lungs too forcefully can bring on collapse of the airway structures. During instruction, the caregiver watches for signs of exhaustion and warns against overdoing the deep breathing until the patient has adjusted to it. A correct breathing pattern should be coordinated with all of the patient's daily activities so that it becomes habitual and is done without too much thought.

Effective coughing does not come easily to patients with this condition. They may have experienced too many episodes in which a dry hacking cough has caused exhaustion, increased dyspnea, and prevented removal of tenacious sputum from the air passages. They must be convinced that, when done correctly, coughing can remove mucous plugs and relieve rather than produce dyspnea. Patients should be warned that explosive coughing is not very effective, can damage the airways, and can lead to exhaustion. The objective of coughing is to move secretions upward gradually so that they can be expectorated.

Postural drainage is also valuable in facilitating the removal of mucus from the air passages. The various maneuvers involved in this procedure are designed to take advantage of gravity flow as a means of clearing specified segments of the air passages when normal air flow is not sufficient to move secretions or stimulate the cough reflex. Chest percussion and vibration may be employed during postural drainage to loosen secretions. oxygen therapy is used as a supportive measure when there is decreased oxygenation of arterial blood. It can be administered to ambulatory patients being cared for at home. Blood gas analysis is an excellent guide in determining the need for initiating oxygen therapy and for monitoring dosage.
Patient Education. As with all chronic diseases that require long-term planning and management, patient education is of primary importance in successful execution of the plan. Each of the measures previously described involves instruction of the patient and family, particularly when care is carried out on an outpatient basis. The patient should be told why it is necessary to stop smoking, avoid other irritating inhalants, carry out good health practices, take medication only as prescribed, and faithfully perform techniques to improve ventilation. Those patients who follow the exercises prescribed for them often find they can lead more active lives than formerly. Exertional dyspnea becomes less severe and complications from infections caused by bacteria in secretions formerly trapped in the respiratory tract are less frequent. Active participation in a program of self-care gives these patients a sense of control and improves their self-esteem.
chronic fatigue syndrome (chronic fatigue and immunodeficiency syndrome) persistent debilitating fatigue of recent onset, with reduction of physical activity to less than half of usual, accompanied by some combination of muscle weakness, sore throat, mild fever, tender lymph nodes, headaches, and depression, with the symptoms not attributable to any other known causes. Its nature is controversial; viral infection (including Epstein-Barr virus and human herpesvirus-6) may be associated with it, but no causal relationship has been demonstrated. A number of names have been used for this syndrome, including Iceland disease and benign myalgic encephalomyelitis.
chronic granulomatous disease chronic suppurative lymphadenitis, eczematoid dermatitis, enlargement of the liver and spleen, and chronic pulmonary disease associated with a genetically determined defect in the intracellular bactericidal function of leukocytes.
chronic obstructive lung disease (COLD) (chronic obstructive pulmonary disease (COPD)) chronic airflow limitation.
chronic regional pain syndrome reflex sympathetic dystrophy.

chron·ic gran·u·lom·a·tous dis·ease

a congenital defect in the killing of phagocytosed bacteria by polymorphonuclear leukocytes, which cannot increase their oxygen metabolism due to dysfunctional NADPH oxidase, either because of defective cytochrome [MIM*233710 and MIM*233690] or other specific factor deficiencies [MIM*233700 and MIM*306400]. As a result there is an increased susceptibility to severe infection by catalase-positive microorganisms; inheritance is usually autosomal recessive or X-linked.

chronic granulomatous disease

sex-linked recessive disorder in which myeloperoxidase is diminished in the primary granules of neutrophils, causing delayed intracellular killing of fungi and bacteria by neutrophils.

chronic granulomatous disease

Any of a heterogeneous group of inherited (2/3 are X-linked; 1/3 autosomal recessive) phagocytic defects, characterised by recurrent and potentially fatal pyogenic infections of early onset. PMNs ingest pathogens, but do not produce superoxide and microbicidal oxygen intermediates (the respiratory burst) due to defective NADPH oxidase, resulting in recurrent infections by catalase-bacteria—e.g., Staphylococcus aureus, Enterobacteriaceae, Aspergillus spp—and fungi with sinusitis, pneumonia and abscess formation; male:female ratio, 4:1.
 
Diagnosis
Nitroblue tetrazolium test (see there) is negative due to defective NADPH oxidase; other assays directly measure (via luminol) enhanced chemiluminescence superoxide production or fluorescent substrate oxidation.
 
Management
Allogeneic haematopoietic stem cell transplantation from an HLA-identical donor is currently the only proven curative treatment for CGD. Less effective is prophylaxis with trimethoprim-sulfamethoxazole, itraconazole and in some cases, interferon gamma.

chronic granulomatous disease

Immunology Any of a heterogeneous group of inherited (23 are X-linked;13 AR) phagocytic defects, characterized by recurrent and potentially fatal pyogenic infections of early onset; PMNs ingest pathogens, but don't produce superoxide and microbicidal oxygen intermediates–the respiratory 'burst'–due to defective NADPH oxidase, resulting in recurrent infections by catalase-bacteria–eg, S aureus, Enterobacteriaceae, Aspergillus spp, and fungi with sinusitis, pneumonia, abscess formation; ♂:♀ ratio 4:1 Management IFN-γ may ↓ serious infection by 'boosting' the immune system

chron·ic gran·u·lom·a·tous dis·ease

(kron'ik gran'yū-lom'ă-tŭs di-zēz')
A congenital defect in the killing of phagocytized bacteria by polymorphonuclear leukocytes; results in increased susceptibility to severe infection.
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