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Sumy State University Internal Medicine Department Methodological Instructions for the 4th course students, 8 semester Module 2 “Pulmonology, Haematology” Prepared by Orlovsky A. V., assistant, D.Ph, Murenets N. A., postgraduate Sumy - 2009 Methodological Instruction to Lesson № 1. Propedeutics in pulmonology. Hours: 5. Working place: classroom, hospital wards. Questions. 1. Structure of the bronchial tree. 2. Determination of the lungs border. 3. Structure of the respiratory segment (part) of the lung. 4. Comparative percussion of the lungs. 5. Blood supply of the lung. 6. Cough, its characteristics. 7. Structure of the bronchial mucous. Concept of bronchial clearance. 8. Rales and their characteristics. 9. Physiology of respiration. 10.What is vocal fremites and method of its indication? 11.Show the spirogram schematically. What is the purpose of the spirogram? 12.Name kinds of dispnoea. 13.What is forced expiration volume in 1 second (FEV1), forced vital capacity (FVC)? 14.Comparative percussion of the lungs. 15.What is this pneumotachometry? 16.Name main symptoms of respiratory diseases. 17.Name main groups of drugs in patients with respiratory diseases. References. 1. Propedeutics to Internal medicine Part 1 Diagnostics/O. M. Kovalyova, T. V. Ashcheulova. – Vinnytsya. – 2006. – P.60 - 138. 2. Davidson’s Principles and practice of medicine (nineteenth edition)/Christopher Haslett, Edvin R. Chilvers and others. – Edinburgh, 2002. Prepared by Orlovsky A. V., assistant, D.Ph., Murenets N. A., postgraduate Methodological Instruction to Lesson № 2. Chronic obstructive pulmonary disease (COPD). Hours: 5. Working place: classroom, hospital wards. Questions. 1. Give the definition of COPD. 2. Etyology of COPD. Give external and internal risk factors of COPD. 3. Pathogenesis of COPD. What reflects airflow limitation. 4. Pathology of COPD. 5. Clinical symptoms of COPD. 6. Name co-morbidities in patients with COPD. 7. Physical findings of patients with COPD. 8. X-Ray findings of patients with COPD. 9. Studing of external respiration functions. Spyrometry. 10.Clinical and functional monitoring. 11.Give the classification of COPD. 12.Name main treatment principles of patients with COPD. 13.Name drug, which are used in treatment of patients with COPD. 14.Name the phaemacotherapy for patienta with COPD depending on the level of gravity of the disease. 15.Role of glucocorticosteroids in treatment of patients with COPD. 16.Name the other pharmacological treatment of patients with COPD. 17.Rehabilitation of patients with COPD. 18.Name the reasons exacerbations of COPD. 19.Algorithm of managing exacerbation of COPD in the outpatient setting. 20.Name the indications for hospitalisation in case of exacerbation of COPD. 21.Name the indications to antibacterial therapy. What is influenced on choosing antibacterial therapy. 22.Name antibacterial therapy of patients with COPD. Examples of tests 1. What is the most important cause of COPD? a. exposure to dusty or polluted air b. alpha1- antitrypsin deficiency c. cigarette smoking d. familial predisposition e. low birth weight 2. Chronic cough, which characterised COPD, is: a. cough precedes dyspnea b. cough is parallel to dyspnea c. cough after marked dyspnea d. there are no defined law e. cough may be absent 3. Inhalation β2- agonists of short – term action are the following drugs, except: a. Salbutamol b. c. Fenoterol Terbutalin d. Salmeterol 4. The main symptoms of the COPD are: a. abdominal pain and diarrhea,vomiting b. cough c. headache d. constipation e. sneezing 5. Differential diagnosis of the COPD with: a. Asthma b. Peritonitis c. Piothorax d .appendicitis e.myocardial infarction 6. The Symptoms and Signs of the COPD are: A. constipation B. bloody vomiting C. frequent headache D. chronic cough and sputum production E. sneezing Answers to the self-assessment: 1-c, 2-a, 3-d, 4-b, 5-a, 6-d References. 1. Therapy: Manual. The course of lectures/V. M. Fedosyeyeva, A. A. Chrenov. – Simferopol, 2003. – 27 - 37 p. 2. Davidson’s Principles and practice of medicine (nineteenth edition)/Christopher Haslett, Edvin R. Chilvers and others. – Edinburgh, 2002. – 508-513 p. 3. Harrisons Principle if internal medicine (seventeenth Edition)/Fauci, Braunwald, Hasper and other. – Part 10, section 2, Chapter 254. 4. The Merck Manual of Diagnosis and Therapy (seventeenth Edition)/ Robert Berkow, Andrew J. Fletcher and others. – published by Merck Research Laboratories, 1999. Short theoretic material CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) Chronic obstructive pulmonary disease is the internationally preferred term encompassing chronic bronchitis and emphysema. By definition COPD is a chronic, slowly progressive disorder characterised by airflow obstruction (FEV1 < 80% predicted and FEV1/VC ratio <70%) which does not change markedly over several months. The impairment of lung function is largely fixed but may be partially reversible by bronchodilator therapy. Historically, the term 'chronic ronchitis' was used to define any patient who coughed up sputum on most days of at least 3 consecutive months for more than 2 successive years (provided other causes of cough had been excluded) and 'emphysema' referred to the pathological process of a permanent destructive enlargement of the airspaces distal to the terminal bronchioles. Although 'pure' forms of these two conditions do exist, there is considerable overlap in the vast majority of patients. The death rate from COPD currently exceeds 25 000/year (> 20-fold higher than asthma) in England and Wales and this condition accounts for over 10% of all hospital medical dmissions in the United Kingdom. Etiology The single most important cause of COPD is cigarette smoking although in developing countries exposure to smoke from biomass and solid fuel fires is also important. Smoking is thought to have its effect by inducing persistent airway inflammation and causing a direct imbalance in oxidant/antioxidant capacity and proteinase/antiproteinase load in the lungs. Individual susceptibility to smoking is, however, very wide, with only 15% of smokers likely to develop clinically significant COPD. Recent studies have also emphasised the strong familial risks associated with the development of COPD. A small additional contribution to the severity of COPD has been reported in patients exposed to dusty or polluted air. An association also exists between low birth weight, bronchial hyper-responsiveness and the development of COPD. Alpha1-antitrypsin deficiency can cause emphysema in non-smokers but this risk is increased dramatically in enzyme-deficient patients who smoke. Stopping smoking slows the average rate of the decline in FEV1 from 50-70 ml/year to 30 ml/year (i.e. equal to non-smokers). Interestingly, there is no evidence that acute exacerbations or drug therapy affect the rate of decline of the FEV1. Pathology The pathologic findings include hypoplasia and hypertrophy of the submucosal bronchial mucous glands, hyperplasia of bronchiolar goblet cells, squamous metaplasia of bronchial mucosal cells, chronic and acute inflammatory infiltrates in the bronchial submucosa, profuse inflammatory exudates in the lumens of bronchi and bronchioles, and denudation of bronchial mucosa. Airflow limitation reflects both mechanical obstruction in the small airways and loss of pulmonary elastic recoil. Loss of alveolar attachments around such airways makes them more liable to collapse during expiration. Clinical Findings Initially, cough with sputum production, often in the morning, may be the only symptom. Gradually the cough and sputum production increase and symptoms of dyspnea on exertion develop. As the disease progresses, the patient's course is usually marked by recurrent episodes of acute respiratory failure resulting from infectious exacerbations of the bronchitis. Clinically, these are marked by increased cough, change in sputum from clear and mucoid to purulent, fever, dyspnea, and varying degrees of respiratory distress. Respiratory failure often ensues, with both elevated PaCO2 and diminished PaO2. These episodes are often reversible at first with appropriate antibiotics, bronchodilators, and respiratory therapy. Signs and symptoms of cor pulmonale are frequent in chronic bronchitis and are exacerbated along with episodes of acute respiratory failure. The course of the disease is one of gradual increase in frequency and severity of episodes of acute infection and respiratory failure, eventually resulting in intubation and the need for almost constant ventilatory assistance. Death usually occurs during an episode of respiratory failure. Depending on the stage in which the patient is examined, the physical findings may vary. During relatively quiescent periods, the only finding may be increased anteroposterior diameter of the chest, hyperresonance to percussion, prolonged expiratory phase, rales, mainly low and medium-pitched, are audible in most patients, and wheezing. Later, the patient may manifest the signs and symptoms of pulmonary hypertension and right ventricular failure, ie, increased second heart sound, pedal edema, hepatomegaly, and ascites. These patients commonly have a plethoric appearance resulting from secondary polycythemia. If examined during an acute attack, the patient will be in respiratory distress, as evidenced by tachypnea and use of accessory muscles of respiration, in addition to the signs described above. Cough is often prominent, and cyanosis during acute attacks is not uncommon. X-Ray Findings Chest x-rays show evidence of pulmonary overinflation, with increased anteropostenor diameter, flattened diaphragms, and increased retrosternal air space. There are often prominent and increased bronchial markings at the lung bases, seen as parallel or tapering shadows ("tram lines"), which reflect the increased thickness of the bronchial wall. Bullae of varying sizes may be seen primarily in the upper lung fields rather than the lung bases. Studying of external respiration functions Spirometry is obligatory when diagnosing COPD. It’s also necessary for estimating the level of gravity and for periodical monitoring to assess disease progression. For patients with mild and moderate COPD slight decrease of both forced expiration volume during the first second (FEV1) and forced vital capacity of the lungs (FVCL) is characteristic. The value of FEV1 after introducing bronchial spasmolytic < 80% on the background of the ratio FEV1/FVCL < 70% proves the presence of limitation of respiratory tracts which is not fully reversible. If there is no possibility for a spirometric research, then forced expiration lasting more than 6 seconds is a rough but useful decrease detection-predictor of the ratio FEV1/FVCL < 50%. With disease progression bronchial obstruction grows, total bronchial resistance (Rtot) rises, expiratory lungs hyperinflation appears and increases, air traps develop in the lungs, which results from resilient lung return loss and respiratory tracts collapse, the structure of total lung capacity (TLC) is redistributed. In order to give an integrated assessment of these indices it’s necessary to carry out a more profound and informative research – total bodyplethysmography. In difficult diagnostic cases diffuse capacity of the lungs, which reveals gas exchange disturbances, is measured to make a decision concerning operative intervention. To carry out the monitoring of COPD progression, to assess the efficacy of prescribed medicines in certain patients annual spirometry is carried out. Thus, in healthy people annual decrease of FEV 1 is < 30ml, in patients with COPD it’s 30-60ml and more. Arterial blood gases measuring is carried out in patients with FEV1 < 40% of the due, or if clinical presentations of lung insufficiency, right heart portions insufficiency are observed. Clinical and functional monitoring Frequency of visits to a doctor depends on the gravity of COPD and grows with increase of disease gravity. Visits can be planned and unplanned (e.g. if the state worsens or undesirable therapy manifestations, exacerbations are observed, etc.). During every visit noxious agents influence, the status of smoking are estimated; also disease progression and appearance of aftereffects; efficacy of earlier prescribed medicines is assessed, if necessary – medication dosing is changed, undesirable therapy manifestations are detected; anamnesis of exacerbation is studied (frequency, gravity are estimated, the causative agent is identified, if possible); also concomitant pathology; compliance of the sick man and skills in handling inhaler are checked. Spirometric examination is carried out periodically (usually once a year or when significant aggravation of symptoms or complications are observed). Classification of COPD. There are 4 stages of COPD according to the levels of gravity of the disease which are singled out after results of examination of the patient during clinically stable period in case there is no exacerbation. Intensity of clinical signs of the disease and of functional characteristics of broncoobstructive syndrome are taken into consideration. COPD stage (levels of gravity) signs Stage and level Signs of COPD of gravity of COPD 1. mild 2. moderate - FEV1/FVCL < 70% - FEV1 ≥ 80% of the due - usually but not always chronic cough, expectorations - FEV1/FVCL < 70% - 50% ≤ FEV1 < 80% of the due - Symptoms are aggravating, exertional dyspnea and dyspnea after complications appear 3. severe - FEV1/FVCL < 70% - 30% ≤ FEV1 < 80% of the due - Dyspnea intensifies, repeated exacerbations, which worsen patients’ lives 4. very severe - FEV1/FVCL < 70%*, FEV1 < 30% of the due, or FEV1 < 30% of the due in the presence of chronic lung insufficiency - Further aggravation of symptoms, life quality is considerably worsened, exacerbations may threaten life Notice. *In case of very severe COPD and significant decrease of FVCL ratio FEV1/FVCL increases and loses diagnostic value. Treatment of patient with COPD Main treatment principles of patients with COPD are: gradual treatment intensity grows depending on the gravity level of the disease; regularity, constancy of basic therapy corresponding to the gravity level of the disease; variability of individual drug response denotes the necessity of attentive and regular monitoring of clinicofunctional characteristics of the disease. When treating COPD, preference is given to inhalation way of introducing medicines – bronchial spasmolytics, inhalation corticosteroids, combined medicines. Efficacy of this route of administration depends significantly on the patient’s mastering inhalation technique. When indicating high medication dosing and to improve inhalation technique it’s recommended to use spacers of big volume. Usage of nebuliser gives the opportunity to take high doses of medicines and to get therapeutic responses in short periods of time and at the same time to supply oxygen to the circuit (if necessary). Bronchial spasmolytics improve patency of airways, improve emptying of lungs, reducing hyperinflation, ameliorate physical endurance; play the main role in the symptomatic treatment of patients with COPD. They are prescribed both as basic therapy and to remove some acute symptoms; inhalation forms of bronchial spasmolytics are of higher value. Inhalation ß2-agonists of short-term action (salbutamol, fenoterol) have comparatively fast beginning of broncholytic action, which depends on the dosing and lasts for 4-6 hours. Inhalation ß2- agonists of prolonged action (salmeterol, formoterol fumarat) cause stronger and more stable effect during 12 hours and more, and have some anti-inflammatory action. Inhalation cholinergic antagonists of short-term action (ipratropium bromid) are characterized by dosing-depending effect with slower beginning and action lasting longer than that of ß2- agonists of short-term action. Inhalation cholinergic antagonists of long-term action (tiotropium bromid) cause stable significantly stronger broncholytic action than ipratropium, lasting for 24 hours and longer, have some anti-inflammatory action. Protracted usage of bronchial spasmolytics of prolonged action (ß2-agonist or cholinergic antagonist) or their combination depending on COPD gravity; positively influences respiratory function (improves patency of airways, reduces hyperinflation of the lungs, optimizes the structure of total lung capacity); significantly reduces dyspnea – especially aggravating symptom in patients with COPD; increases exercise tolerance; improves patients’ health in general and their quality of living; decreases the quantity of exacerbations and cases of hospitalization. Thus, regular treatment with inhalation bronchial spasmolytics of prolonged action is more effective and convenient than therapy with bronchial spasmolytics of short-term action, but it’s more costly. Xanthines have small broncholytic action and are potentially toxic. At the same time besides possible additional bronchodilation Xanthines cause some antiinflammatory action, increase respiratory muscle strength. Xanthines are bronchial spasmolytics of the second choice and may be added to earlier prescribed bronchial spasmolytics of the first choice (ß 2agonists and/or cholinergic antagonists) in cases of severe and very severe COPD in order to increase therapeutic efficacy. Glucocorticosteroids. The role of GCS in cases of COPD is less marked than in bronchial asthma. In the basic therapy of COPD inhalation GCS are prescribed according to specific indications. Oral GCSs are recommended only in cases of COPD exacerbation. Protracted administration of oral GCS in the basic therapy is not recommended regarding the absence of obvious advantage, undesirable systemic consequences and side action of such therapy (steroid myopathy, muscle weakness, deterioration of functional abilities, lung insufficiency…). Inhalation GCSs are prescribed in long basic therapy for COPD (in patients at the 3rd, 4th stages of the disease, when FEV1 < 50% of the due, often exacerbations taking place 3 times or more for the past 3 years). At the same time the frequency of acute exacerbations and cases of hospitalization decrease, general level of health and living quality of the patients improve, death rate caused by all reasons in case of COPD reduces. Combination of inhalation GCS and ß2- agonists of the prolonged action is more effective than each component apart. The chart of pharmacotherapy for patients with COLD depending on the level of gravity of the disease. mild 1 stage. 2 stage. 3 stage. 4 stage. very severe moderate severe Avoid risk factors, stop smoking, influenza virus vaccine Bronchial spasmolytics of short-term action should be prescribed 1 or 2 bronchial spasmolytics of prolonged action should be added according to plan + rehabilitation GCS inhalation, by frequent exacerbations, must be included In case of chronic lung insufficiency (CLI) O2therapy must be added. The possibility of operative intervention should be regarded. Other pharmacological treatment: anti-inflammatory medicines of nonsteroid action (fenspirid hydrochlorude) are prescribed by moderate exacerbation and are included into basic therapy during 25- months after COPD exacerbation. Influenza virus vaccine can decrease severity of the exacerbation and reduce death rate among people with COPD. Antioxidants: acetilcystein reduces the quantity of exacerbations. It’s recommended to prescribe it to patients with frequent exacerbations, history of long-term smoking. Antibiotics are indicatede in case of the proved infectious exacerbation of COPD. Rehabilitation of patient with COPD Rehabilitation must be prolonged, including physical training, consultations as for nourishment, teaching and support of sick people. Oxygenotherapy. Decision on the necessity of oxygenotherapy for patients with COPD is made after taking into consideration disease gravity level, clinic symptoms manifestation, adequacy and efficacy of basic therapy, level of lung insufficiency and of blood oxygen balance. Surgical treatment. Bullectomy, if there are emphysematous bullae causes decrease of dyspnea and improvement of external respiration function (ERF). Before operative intervention it’s necessary to study ERF, gas exchange and come to a conclusion as for its indication and safety. Exacerbation of COPD Exacerbations of COPD are divided into infectious and noninfectious. Most exacerbations are provoked by infectious agents, environmental pollution growth, inappropriate basic therapy, oxygenotherapy. Algorithm of managing exacerbation in the outpatient setting - to initiate or intensify broncholytic therapy (bigger dosing and more often administration, combination of different bronchial spasmolytics (ß2-agonists, cholinergic antagonists), usage of nebuliser or spacer; - prescribing antibiotics in case of infectious exacerbation; - repeated estimation of the patient’s condition; - if symptoms and signs of exacerbation are improving prescribed treatment must be continued, after exacerbation is gone basic treatment must be revised; - if symptomatic improving is not observed then oral GCS (30-40mg prednisolone during 10 days) must be introduced; - repeated estimation of the patient’s condition; - if the patient’s condition is better, when exacerbation is gone basic treatment must be revised; - if symptoms and signs of exacerbation are worsening the patient must be taken to a hospital. Indications for hospitalisation in case exacerbation of COPD - considerable worsening of symptoms intensity (e. g. sudden onset of dyspnea at rest); complicated clinical course without exacerbation; presence of new physical signs (cyanosis, peripheral oedemata); feeble response to initial treatment for exacerbation; marked concomitant diseases; onset of arrhythmia bouts; worsening of consciousness; uncertain diagnostics, lack of possibility to verify the diagnosis reliably; elderly age; unfavourable living conditions. It’s first of all pus increase in sputum that indicates infectious exacerbation. Also dyspnea intensifies and sputum amount grows. Choosing antibacterial therapy it’s necessary to take into consideration such criteria as the age of the patient, exacerbation frequency for the last year, presence of concomitant pathology and level of FEV1 value. In patients younger than 65 with COPD frequency less than 4 times a year, without concomitant diseases and FEV1 more than 50% of the proper value the main causative agents are H. influenzae, S. pneumoniae, M. catarrhalis and atypical microorganisms. As the antibiotic of choice aminopenicillin (amoxicillin) or macrolide is recommended, or respiratory fluoroquinolone for oral administration which is prescribed when ß-lactams and macrolides are not effective, or there is allergic response. In patients olderer than 65 with COPD frequency 4 times a year or more, with concomitant diseases and FEV1 ranging from 30 to 50% of the proper value the main causative agents are H. influenzae, representatives of Enterobacteriaceae, and also S. pneumoniae. That’s why as the medicine of choice protected aminopenicillin or cephalosporin of the second generation, or respiratory fluoroquinolone for oral administration is recommended. When FEV1 is less than 30% of the proper value, antibacterial therapy is often (more than 4 times a year) and it’s necessary to take corticosteroids constantly, the reason of COPD exacerbation may be P. aeruginosea. Hence parenteral administration of fluoroquinolone of the second generation (ciprofloxacin) or respiratory fluoroquinolone of laevofloxacin – in high dosing, or ß-lactam with anti blue pus action in combination with aminoglycoside is recommended. Regardless the fact that COPD is a progressing disease correctly chosen and therapy prescribed in time and rehabilitation can significantly slow down broncoobstructive progression, reduce frequency and gravity of exacerbations, prevent development of exacerbation and systemic aftereffect, improve level of life. Prepared by Orlovsky A. V., assistant, D.Ph., Murenets N. A., postgraduate Methodological Instruction to Lesson № 3. Bronchial Asthma. Hours: 5. Working place: classroom, hospital wards. Questions. 1. Give the definition of bronchial asthma. 2. Name essential of diagnosis. 3. Name clinical symptoms of bronchial asthma. 4. What induces development the symptoms of bronchial asthma. 5. What characterizes the acute attack of bronchial asthma? 6. Name the criteria of respiratory function violence. 7. Give the clinical picture of classic allergic (atopic) bronchial asthma. 8. How is the studying of bronchi hyperreactivity carried out? 9. List the diagnostic tests, which are made at ambulatory-polyclinic stage. 10.Give the classification of bronchial asthma. 11.What is intermitting bronchial asthma? 12. What is mild persistent bronchial asthma? 13. What is permanent bronchial asthma of moderate severity? 14. What is severe permanent bronchial asthma? 15. For what purpose is conception “bronchial asthma control” introduced? 16. What is controlled course of bronchial asthma? 17. What is partially controlled course of bronchial asthma? 18. What is non-controlled course of bronchial asthma? 19. Laboratory findings in patient of bronchial asthma. 20. X-Ray findings in patient of bronchial asthma. 21.Name ways of medications introductions which use in treatment of patients with bronchial asthma. 22.Which is the main way of medications introductions which use in treatment of patients with bronchial asthma? 23.Name controlling medicines. 24.When can we prescribe glucocorticosteroids of system action? 25.Name glucocorticosteroids of system action. 26.How will we decrease the dosage of prednisolon? 27.Name inhalation glucocorticosteroids. 28.Name side effects of system and inhalation glucocorticosteroids. 29.Name preventive measures of inhalation glucocorticosteroids side effects. 30.What can you say about steps 1, 2, 3, 4 in treatment of patients with bronchial asthma? 31.What is steroid-sparring therapy? 32.Name steps for achievement and keeping up the control of bronchial asthma. 33.What can you say about cromons, methylxantines, leucotrien-modificator? 34.What can you say about β2-agonists of prolonged action and short-term action? 35.What can you say about symptomatic therapy? 36.What will you do if control of the disease is achieved for a period of 3 months? 37.What is the duration of controlling theropy? 38.What is bronchial asthma exacerbation and it stages? 39.Where may be treated patients with mild and moderate severity and severe bronchial asthma? 40.Name treatment the ambulatory stage. 41.What is complete response on therapy? 42.What will you do if the patient gives non-complete response? 43.Name treatment of patients with severe exacerbation of bronchial asthma. Examples of tests 1. A. B. C. D. E. 2. A. B. C. D. E. 3. A. B. C. D. E. Clinical symptoms of bronchial asthma are usually connected with spread but various bronchiobstruction which is: partially reversible by bronchodilator therapy the impairment of lung function is largely fixed reversible spontaneously or under treatment non-reversible under treatment non-reversible spontaneously Clinical symptoms of bronchial asthma are, except: cough with purulent sputum episodic breathlessness with laboured exhalation cough with expectoration of tenacious mucoid sputum more at night and physical loading episodic wheezes in lungs repeated chest constraint Laboratory findings are characterized by, except: sputum is characteristically tenacious and mucoid sputum is characteristically purulent sputum contains "plugs" and "spirals" eosinophils are seen microscopically arterial hypoxemia may be present Answers to the self-assessment: 1- c, 2-a, 3-b 1. Real-life situation: Patient K., 42 years old, was admitted to the hospital with complaints on bad cough, breath insufficiency, pain in the right lower part of ribcage that increases while deep breathing. It is known from anamnesis that K. has been working in coal industry for 26 years. Chronic pneumonia was diagnosed in this patient 5 years ago. What methods of examination can prove the absence of pleurisy in this patient? Answer. X-ray examination 2.Patient 17 years old, complain of сough, recurrent attacks of dyspnea, t – 37.0-37.2C. Beginning of disease she ties to pneumonia (three years ago). In childhood often had respiratory infection diseases, such us bronchitis, pneumonia. In lungs- musical rales, in blood- eosinophillia. X-ray Findings: Chest films show no abnormalities. What disease has this patient? . Answer: Bronchial asthma References. 1. Therapy: Manual. The course of lectures/V. M. Fedosyeyeva, A. A. Chrenov. – Simferopol, 2003. – 41 - 60 p. 2. Davidson’s Principles and practice of medicine (nineteenth edition)/Christopher Haslett, Edvin R. Chilvers and others. – Edinburgh, 2002. – 513-521 p. 3. Harrisons Principle if internal medicine (seventeenth Edition)/Fauci, Braunwald, Hasper and other. – Part 10, section 2, Chapter 240. 4. The Merck Manual of Diagnosis and Therapy (seventeenth Edition)/ Robert Berkow, Andrew J. Fletcher and others. – published by Merck Research Laboratories, 1999. Short theoretic material Bronchial asthma (BA) – chronic inflammatory disease of upper respiratory tracts, caused by considerable amount of inflammatory cells and mediators. Chronic inflammation combines with bronchi hyperreactiveness what show up in relapsing symptoms of whistling breathing, breathlessness, chest constraint, cough, especially at night and in the early morning. That episodes are usually connected with spread, but variation bronchiobstruction, which is reversible spontaneously or under treatment. If a patient has clinical and functional symptoms, the diagnosis of BA will be made BA. Essentials of Diagnosis: 1. Recurrent acute attacks of dyspnea, cough, and mucoid sputum, usually accompanied by wheezing. 2. Prolonged expiration with generalized wheezing and musical rales. 3. Bronchial obstruction reversible by drugs. Clinical symptoms: episodic breathlessness with laboured exhalation. cough with expectoration of tenacious mucoid sputum more at night and physical loading. episodic wheezes in lungs. repeated chest constraint Symptoms are especially severe at night and in the morning and awake a patient; develop or become worse at: physical loading, viral infection, antigens influence, smoking, external temperature overfall, aerosols action, intake of some medicines (nonsteroidal anti-inflammatory drugs, β-blockers). Circadian and circannual (seasonal) symptoms variation is characteristic. Classic allergic (atopic) asthma usually begins in childhood and becomes progressively more severe throughout life, although spontaneous remissions may occur in adulthood. Hay fever often accompanies atopic asthma. The acute attack is characterized by dyspnea usually associated with expiratory wheezing that may be heard without a stethoscope. Cough may be present but is usually not the predominant symptom. There is a small group of patients with asthma in whom paroxysmal cough may be the predominant symptom. When asthtna becomes prolonged, with severe intractable wheezing, it is known as status asthmaticus. - Criteria of respiratory function violence. - decrease of peak volume in 1 second (FEV 1.0) 80% of proper. - expressed reversibility of bronchial obstruction – increasing of PVES and FEV 1.0 12% (or 200 ml) by results of pharmacological test with short action β-agonist. - daily variation PVES and FEV 1.0 20%. Medical aid at ambulatory – polyclinic stage list and volume. Diagnostic tests: 1. External breathing function (EBF), (PVES and FEV 1.0) 2. Allergologic tests (allergologic anamnesis – allergic rhinitis, atopic dermatitis presence at patient or BA or atopic diseases at his family members; positive skin tests with allergens general and specific 1gE level increasing. 3. Studying of bronchi hyperreactivity is carried out at patients with clinical symptoms, which are characteristic for BA but at absence of characteristic EBF violations; is estimated by results of provocative tests with histamines metacholine, physical loading. Classification BA is classified by rate of course severity by complex analysis of bronchi obstruction clinical and functional symptoms. Answer on treatment in the period between attacks. Functional indexes changes estimation for disease severity determination is conducted in period without expiratory breathlessness episodes. BA classification according to rate of severity is especially important at solution of a question of disease management at patient’s condition primary examination Intermitting (episodic), persistent (permanent stable) (mild, moderate severity, severe) course are distinguished. Intermitting BA: symptoms (episodes of cough whistling breathing, breathlessness) are transitory, arise rarely than 1 time a week during at least 3 months; exacerbations of short duration, night symptoms arise not more frequently than 2 times a month. Between exacerbations symptoms are absent, normal indexes of EBF: PVES or FEV 1.0 ≥80% of proper; daily variation PVES and FEV < 20%. Mild persistent BA: symptoms arise at least 1 time a week, but more rarely than 1 time a day during more than 3 months. Symptoms of exacerbation may disturb activity and sleep; presence of chronic symptoms, which requires symptomatic treatment almost every day; night asthma symptoms arise more than 2 times a month, PVES or FEV 1.0 ≥ 80% of proper; daily variation of PVES or FEV 1.0 20-30%. Permanent BA of moderate severity: everyday symptoms; exacerbations disturb activity and sleep; night symptoms of asthma arise more than 1 time a week; necessity of short action β2 agonists every day intake, PVES or FEV 1.0 >30%. Severe permanent BA: presence of variable to a considerable extent, prolonged symptoms; frequent night symptoms, limiting of activity, severe exacerbations in spite of treatment, which is conducted, proper decease control is absent: prolonged, daily symptoms are constantly present; frequently night symptoms, frequently severe exacerbations; conditioned by BA limiting of physical activity. PVES or FEV 1.0 <60% of proper; PVES or FEV 1.0 daily variation >30%. Achievement of the BA control may be impossible. For the purpose of determination of the possible best results of treatment, answer the questions how the patient must react on prescribed treatment, conception “BA control” is introduced. They distinguish: controlled course absence or minimal (≤ 2 times a week) daily symptoms, absence of activity limiting, night symptoms, absence or minimal (≤2/week) necessity in bronchial spasmolytic to relieve symptoms, normal PVES index, exacerbations absence; Partly control (any symptom may occur in any week) non controlled course (≥3 symptoms of partly control are present at any week); Control lever and extend of treatment at the present moment determinate the choice of proper tactic of further treatment. . Laboratory Findings: The sputum is characteristically tenacious and mucoid, containing "plugs" and "spirals." Eosinophils are seen microscopically. The differential blood count may show eosinophilia. In severe, acute bronchospasm, arterial hypoxemia may be present as a result of disturbed perfusion /ventilation relationships, alveolar hypoventilation, or functional right-to-left shunts. X-Ray Findings: Chest films usually show no abnormalities. Reversible hyperexpansion may occur in severe paroxysms, or hyperexpansion may persist in long-standing cases. Transient, migratory pulmonary infiltrations may be present. Severe attacks are sometimes complicated by pneumothorax. Pharmacotherapy of patients with BA. BA patients medical treatment is conducted with use of different ways of medicines introductions: inhalation, oral, parenteral. Inhalations, which provide expressed local action of medicines in lung don’t cause their undesirable system action, enable an opportunity to accelerate positive treatment effect using lesser doses of medicines has the greatest advantages. Controlling medicines. Are taking every day, to the basis, for a long term, to achieve and keep up the control of persistent BA. Include: inhalation glucocorticosteroids (GCS) (first choice), system GCS, cromones, leucotriens modificators, prolonged action bronchial spasmolitics (inhalation prolonged action β2-agonists), oral prolonged action β2-agonists, prolonged action xantines) and system steroid – sparring therapy. System action GCS (oral) may be prescribed as basis control therapy at some severe BA patients but their using must be limited because of risk of considerable side effects development. Oral GCS long-term therapy is worth prescribing just in cases of non-efficiency of other methods of BA treatment, including inhalation steroids in high doses in combination with bronchi spasmolytics of prolonged action and continuing just then, when relieving of clinical symptoms, bronchial obstruction and frequency of severe exacerbations occurring is a success. Short action medicines (prednisolone, methilprednisolone) are recommended for intake; daily supporting dose should be taken in in the morning, and if it is possible should be changed to intermitting therapy. It is advisable to take minimal efficient doses of system GCS, and if it is possible to decrease their dose or to stop taking them, pass to high doses of inhalation GCS (2000 mkg/day), combination of the last and prolonged action bronchi spasmolitics. Cromones may be used as controlling therapy at mild persistent BA, although their effect is considerably lesser in comparison with taking inhalation GCS. Xantines have relatively low bronchi spasmolytic effect and risk of side effect if are used in high doses. Xantines are characterized by some anti-inflammatory action if low doses are prescribed in prolonged BA treatment. Prolonged action β2-agonists (salmeterole, formoterole fumaratis) have prolonged (duration more then 12 hours) bronchi spasmolytic effect and some anti-inflammatory action. The mentioned medicines are prescribed additionally (instead of inhalation GCS doses increasing), when basis therapy with standard doses of inhalation GCS is not enough to achieve control of the disease. Using of combinations (fluticasone propionatis+ salmeteroli, budesonide + formoterole fumoratis) makes possible achievement of high level control of disease at most moderate severity, severe persistent BA patients. Fixed combination budesonide + formoterole fumaratis, in favour of rapid beginning of its action (beginning of the salmeterole’s action – in 4-3 minutes after inhalation) may be taken “When needed”. Symptomatic therapy: “first aid” preparations are used to relieve attacks of acute bronchi spasm and other BA symptoms: first of all short action β2-agonists (salbutamole sulfatis, fenoterole hydrobromide); additionally – short action anticholinergic drug (fenoterole hydrobromide + ipratropium bromide; salbutamole sulfatis + ipratropii bromide). Stepped method of BA patients pharmacotherapy Step №1 – Intermitted BA Treatment – symptomatic when it is needed: inhalation short action β2-agonists when it is needed (at presence of symptoms) – first choice prophylactic intake before physical loading or possible allergen influence. Other bronchi spasmolytics: Inhalation short action anticholinergic drugs, oral β2-agonists of short action, short action xantines – have more slow beginning and/or higher risk of side effects development. Step№2 – mild persistent BA. Treatment – symptomatic plus one controlling preparation: every day regular treatment by antiinflammatory drugs to achieve control of the BA. Preference is given to inhalation GCS prescribing in low doses. Daily dose may be prescribed at one intake a day for some of them. Alternative controlling medicines cromones leucothienes modificators are less efficient in comparison with inhalation GCS; prolonged action xantines – have mild antiinflammatory effect; using is connected with considerable side effect. Step№3 – Moderate severity persistent BA. Treatment: symptomatic therapy plus one or two controlling medicines. Everyday regular treatment by antiinflammatory preparations to achieve and keep up control of BA. Combined taking in of inhalation GCS in low doses and prolonged inhalation β2agonists, as in separate introducing apparitions, so in fixed combinations is recommended. Fixed combination of inhalations and prolonged inhalation β2-agonist in one medicinal preparation is usually better (comfortable way of introduction, usually better pharmacological indexes). It is necessary to remember, that prolonged β2-agonists as a monotherapy, without inhalation GCS are not prescribed! Another choice is to prescribe average or high doses of inhalation GCS. Another choice – combination of inhalation GCS in low doses with leucotriens modificators or with prolonged action xantines (higher risk of side effects development). Step№4 – Severe persistent BA Treatment: symptomatic therapy plus one or more controlling medicines. Combined intaking of inhalation GCS in average – high daily doses with inhalation prolonged β2-agonists (it may be in one preparation) has the advantages. If efficiency is not enough leucohienes modificators and/or prolonged xantines may be prescribed. If it is necessary at severe non-controlled BA with everyday limiting of activity and frequent exacerbations oral GCS are prescribed supplementary in minimal doses which allow to achieve effect. When high doses of inhalation GCS are prescribed after oral GCS, monitoring of adrenocortical insufficiency symptoms is necessary. At severe BA with high 1gE level prescribing of recombinant human anti 1gE antibodies is effective. At low GCS clinic-functional effect, their expressed system side effects, absence of effect of other medicines. Sparring therapy is prescribed with using of immunesuppressors (methotrexat, cyclosporine A, preparations of gold). At that their efficiency is estimated in test course. Although, that treatment has low effectiveness, and side effects, which may by more severe, in comparison with side effects of steroids. Steroid-sparring therapy may be used only if its advantage in BA treatment is proved. Patient should be informed about risk and advantages of the treatment, and the therapy should be conducted under observation of specialists, which have experience of such therapy and monitoring of the patient’s general condition. It is necessary to remember, resistant to treatment persistent BA may be the precursor of non-diagnosed, dangerous for life diseases (system vasculitis) which require for proper treatment schemes. Steps for achievement and keeping up of the control of the BA Step 1 Step 2 Step3 Asthma-classes Control of the environment (surrounding) Short action β2-agonists when it is needed Controlling To choose 1 To choose 1 therapy Inhalation GCS Inhalation GCS in low doses in low doses + prolonged β2agonists Leucotrienes modificators Step 4 Step 5 To add 1 or To add 1 or more both average or high oral GCS doses of (minimal dose) inhalation GCS + prolonged β2agonists leucotrienes Anti-IgE modificators Average or high doses of inhalation GCS Inhalation GCS prolonged in low doses + xantines leucotrienes modificators Inhalation GCS in low doses + prolonged xantines If control of disease motion is achieved for a period of 3 months, using scheme which corresponds with the determined at patient control step, it is possible to reduce supporting therapy, to use treatment of lower step, that allows to determine minimal necessary to keep up control volume of treatment. If proper control at clinical symptoms is not achieved using prescribed treatment, you should use the next higher classification step of the scheme, at first having insured oneself that patient fulfilled right doctor’s prescription. It is necessary to inform a patient about early symptoms of BA exacerbation, teach him to control his condition, to conduct peakflowmetry. To form rules of behavior, which may prevent undesirable outcomes of their violation. Treatment efficiency criteria: disease control achievement. Treatment duration: basic therapy is conducted unceasing. BA exacerbation BA exacerbation – episodes of progressive laboured breathing, cough, whistling breathing, chest constraint, or combination of this symptoms, is characterized by decrease of air slow at exhalation (PVES, FEV 1.0). 4 stage of exacerbation are distinguished: mild moderate severity, severe and danger of respiratory standstill. Mild and moderate severity disease may be treated in the out patient setting. If the patient gives response on increasing of treatment intensity, there is no necessity in treatment at emergency department. The patient remains under physician control. Teaching of the patient is recommending therapy reconsideration. Severe exacerbations potentially are dangerous for patient’s life, their treatment demands medical monitoring, such patients must be treated in the hospital. It is necessary to monitor clinical symptoms, objective sighs, stabilization or returning to functional index (PVES, FEV 1.0) best for patient. Initial therapy at ambulatory stage: increase of inhalation β2-agonists dose: 2-4 inhalations every 20 minutes during the first hour. After that dose taking into attention patient’s individual response and severity of exacerbation must be reconsidered. Intaking of dosed inhalator or using spacer or nebulization If the patient gives complete response on bronchi spasmolytic therapy (PVES increases >80% or proper or best for the patient and last to 3-4 hours) it is not needed to introduce other medicines. At noncomplete response: to continue inhalation β2-agonists taking 6-10 inhalations every 1-2 hours; to add oral GCS (0,5-1 mg/kp of prednisolone or equivalent doses of other oral GCS for 24 hours). Inhalation cholinolitics: It is possible to take combined form inhalation cholinolitics plus β2-agonists; consult a doctor) At low effect: To continue taking of inhalation β2-agonists – to 10 inhalations (better using spacer) or complete doses with less then 1 hour interval nebulization; to add inhalation cholinolitics, it is possible to use combined forms: inhalation cholinolitics + inhalation β2-agonists to add oral GCS, to take an immediate medical advice, call an ambulance. Severe exacerbations are dangerous for patient’s life and should be treated at emergency department Ininial treatment: - Oxygenetherapy - Inhalation β2-agonists of short action constantly during 1 hour (nebulization is recommended); - System GCS Secondary estimation with therapy correction is 1 hour: if exacerbation corresponds to moderate severe stage: - Oxygenetherapy - Inhalation β2-agonists + cholinolitics - system GCS Next estimation in 1-2 hours: At good effect: during 1-2 hours after the last manipulation patient may be discharged. At home: - to continue treatment by β2-agonists; - Oral GCS are recommended in most cases; - Combined inhalators are recommended; - Teaching of the patient (how to take medicines reconsideration or individual treatment plan, active medical observation) At non complete response: - Oxygenetherapy - Inhalation β2-agonists + cholinolitics - system GCS - Intravenous xantines - Monitoring of: PVES, O2 saturation in arterial blood (SaO2), Pulse. If therapy is not effective during 1-2 hours: Treatment in the intensive care department: - Oxygenetherapy - Inhalation β2-agonists + cholinolitics - intravenous GCS - Parenteral β2-agonists - Intravenous xantines - Intubation and artificial pulmonary ventilation Prognosis : Most patients with asthma adjust well to the necessity for continued medical treatment throughout life Inadequate control or persistent aggravation by unmodified environmental conditions favors the development of incapacitating or even life threatening complications Prepared by Orlovsky A. V., assistant, D.Ph., Murenets N. A., postgraduate Methodological Instruction to Lesson № 4. Pneumonia. Hours: 5. Working place: classroom, hospital wards. Questions. 1. Give the definition of community-acquired pneumonia. 2. Give the classification of community-acquired pneumonia. 3. Give the main causative agents of community-acquired and nosocomial pneumonia. 4. Give the pathogenesis of lobar pneumonia. 5. Clinical manifestation of pneumonia. 6. What are the changes of the laboratory induces in pneumonia. 7. Radiological examination of the patient with pneumonia. 8. Characteristic of the first and second group of patients with communityacquired pneumonia. 9. Antibiotic treatment of the first and second group of patients with community-acquired pneumonia. 10.Characteristic of the third and fourth group of patients with communityacquired pneumonia. 11.Antibiotic treatment of the third and fourth group of patients with community-acquired pneumonia. 12.Give the classification of pneumonia by gravity. 13.Name small and big criteria’s of severe gravity pneumonia. 14.Give the definition and diagnostic criteria’s of nosocomial pneumonia. Table of antibacterial drugs. Drugs Aminipenicillins Amoxicillin Amoxicillin/clavulanic acid Route of introduction orally i.v., orally, orally Ampicillin/sulbactam i.v., i.m. Cefalosporins of the II generation Cefamandol i.v., i.m. Cefoxitin i.v., i.m. Cefuroxim i.v., i.m. Cefuroxim axethyl orally Cefaclor orally Cefalosporins of the III generation Cefoperazon i.v., i.m. Cefotaxim i.v., i.m. Ceftriaxon i.v., i.m. Dosing regimen 0,5-1 г 8 hourly 1,2 г 8-12 hourly 0,625 г 8 hourly 0,625 г 12 hourly 1,5-3 г 6-8 hourly 1-2 г 6 hourly 1-2 г 4-8 hourly 0,75-1,5 г 8-12 hourly 0,5 г 12 hourly 0,5 г 8 hourly 1-2 г 8-12 hourly 1-2 г 8-12 hourly 1-2 г 24 hourly Ceftazidim i.v., i.m. Cefalosporins of the IV generation Cefepime i.v. Cefpirome i.v. Carbapenems Meropenem i.v., i.m. Imipenem/celastatin i.v. Monobactams Aztreonam i.v., i.m. Aminoglucozydes Hentamycin i.v. Tombremycin i.v. Netylmycin i.v. Amicacin i.v. Macrolids Azithromycin orally Clarithromycin orally Midecamycin orally Spiramycin i.v., orally Fluoroquinolines ІІ generation Ciprofloxacin i.v., orally Ofloxacin i.v., orally Fluoroquinolines ІІI generation Levofloxacin i.v., orally Fluoroquinolines ІV generation Moxifloxacin orally Tetraciclin Doxiciclin orally Drugs of other groups Vankomycin i.v. Rifampicin i.v., orally Clindamycin i.v., i.m., orally 2 г 8 hourly 2 г 12 hourly 2 г 12 hourly 1 г 8 hourly 0,5 г 6 hourly 2 г 8 hourly 3-5 мг/кг 24 hourly 5 мг/кг 24 hourly 4-6 мг/кг 24 hourly 15 мг/кг 24 hourly 0,5 г 24 hourly 3 days 0,5 г 12 hourly 0,4 г 8 hourly 1 500 000 – 3 000 000 IU 8-12 hourly 0,4 г 12 hourly 0,5 г 12 hourly 0,4 г 12 hourly 0,5 г 12-24 hourly 0,4 г 24 hourly 0,2 г 24 hourly 1 г 12 hourly 0,5 г 12 hourly 0,6-0,9 г 24 hourly 0,45-0,6 6-8 hourly Real-life situation: 1. The patient 35 years old, had sudden onset, complains on fever, high temperature, headache, dry cough. He caught a cold during fishing and got all these complains at one moment. At examination: body temperature 39.9C, hyperemia of the cheeks, a light cyanosis of the lips, the skin is pale, humid, hurried breathing – 32/min, superficial. The expansion of the right lung is limited, there is dullness to percussion on the right side, bronchial breathing, moist rales. Heart sounds are weak, tachycardia- 96/min, rhythmical, blood pressure – 110/60. The others systems without any changes. Laboratory findings: Le – 17.1, Hb – 120, e – 3.8, ESR- 46 mm/h. The X-ray findings: confluent consolidation of the lobe. On the 3 day from the onset of disease the patient had haemoptysis. 1. Your diagnosis. 2. What diseases it is necessary to differentiate with? 3. Treatment. Answer. 1. Left-sided lobar severe community-acquired pneumonia 2. Pyogenic Lung disease 3. Antibiotics (amoxiclav 625 mg x 3 times a day), expectorants, broncholytics 2. A patient, 38 years old, admitted to the clinic with the following complaints: anorexia, general weakness, weight loss, sweating, cough of pus, sometimes – blood spitting, the sputum brought up is foul – smelling. The man fall ill 2 weeks ago, when appeared productive cough, fatigue and fever. During several days he did not apply to a doctor. His general state became worth to the end of the 1st week, when appeared general excessive sweating, weakness, the temperature elevated between 390 C in the evening and 37,50 C in the morning, the cough strengthened. The patient‘s state was heavy a few days. Two days before the man entered to the clinic he had had a troublesome cough with a blood-streaked sputum with a putrefactive smell (the amount of sputum was more than 250 ml), after that his general state improved. Visual examination: general state is satisfactory, the temperature is 37,60 C. The pulse is 80 per minute, rhythmical. Respiration is 20 per minute. The heart is without peculiarities. Questions: 1. What signs of the disease we should reveal with the help of palpation, percussion and auscultation of the lungs? 2. X-ray findings of the disease? 3. Your diagnosis? 4. Your treatment? Answers: 1. Palpation data: strengthened vocal fremitus to the right, lower the scapula. Percussion data: dull percussion sound. Auscultation data: weakened vesicular respiration and moist fine and coarse bubbling rales in the place of dull sound. 2. X-ray findings: a “basket” symptom. 3. Acute bronchopneumonia complicated with acute abscess of the right lung, recurrent stage (rupture of the abscess into the bronchi). 4. Intensive antibacterial therapy, detoxication therapy. References. 1. Therapy: Manual. The course of lectures/V. M. Fedosyeyeva, A. A. Chrenov. – Simferopol, 2003. – 10 - 17 p. 2. Davidson’s Principles and practice of medicine (nineteenth edition)/Christopher Haslett, Edvin R. Chilvers and others. – Edinburgh, 2002. – 501-508 p. 3. Harrisons Principle if internal medicine (seventeenth Edition)/Fauci, Braunwald, Hasper and other. – Part 10, section 2, Chapter 251. 4. The Merck Manual of Diagnosis and Therapy (seventeenth Edition)/ Robert Berkow, Andrew J. Fletcher and others. – published by Merck Research Laboratories, 1999. Short theoretic material Pneumonia is an acute infectious – inflammatory lung disease with involvement of all structural elements of lung tissues, obligatory including alveolars with development of exudation in them. Classification As the setting in which a pneumonia develops has such major implications for the likely organisms involved and hence dictates the immediate choice of antibiotics, pneumonias are now classified as: 1.community-acquired pneumonia 2.nasocomial pneumonia 3.aspiration pneumonia 4.pneumonia in immunocompromised patient By gravity of the disease pneumonia is classified into mild, medium gravity and severe. Besides depending on severity the following pneumonias are discerned: mild, moderate and severe. But even now there are no precise criteria as for distinguishing between mild and moderate pneumonias. As the amount of diagnostic and therapeutic measures for pneumonias of these stages of severity are almost the same it’s reasonable to unite them in the same group – moderate pneumonia. The following definition of severe pneumonia should be used. Severe pneumonia is a disease of a special form of various etiologies which show themselves through severe intoxication syndrome, hemodynamic changes, marked respiratory compromise and/or signs of severe sepsis or septic shock, and is characterized by unfavourable prognosis and demands intensive care. It’s recommended to distinguish “small” and “large” criteria of severe pneumonia. “Small” criteria of severe pneumonia: - respiratory rate 30/min and more; - impairment of consciousness; - SaO2 is less than 90% (according to pulsometry), partial pressure of oxygen in the arterial blood (further PaO2) is lower than 60mm of mercury column; - systolic arterial pressure is lower than 90 mm of mercury column; - bilateral or multiple lesion of lungs, destruction cavities and pleural effusion. “Large” criteria of severe pneumonia: - necessity of an artificial ventilation; - rapid aggravating of focal-infiltrative changes in the lungs – increasing amount of infiltration by more than 50% during the following two days; - septic shock or necessity of introduction of vasopressor medicines for four hours or more; - acute renal insufficiency (urine amount is less than 80 ml in 4 hours or kreatinine level in blood serum is higher than 0,18m mole/l or urea nitrogen concentration is higher than 7 mmole/l (urea nitrogen = urine (mmole/l) / 2,14) if there’s no chronic renal insufficiency. Severe course of pneumonia is confirmed by detection of at least two “small” or one “large” criterion. Each of them increases considerably the probability of fatal outcome. In such cases urgent hospitalization to the department of anesthesiology and intensive care is recommended. Etiology Community-acquired pneumonias may be induced by specific organisms, such as: Streptococcus pneumonia, Haemophilus influenza, Mycoplasma pneumonia, Chlamydia pneumonia, Legionella pneumonia, Klebsiella pneumonia, Staphylococcus aureus, Chlamydia psittaci, Coxiella burnetti. Nosocomial pneumonia may be induced by such organisms as: Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumonia, Escherichia coli, Proteus mirabilis, Haemophilus influenza, Enterobacter, Peptostreptococcus, Fusobacterium, Bacteroides. Other risk factors include exposure to cold, stress, fatigue, cigarettes smoke, alcohol and also old age, recent influenza infection, preexisting lung disease, heart failure with disordered lesser circulation, exposure to occupational and domestic hazard malnutrition, depression of cerebral functions by drugs. Pathogenesis Aspiration Of Organisms That Colonize The Oropharynx is the most common mechanism for the production of pneumonia. These pathogens include Streptococcus pneumoniae, Streptococcus pyogenes, Mycoplasma pneumonia, Haemophilus influenzae, and Moraxella catarrhalis. Nasogastric tubes can facilitate the transfer of gastric bacteria to the pharynx. About 50 percent of healthy adults aspirate oropharygeal secretions into the lower respiratory tract during sleep. Aspiration occurs more frequently and may be more pronounced in individuals with an impaired level of consciousness (eg. Alchogolics, drug abusers, and patients who have had seizures, strokes, or general anesthesia), neurologic dysfunction of the oropharynx and swallowing disorders or mechanical impediments (eg. Nasogastric or endotracheal tubes). Inhalation Of Infectius Aerosols Deposition of inhaled particles within the respiratory tract is determined primarily by particle diameter. Particles that are more than 10 um in diameter are deposited mostly in the nose and upper airways. Particles that are less than 3 to 5 um in diameter (also called airbone droplet nuclei) and that contain one or perhaps two microorganisms fail to settle out by gravity but rather remain suspended in the atmosphere for long periods unless removed by ventilation or by filtration in the lungs of the individual breathing the contaminated air. These infectious aerosols are small enough to bypass host defenses in the upper respiratory tract and airways. More particles are deposited in small bronchioles and alveoli as particle size decreases below 5 um. One inhaled particle of appropriate size may be sufficient to reach the alveolus and initiate infection. The etiologies of pneumonia typically acquired by inhalation of infectious aerosols include tuberculosis, influenza, legionellosis, psittacosis, histoplasmosis and Q fever. Hematogenous Disemination From An Extrapulmonary Site Infection, usually with Staphylococcus aureus, disseminates hematogenously to the lungs in patients (such as intravenous drug abusers) who have either right- or left-sided bacterial endocarditis and in patients with intravenous catheter infections. Fusobacterium infections of the retropharyngeal tissues (retropharyngeal abscess and jugular venous thrombophlebitis) also disseminate to the lungs. Essentials of Diagnosis 1.Sudden onset of shaking chills, fever, chest pain, and cough with rust-colored sputum. 2.X-rays show infiltration, often lobar in distribution, but sometimes patchy. 3.Pneumococci are present in the sputum and often in the blood. 4.Leukocytosis. Clinical manifestation The “typical” pneumonia syndrome is characterized by the sudden onset of fever with shaking chills, cough productive of purulent or even “rusty” sputum and in some cases pleuritic chest pain, exaggerated by respiration but sometimes referred to the shoulder, abdomen, or flank. The patient appears severely ill, with marked tachypnea (30-40/min) but no orthopnea. Respirations are grunting, nares flaring, and the patient often lies on the affected side in an attempt to splint the chest. Herpes simplex facial lesions are often present. Initially, chest excursion is diminished on the involved side, intensified vocal fremitus and bronchophony over the involved area. Percussion sound is shortening over the involved area. The character of respiration can change in a different manner. Respiration can be weak with elongated expiration and initial crepitation can appear during the initial stage of croupous pneumonia. At the hepatization stage bronchial respiration and moist consonating fine-bubbling rales develop with increasing dullness of the percussion sound. When resolution begins, numerous coars crepitations are heard, indicating liquefaction of the alveolar exudates. Respiration becomes harsh with lessening of dullness. A pleural friction rub may be present. These distinct changes in the physical findings are absent in bronchopneumonia. Harsh respiration and moist consonating fine-bubbling rales are the common symptoms of bronchopneumonia. Sometimes (eg. In central periradicular pneumonia) the physical signs are very scarce and pneumonia can only be revealed by x-ray examination. Radiological examination In lobar pneumonia, the chest radiograph shows a homogeneous opacity localised to the affected lobe or segment; this usually appears within 12-18 hours of the onset of the illness. Radiological examination is also particularly helpful if a complication such as pleural effusion, intrapulmonary abscess formation or empyema is suspected. Hilar lymphadenopathy is occasionally seen in mycoplasma pneumonia, and lung cavities are more frequently observed in patients with staphylococcal or pneumococcal serotype 3 pneumonia. General blood tests Acuity of inflammation can be determined by the acute phase blood indices and their dynamics (high leucocyte count, neutrophilic shift, accelerated ESR, high content of α2 globulins and fibrinogen, appearance of C reactive protein, high sialic acid content). Bacterial pneumonia is characterized by a high neutrophilic count with the shift to the left; ESR is high and it increases with the spread and severity of the process. Leucopenia is the specific feature of viral pneumonia. In micoplasmal pneumonia and ornitosis leucopenia combines with very high ESR. Microbiological investigations Sputum must be examined by Gram’s stain, by culture and by antimicrobical sensitivity testing. Typical sputum from pneumococcal pneumonia contains many red and white cells and many pneumococci. If sputum cannot be obtained, an attempt should be made to aspirate secretions or washings from the trachea or lower respiratory tract either by bronchoscopy or by inserting a needle through the cricothyroid membrane. Identification of the etiologic microorganism is of primary importance, since this is the key to appropriate antimicrobial therapy. However, because of the serious nature of the infection, antimicrobial therapy generally needs to be started immediately, often before laboratory confirmation of the causative agent. The specific microbial etiology remains elusive in about one-third of cases, eg. When no sputum is available for examination, blood cultures are sterile, and there is no pleural fluid. Serologic studies are sometimes helpful to diagnose mycoplasma, chlamydia, legionella and viral infection. But serologic confirmation requires weeks because of the late formation of specific antibody. Groups of patients with pneumonia Taking into consideration certain known limits of traditional methods of etiological diagnosis of pneumonia it’s reasonable to divide patients into separate groups. We can distinguish the most probable causative agents and their probable response to antimicrobial drugs with respect to each of them. All grown-up patients with pneumonia are suggested to be divided into four groups. The first group – patients with moderate pneumonia, who don’t need hospitalization, without concomitant pathology and other modifying factors. The most frequent causative agent among such patients is S. pneumoniae, M. pneumoniae, C. pneumoniae, H. influenzae (as a rule among smokers) and respiratory viruses. In 30 – 50% of cases the causative agent is not detected at all, that’s why it’s not reasonable to carry out conventional microbiological diagnostics. Epidemiologic investigation findings (general disease incidence among a set group of young people provoked by S. pneumoniae or M. pneumoniae) can be of value. The second group – patients with moderate pneumonia, who don’t need hospitalization, with concomitant pathology (chronic obstructive lung disease, renal or cardiac insufficiency, cerebrovascular disease, tumour, diabetes mellitus, chronic hepatic disease of various etiology, mental insanity, alcoholism) and/or other modifying factors. Pneumonia causative agents in these cases are S. pneumoniae (including antibiotic resistant strain), H. influenzae, S, aureus, M. catarrhalis. The possibility of gram-negative infection – family Enterobacteriacaea (E. colli, Klebsiella spp.) also should be taken into consideration, especially among elderly people. It’s also necessary to foreseethe the possibility of an anaerobic infection in the presence of pneumonia in cases when patients dont have sanitized mouth cavities and there are clinicoanamnestic data about neural disease and/or deglutition disoders. Routine microbiological diagnostics of these patients is also of little effectiveness and scarcely influences the choice of antibiotics. In approximately 20% of cases in this group hospitalization may appear necessary because of the lack of treatment effect among outpatients and/or exacerbation/decompensation of concomitant diseases. The third group – there belong patients with moderate pneumonia who need administration to the therapeutics department according to medical indications (presence of unfavourable prognostic factors). Pneumonia in cases of this group may be brought up by S. pneumoniae, H. influenzae, atypical causative agents, gram-negative enterobacteria. A “mixed” infection (i. e. combination of atypical bacterial an typical causative agents) is often detected among 10-30% of patients of the 3rd group. Such difference in detection rate of causative agents is explained by peculiarities of microbiological diagnostic methods, which are used by different researchers. The fourth group – patients with severe pneumonia who require hospitalization to reanimation department. The spectrum of microbal flora of such patients includes S. pneumoniae, Legionella spp., H. influenzae, gram-negative enterobacteria, S. aureus and M. pneumonia (quite seldom). If there are modifying factors P. aeruginosa may be a causative agent. Antibacterial therapy of pneumonia. The diagnosis - pneumonia – is an indisputable indication for prescription of antibiotics, which constitute the basis of treatment of such patients. Antibacterial treatment must be started immediately after a diagnosis is made, especially for those patients with pneumonia who need hospitalization. It’s absolutely inadmissible to waste time with prescribing antibiotics for patients with severe disease because of absence of bacterioscopy and sputum smear findings. As postponing of the 1st dose injection for four hours calls forth mortality risk among such patients considerably. An adequate clinical effect among patients of the 1st group is possible after peroral administration of an antibacterial drug (monotherapy!). As a drug of choice amoxicillin or macrolide (azithromycin, clarithromycin, midecamycin, spyramycin) is recommended. If the drug of choice can’t be taken by the patient an alternative medicine – respiratory phtorchynolone of the 3-4 generation is prescribed. In case when amoxicillin is ineffective after 48-72 hour treatment macrolide or doxycyclyne is chosen as a medicine of the second series. This is explained by their high activity towards atypical causative agents, which can be the most probable reason of fail of treatment with ampicillin. In case of ineffective initial antibiotic therapy with macrolide drugs of the second series can be amoxicillin or phtorchynolone of the 34 generation. The possible reasons of ineffective treatment with macrolide can be the presence of pneumococcal strains resistant to this group of antibiotics or a disease brought up by gramnegative causative agents. Among patients of the 2nd group marked clinical effect can also be reached by peroral administration of an antibiotic. But as the probability of gram-negative organisms etiological role increases (including those which have some mechanisms of antibiotic resistance development) protected aminopenicilline (amoxicillin/clavulanic acid) or cephalosporin of the 2nd generation (cefuroxim axetyle) should be used as a medicine of choice. phtorchynolone of the 3-4 generation can be used as an alternative therapy. If the medicine can’t be taken orally parenteral cephalosporin antibiotic of the 3 generation (more preferable is ceftriaxone intramuscularly which can be take once a day) is given. Among the patients of the 2nd group the effectiveness absence of treatment with medicines of choice may be connected with the fact that pneumonia etiopathogens are represented by atypical causative agents. That’s why at the 2nd stage of the antibiotic therapy macrolide should be added to β-lactam or monotherapy with phtorchynolone of the 3-4 generation is prescribed instead of this combination. Patients of the 1st and 2nd groups who are hospitalized because of social conditions are prescribed the corresponding peroral antibacterial therapy. Patients who are taken to hospital according to medical indications are suspected to have a severe clinical course of pneumonia. That’s why it’s more reasonable to start therapy with prescription of antibiotics – parenteral introduction (intramuscularly, intravenously). In 3-4 days after getting positive clinical effect (body temperature normalization, intoxication intensity diminution and other disease symptoms decrease) a change for oral introduction of antibiotics is possible, till completion of a full course of an antibacterial therapy (stage therapy – see below). It’s necessary to apply combined antibiotic therapy using protected aminopenicillin (amoxicillin / clavulanic acid, ampicilin/sulbactam) – oral administration or цефалоспорин of the 2-3 generation (цефуроксима аксетил, цефотаксим, цефтриаксон) in combination with macrolide for patients of the 3rd group taken to the therapeutics department. If there is no digestive tract disturbance macrolide is administered orally. If the medicine of choice can’t be taken by the patient phtorchynolone of the 3-4 generation (monotherapy) should be prescribed. Among patients of this the efficacy absence during the treatment with the medicine of choice may be connected with the fact that gram-negative bacteria producing β-lactamase of a wide action spectrum which are inactivators of these groups of antibiotics are the causative agent of pneumonia. Thus at the 2nd stage of the antibacterial therapy should be continued with phtorchynolone of the 3-4 generation or carbapenem. Patients of the 4th group should be immediately prescribed antibacterial therapy as its postponing even for four hours increases mortality risk among such patients. The following medicines should be prescribed intravenously for the treatment of the 4th group patients having risk factors of contamination with P. aeruginosa: antipseudoponas cephalosporin 3-4 generation (ceftazidin, cefoperazon, cefepim) in combination with aminoglycocide and levofloxacine or ciprofloxacine. Cefaropim active towards morbus caeruleus (ceftazidim, cefoperazone, cefepim) is offered as an alternative therapy in connection with aminoglycocide and macrolide. The estimation of antimicrobial treatment efficacy of the first series medicine must be obligatory carried out in 48 hours after the beginning of treatment (repeated inspection of the patient). Phone contact with the patient is also recommended on the second day of treatment. Main efficacy criteria during this time should be intoxication intensity decrease and body temperature dropping, absence of respiratory compromise signs. If these signs weren’t present at the beginning of the treatment one should take into consideration his general condition and general clinical blood count (leucocytes amount, erythrocyte sedimentation rate). The prescribed antimicrobial therapy is continued if there is positive dynamics of the named data. If high fever and intoxication or symptomatology aggravate then treatment must be regarded as ineffective, the antibacterial drug must be replaced by an antibiotic of the second series and appropriateness of hospitalization must be considered once again. For patients with moderate pneumonia antibacterial therapy may be finished after the temperature has been normal for 3-5 days. In such cases treatment course makes up as a rule 710 days. If clinical or epidemiological findings indicate mycoplasmal or clamydia etiology of pneumonia the course of antimicrobial treatment makes in general 10-14 days. If positive efficacy is reached then change of an antibiotic during this time is not reasonable. If patients with staphylococcal pneumonia or that caused by gram-negative enterobacteria are treated then a longer course of antibacterial therapy is recommended – 14- 21 days, if findings show Legionella etiology of the disease – 21 days. Ventilation and oxygenation An adequate airway must be maintained if necessary, by tracheal suction, endotracheal tube, or tracheostomy. Oxygen must be supplied to any patient with severe pneumonia, cyanosis with PaO2 below 60, or marked dyspnea; this will also help to prevent pulmonary edema. Oxygen may be supplied by nasal catheter, soft rubber mask, or oxygen tent. With masks, a 95% oxygen concentration can be maintained, whereas with nasal tubes or tents the concentration will reach only 40- 50%. However, masks are difficult to tolerate because of cough and expectoration. Oxygen must be humidified to prevent drying of secretions. Symptomatic therapy If cough interferes with sleep and rest, it may be suppressed with codeine phosphate, 0,1g times a day. Antipyretics are indicated for patients with high body temperature (analgin, acetylsalicylic acid). Detoxicating therapy – intravenous administration of rheopolyglucin, haemodes, and other solutions are indicated for patients with pronounced toxaemia and degradation of pulmonary infiltration. Treatment of pleural pain It is important to relieve pleural pain in order to allow the patient to breathe normally and cough efficiently. Mild analgesics such as paracetamol are rarely adequate and most patients require pethidine 50-100 mg or morphine 10-15 mg by intramuscular or intravenous injection. Opiates, however, must be used with extreme caution in patients with poor respiratory function. Abdominal distention is usually due to air swallowing in severe dyspnea and is a frequent problem in patients with pneumonia. Insertion of a rectal tube will usually produce rapid initial decompression. Gastric dilatation can be relieved by suction through a nasal tube passed into the stomach. Cardiac arrhythmias - extrasystoles usually require no treatment. If atrial fibrillation or flutter develops, rapid failure may be precipitated. Rapid digitalization is usually indicated in these cases. Management of toxic delirium - toxic delirium occurs in any severe pneumonia and may be particularly difficult to manage in alcoholics. Delirium, anxiety, and restlessness during waking hours may be treated with diazepam, 5 mg, or chlordiazepoxide, 10 mg, or phenobarbital, 15-30 mg orally 4-6 times daily. Pentobarbital, 0.1 g, or flurazepam (Dalmane), 30 mg, at bedtime helps to ensure adequate rest. Diet - initially, the dyspneic patient is anorectic, and a liquid diet is preferred. With improvement, a normal diet will be tolerated. If complications suggest a long illness, a highprotein, high-calorie diet with vitamin supplementation is indicated. Evaluation of Treatment: With proper selection of antimicrobial drugs, there should be marked improvement and defervescence in 72 hours or less. If this fails to occur, one must consider 3 main possibilities: (1) the presence of a serious complication such as empyema, pulmonary suppuration associated with bronchial obstruction, endocarditis, or meningitis; (2) infection by an organism other than the pneumococcus and resistant to the drug used; and (3) possible drug fever or other associated disease. If there is much pleural fluid, it must be aspirated promptly, smeared, and cultured to detect infection or empyema that requires drainage. If an organism other than the pneumococcus is shown to be the probable agent, treatment must be directed against it. Complications Complications of pneumococcal pneumonia occur with the following approximate frequencies: sterile pleural effusion (4-8%), empyema (0.5-2%), endocarditis and meningitis (0.1-0.3%), and pericarditis (0.1%). Other complications such as pneumococcal arthritis or lung abscess are even more rare. Fibrous organization of the pneumonia (in place of resolution) occurs sometimes but rarely causes disability. All pleural fluid collections must be aspirated and examined by smear and culture to permit early treatment of empyema. Prognosis Untreated pneumococcal pneumonia has a mortality rate of 20-40%. The following are unfavorable prognostic signs: age over 50 years, presence of underlying disease (eg, heart failure, cirrhosis), pregnancy, bacteremia, marked proteinuria, absence of leukocytosis, pulmonary edema, and shock. With early and adequate antimicrobial treatment, the fatality rate is about 5-8% but in bacteremic pneumonia it is 17-25%. Most fatalities occur in the age groups under 2 years and over 50 years. In untreated, uncomplicated cases, resolution by crisis (or more gradually) occurs 7-10 days after onset. Prevention A polyvalent vaccine containing polysaccharides from the 14 pneumococcus types that most frequently cause infection (1,2, 3,4,6, 8, 9, 12,14,19, 23,25, 51, and 56) is available in the USA. It has given significant protection against disease in persons at high risk: persons with sickle cell disease, splenectomized children, persons with chronic bronchopulmonary, cardiac, or renal disease, and elderly or debilitated persons. A single dose of 0.5 mL is given intramuscularly and may cause local erythema, soreness, or fever. It should not be given during pregnancy. Children at high risk can receive vaccine at age 6 months and again at 2 years. In addition, prophylactic penicillin may be required. Regrettably, some children under 2 years of age and some patients with myeloma or lymphoma have a poor antibody response to the vaccine. In adults, the need for revaccination is not established. Nosocomial pneumonia – is a disease, characterized by the appearance of new radiological focal-infiltrative changes in the lungs in 48 hours or more after hospitalization together with clinical symptomatology, which confirms its infectious nature (new wave of fever, purulent sputum or purulent eliminations from the tracheo-bronhial tree, leukocytosis etc.), excluding infections in the incubation period at the moment of hospitalization. Diagnostic criteria of nosocomial pneumonia include: - appearance of new radiological focal-infiltrative changes in the lungs - two of given below signs: 1) body temperature is higher than 38,3°C; 2) bronchial hypersecretion; 3) PaO2/FiO2 (FiO2 – oxygen fraction in the exhalant air) is less then 240; 4) cough, tachypnea, local crepitation, moist rales, bronchial respiration; 5) leukocytes amount in the blood is smaller than 4,0 × 109/ l or more than 12,0 × 109/ l, stab shift is more than 10%; 6) purulent sputum/bronchial secretion (more than 25 polymorphonuclear leukocytes in the field of vision during microscopy with small magnification, × 100). Diagnos – nosocomial pneumonia – is an undisputable indication for prescribing antibiotics, which represent the main treatment in such patients. It’s necessary to start antibacterial treatment immediately after the case is diagnosed. It’s absolutely unacceptable to delay immediate antibiotic prescription for patients with severe disease course because of the bacterioscopy and smear results. Such delay of the first antibiotic dose for four hours causes considerable increase of mortality level among such patients. Prepared by: Orlovsky A. V., assistant, D.Ph., Murenets N. A., postgraduate Methodological Instruction to Lesson № 5. Pleuritis. Hours: 5. Working place: classroom, hospital wards. Questions. 5. Name definition of pleuritis. 6. Essential of diagnosis in patients with pleural effusion. 7. Name major types of pleural effusion. 8. Name differences between transudates and exudates. 9. Name causes of pleural fluid transudates. 10.Name causes of pleural fluid exudates. 11.Clinical symptoms in patients with dry pleuritis. 12.Clinical symptoms in patients with pleural effusion. 13.Which diagnostic investigations will you prescribe to patients with pleuritis? 14.How will you confirm the diagnosis pleuritis? 15.Name treatment in patients with pleuritis. 16.Name prognosis in patients with pleuritis. Examples of tests 1. What is one of the causes of pleurisy? a) appendicitis b) ectopy of aorta c) myocardial infarction d) atherosclerosis e) heart insufficiency 2. What referration of the pain is typical for irritation of the central portion of the diaphragmatic pleura? a) Middle part of abdomen b) Neck and shoulder c) Head d) arm e) leg 3. The most typical symptoms of pleurisy are: a) Pleuritic pain, shallow breathing, coughing b) Pleuritic pain, dizziness, tachicardia c) High temperature, vomiting, obstipation d) Law temperature, sweating e) Pleuritic pain, vomiting, sneezing 4. Diseases that can simulate pleuritis are: a) Chronicle hepatitis b) Pericarditis c) Thyroiditis d) Pancreatitis e) Ischemic stroke 5. What method of diagnostics is the most helpful inflammatory abdominal disease? a) General blood analyses b) Computer tomography c) X-ray d) Termography e) Ultrasonography 6. What drugs are used in treatment of pleurisy? a) Sedatives b) Antibiotics c) b-blockers d) antidepressants e) vitamins in differentiating of pluerisy with acute Answers to tests: 1. 2. 3. 4. 5. 6. C) B) A) B) C) B) References. 1. Therapy: Manual. The course of lectures/V. M. Fedosyeyeva, A. A. Chrenov. – Simferopol, 2003. – 19 - 27 p. 2. Davidson’s Principles and practice of medicine (nineteenth edition)/Christopher Haslett, Edvin R. Chilvers and others. – Edinburgh, 2002. – 501-508 p. 3. Harrisons Principle if internal medicine (seventeenth Edition)/Fauci, Braunwald, Hasper and other. – Part 10, section 2, Chapter 257. 4. The Merck Manual of Diagnosis and Therapy (seventeenth Edition)/ Robert Berkow, Andrew J. Fletcher and others. – published by Merck Research Laboratories, 1999. Short theoretic material Pleural Effusion The pleural space lies between the lung and chest wall and normally contains a very thin layer of fluid, which serves as a coupling system. A pleural effusion is present when there is an excess quantity of fluid in the pleural space. Etiology Pleural fluid accumulates when pleural fluid formation exceeds pleural fluid absorption. Normally, fluid enters the pleural space from the capillaries in the parietal pleura and is removed via the lymphatics situated in the parietal pleura. Fluid can also enter the pleural space from the interstitial spaces of the lung via the visceral pleura or from the peritoneal cavity via small holes in the diaphragm. The lymphatics have the capacity to absorb 20 times more fluid than is normally formed. Accordingly, a pleural effusion may develop when there is excess pleural fluid formation (from the interstitial spaces of the lung, the parietal pleura, or the peritoneal cavity) or when there is decreased fluid removal by the lymphatics. Diagnostic Approach When a patient is found to have a pleural effusion, an effort should be made to determine the cause. The first step is to determine whether the effusion is a transudate or an exudate. A transudative pleural effusion occurs when systemic factors that influence the formation and absorption of pleural fluid are altered. The leading causes of transudative pleural effusions in the United States are left ventricular failure and cirrhosis. An exudative pleural effusion occurs when local factors that influence the formation and absorption of pleural fluid are altered. The leading causes of exudative pleural effusions are bacterial pneumonia, malignancy, viral infection, and pulmonary embolism. The primary reason to make this differentiation is that additional diagnostic procedures are indicated with exudative effusions to define the cause of the local disease. Approach to the diagnosis of pleural effusions. CHF, congestive heart failure; CT, computed tomography; LDH, lactate dehydrogenase; PE, pulmonary embolism; TB, tuberculosis; PF, pleural fluid. Transudative and exudative pleural effusions are distinguished by measuring the lactate dehydrogenase (LDH) and protein levels in the pleural fluid. Exudative pleural effusions meet at least one of the following criteria, whereas transudative pleural effusions meet none: 1. pleural fluid protein/serum protein >0.5 2. pleural fluid LDH/serum LDH >0.6 3. pleural fluid LDH more than two-thirds normal upper limit for serum The above criteria misidentify ~25% of transudates as exudates. If one or more of the exudative criteria are met and the patient is clinically thought to have a condition producing a transudative effusion, the difference between the protein levels in the serum and the pleural fluid should be measured. If this gradient is greater than 31 g/L (3.1 g/dL), the exudative categorization by the above criteria can be ignored because almost all such patients have a transudative pleural effusion. If a patient has an exudative pleural effusion, the following tests on the pleural fluid should be obtained: description of the fluid, glucose level, differential cell count, microbiologic studies, and cytology. Effusion Due to Heart Failure The most common cause of pleural effusion is left ventricular failure. The effusion occurs because the increased amounts of fluid in the lung interstitial spaces exit in part across the visceral pleura. This overwhelms the capacity of the lymphatics in the parietal pleura to remove fluid. Isolated right-sided pleural effusions are more common than left-sided effusions in heart failure. A diagnostic thoracentesis should be performed if the effusions are not bilateral and comparable in size, if the patient is febrile, or if the patient has pleuritic chest pain, to verify that the patient has a transudative effusion. Otherwise the patient is best treated with diuretics. If the effusion persists despite diuretic therapy, a diagnostic thoracentesis should be performed. A pleural fluid N-terminal pro-brain natriuretic peptide (NT-proBNP) >1500 pg/mL is virtually diagnostic of an effusion secondary to congestive heart failure. Hepatic Hydrothorax Pleural effusions occur in ~5% of patients with cirrhosis and ascites. The predominant mechanism is the direct movement of peritoneal fluid through small openings in the diaphragm into the pleural space. The effusion is usually right-sided and frequently is large enough to produce severe dyspnea. Parapneumonic Effusion Parapneumonic effusions are associated with bacterial pneumonia, lung abscess, or bronchiectasis and are probably the most common cause of exudative pleural effusion in the United States. Empyema refers to a grossly purulent effusion. Patients with aerobic bacterial pneumonia and pleural effusion present with an acute febrile illness consisting of chest pain, sputum production, and leukocytosis. Patients with anaerobic infections present with a subacute illness with weight loss, a brisk leukocytosis, mild anemia, and a history of some factor that predisposes them to aspiration. The possibility of a parapneumonic effusion should be considered whenever a patient with a bacterial pneumonia is initially evaluated. The presence of free pleural fluid can be demonstrated with a lateral decubitus radiograph, computed tomography (CT) of the chest, or ultrasound. If the free fluid separates the lung from the chest wall by >10 mm, a therapeutic thoracentesis should be performed. Factors indicating the likely need for a procedure more invasive than a thoracentesis (in increasing order of importance) include: 1. 2. 3. 4. 5. loculated pleural fluid pleural fluid pH < 7.20 pleural fluid glucose < 3.3 mmol/L (<60 mg/dL) positive Gram stain or culture of the pleural fluid the presence of gross pus in the pleural space If the fluid recurs after the initial therapeutic thoracentesis, and if any of the above characteristics are present, a repeat thoracentesis should be performed. If the fluid cannot be completely removed with the therapeutic thoracentesis, consideration should be given to inserting a chest tube and instilling a fibrinolytic (e.g., streptokinase, 250,000 units) or performing thoracoscopy with the breakdown of adhesions. Decortication should be considered when the above are ineffective. Effusion Secondary to Malignancy Malignant pleural effusions secondary to metastatic disease are the second most common type of exudative pleural effusion. The three tumors that cause ~75% of all malignant pleural effusions are lung carcinoma, breast carcinoma, and lymphoma. Most patients complain of dyspnea, which is frequently out of proportion to the size of the effusion. The pleural fluid is an exudate, and its glucose level may be reduced if the tumor burden in the pleural space is high. The diagnosis is usually made via cytology of the pleural fluid. If the initial cytologic examination is negative, then thoracoscopy is the best next procedure if malignancy is strongly suspected. At the time of thoracoscopy, a procedure such as pleural abrasion should be performed to effect a pleurodesis. If thoracoscopy is unavailable, then needle biopsy of the pleura should be performed. Patients with a malignant pleural effusion are treated symptomatically for the most part, since the presence of the effusion indicates disseminated disease and most malignancies associated with pleural effusion are not curable with chemotherapy. The only symptom that can be attributed to the effusion itself is dyspnea. If the patient's lifestyle is compromised by dyspnea, and if the dyspnea is relieved with a therapeutic thoracentesis, then one of the following procedures should be considered: (1) insertion of a small indwelling catheter; or (2) tube thoracostomy with the instillation of a sclerosing agent such as doxycycline, 500 mg. Mesothelioma Malignant mesotheliomas are primary tumors that arise from the mesothelial cells that line the pleural cavities; most are related to asbestos exposure. Patients with mesothelioma present with chest pain and shortness of breath. The chest radiograph reveals a pleural effusion, generalized pleural thickening, and a shrunken hemithorax. Thoracoscopy or open pleural biopsy is usually necessary to establish the diagnosis. Chest pain should be treated with opiates and shortness of breath with oxygen and/or opiates. Effusion Secondary to Pulmonary Embolization The diagnosis most commonly overlooked in the differential diagnosis of a patient with an undiagnosed pleural effusion is pulmonary embolism. Dyspnea is the most common symptom. The pleural fluid is almost always an exudate. The diagnosis is established by spiral CT scan or pulmonary arteriography Treatment of the patient with a pleural effusion secondary to pulmonary embolism is the same as for any patient with pulmonary emboli. If the pleural effusion increases in size after anticoagulation, the patient probably has recurrent emboli or another complication such as a hemothorax or a pleural infection. Tuberculous Pleuritis In many parts of the world, the most common cause of an exudative pleural effusion is tuberculosis (TB), but tuberculous effusions are relatively uncommon in the United States. Tuberculous pleural effusions are usually associated with primary TB and are thought to be due primarily to a hypersensitivity reaction to tuberculous protein in the pleural space. Patients with tuberculous pleuritis present with fever, weight loss, dyspnea, and/or pleuritic chest pain. The pleural fluid is an exudate with predominantly small lymphocytes. The diagnosis is established by demonstrating high levels of TB markers in the pleural fluid (adenosine deaminase > 40 IU/L, interferon > 140 pg/mL, or positive polymerase chain reaction (PCR) for tuberculous DNA). Alternatively, the diagnosis can be established by culture of the pleural fluid, needle biopsy of the pleura, or thoracoscopy. The recommended treatment of pleural and pulmonary TB is identical. Effusion Secondary to Viral Infection Viral infections are probably responsible for a sizable percentage of undiagnosed exudative pleural effusions. In many series, no diagnosis is established for ~20% of exudative effusions, and these effusions resolve spontaneously with no long-term residua. The importance of these effusions is that one should not be too aggressive in trying to establish a diagnosis for the undiagnosed effusion, particularly if the patient is improving clinically. Chylothorax A chylothorax occurs when the thoracic duct is disrupted and chyle accumulates in the pleural space. The most common cause of chylothorax is trauma, but it also may result from tumors in the mediastinum. Patients with chylothorax present with dyspnea, and a large pleural effusion is present on the chest radiograph. Thoracentesis reveals milky fluid, and biochemical analysis reveals a triglyceride level that exceeds 1.2 mmol/L (110 mg/dL). Patients with chylothorax and no obvious trauma should have a lymphangiogram and a mediastinal CT scan to assess the mediastinum for lymph nodes. The treatment of choice for most chylothoraces is insertion of a chest tube plus the administration of octreotide. If these modalities fail, a pleuroperitoneal shunt should be placed unless the patient has chylous ascites. Patients with chylothoraces should not undergo prolonged tube thoracostomy with chest tube drainage because this will lead to malnutrition and immunologic incompetence. Hemothorax When a diagnostic thoracentesis reveals bloody pleural fluid, a hematocrit should be obtained on the pleural fluid. If the hematocrit is more than half of that in the peripheral blood, the patient is considered to have a hemothorax. Most hemothoraces are the result of trauma; other causes include rupture of a blood vessel or tumor. Most patients with hemothorax should be treated with tube thoracostomy, which allows continuous quantification of bleeding. If the bleeding emanates from a laceration of the pleura, apposition of the two pleural surfaces is likely to stop the bleeding. If the pleural hemorrhage exceeds 200 mL/h, consideration should be given to thoracoscopy or thoracotomy. Miscellaneous Causes of Pleural Effusion There are many other causes of pleural effusion (Table 257-1). Key features of some of these conditions are as follows: If the pleural fluid amylase level is elevated, the diagnosis of esophageal rupture or pancreatic disease is likely. If the patient is febrile, has predominantly polymorphonuclear cells in the pleural fluid, and has no pulmonary parenchymal abnormalities, an intraabdominal abscess should be considered. The diagnosis of an asbestos pleural effusion is one of exclusion. Benign ovarian tumors can produce ascites and a pleural effusion (Meigs' syndrome), as can the ovarian hyperstimulation syndrome. Several drugs can cause pleural effusion; the associated fluid is usually eosinophilic. Pleural effusions commonly occur following coronary artery bypass surgery. Effusions occurring within the first weeks are typically left-sided and bloody, with large numbers of eosinophils, and respond to one or two therapeutic thoracenteses. Effusions occurring after the first few weeks are typically left-sided and clear yellow, with predominantly small lymphocytes, and tend to recur. Other medical manipulations that induce pleural effusions include abdominal surgery; radiation therapy; liver, lung, or heart transplantation; or the intravascular insertion of central lines. Pneumothorax Pneumothorax is the presence of gas in the pleural space. A spontaneous pneumothorax is one that occurs without antecedent trauma to the thorax. A primary spontaneous pneumothorax occurs in the absence of underlying lung disease, while a secondary pneumothorax occurs in its presence. A traumatic pneumothorax results from penetrating or nonpenetrating chest injuries. A tension pneumothorax is a pneumothorax in which the pressure in the pleural space is positive throughout the respiratory cycle. Primary Spontaneous Pneumothorax Primary spontaneous pneumothoraces are usually due to rupture of apical pleural blebs, small cystic spaces that lie within or immediately under the visceral pleura. Primary spontaneous pneumothoraces occur almost exclusively in smokers, which suggests that these patients have subclinical lung disease. Approximately one-half of patients with an initial primary spontaneous pneumothorax will have a recurrence. The initial recommended treatment for primary spontaneous pneumothorax is simple aspiration. If the lung does not expand with aspiration, or if the patient has a recurrent pneumothorax, thoracoscopy with stapling of blebs and pleural abrasion is indicated. Thoracoscopy or thoracotomy with pleural abrasion is almost 100% successful in preventing recurrences. Secondary Pneumothorax Most secondary pneumothoraces are due to chronic obstructive pulmonary disease, but pneumothoraces have been reported with virtually every lung disease. Pneumothorax in patients with lung disease is more life-threatening than it is in normal individuals because of the lack of pulmonary reserve in these patients. Nearly all patients with secondary pneumothorax should be treated with tube thoracostomy. Most should also be treated with thoracoscopy or thoracotomy with the stapling of blebs and pleural abrasion. If the patient is not a good operative candidate or refuses surgery, then pleurodesis should be attempted by the intrapleural injection of a sclerosing agent such as doxycycline. Traumatic Pneumothorax Traumatic pneumothoraces can result from both penetrating and nonpenetrating chest trauma. Traumatic pneumothoraces should be treated with tube thoracostomy unless they are very small. If a hemopneumothorax is present, one chest tube should be placed in the superior part of the hemithorax to evacuate the air, and another should be placed in the inferior part of the hemithorax to remove the blood. Iatrogenic pneumothorax is a type of traumatic pneumothorax that is becoming more common. The leading causes are transthoracic needle aspiration, thoracentesis, and the insertion of central intravenous catheters. Most can be managed with supplemental oxygen or aspiration, but if these are unsuccessful a tube thoracostomy should be performed. Tension Pneumothorax This condition usually occurs during mechanical ventilation or resuscitative efforts. The positive pleural pressure is life-threatening both because ventilation is severely compromised and because the positive pressure is transmitted to the mediastinum, which results in decreased venous return to the heart and reduced cardiac output. Difficulty in ventilation during resuscitation or high peak inspiratory pressures during mechanical ventilation strongly suggests the diagnosis. The diagnosis is made by physical examination showing an enlarged hemithorax with no breath sounds, hyperresonance to percussion, and shift of the mediastinum to the contralateral side. Tension pneumothorax must be treated as a medical emergency. If the tension in the pleural space is not relieved, the patient is likely to die from inadequate cardiac output or marked hypoxemia. A large-bore needle should be inserted into the pleural space through the second anterior intercostal space. If large amounts of gas escape from the needle after insertion, the diagnosis is confirmed. The needle should be left in place until a thoracostomy tube can be inserted. Prepared by: Orlovsky A. V., assistant, D.Ph., Murenets N. A., postgraduate Methodological Instruction to Lesson № 6. Pyogenic lung diseases. Hours: 5. Working place: classroom, hospital wards. Questions. 5. Name essentials of diagnosis of lung abscess. 6. Main causes of lung abscess. 7. Name possible causes when bronchial obstruction may oocur. 8. Name possible microorganisms which may cause an abscess. 9. Clinical findings in patients with lung abscess. 10.When can we say about chronic abscess? 11.Name laboratory findings in patients with lung abscess. 12.When smears and cultures for the tuberculi bacilli are especially required? 13.Name changes in X-Ray findings/ 14.Name differential diagnosis in patients with lung abscess. 15.When can we start treatment in patients with lung abscess. 16.Name treatment in patients with lung abscess. 17.Name complications in patients with lung abscess. 18.Name essential of diagnosis of bronchiectasis. 19.What is bronchiectasis? 20.Name causes of bronchiectasis. 21.When does bronchiectasis often begin? 22.Clinical findings in patients with bronchiectasis. 23.Name laboratory findings in patients with bronchiectasis. 24.Name X-Ray findings in patients with bronchiectasis. 25.What can see in bronchogram? 26.Name the differential diagnosis in patients with bronchiectasis. 27.How can we confirm bronchiectasis? 28.Name complications of bronchiectasis. 29.What is postural drainage? 30.What will you do if respiratory infection is add? 31.Name indications to surgery. Examples of tests 1. A. B. C. D. E. 2. A. How can you confirm broncyiectasis? Bronchographic examination X-Ray examination Laboratory findings Clinical findings None Dosing regimen of Amoxicillin|clavulanic acid: 1,0g 8-12 hurly i.v B. C. D. E. 3. A. B. C. D. E. 4. A. B. C. D. E. 1,2g 8-12 hurly i.v 1,4g 8-12 hurly i.v 1,6g 8-12 hurly i.v 1,8g 8-12 hurly i.v Main way of medicine introduction for abscess is: Orally Intramuscular Intravenous Aerosol All named above What does Kartageners syndrom include, except: Sinusitis Situs in versus Bronchiectasis Osteoporosis All named above Answers to tests: 1. A 2. B 3. C 4. D References. 1. Therapy: Manual. The course of lectures/V. M. Fedosyeyeva, A. A. Chrenov. – Simferopol, 2003. – 17 - 19 p. 2. Davidson’s Principles and practice of medicine (nineteenth edition)/Christopher Haslett, Edvin R. Chilvers and others. – Edinburgh, 2002. – 501-508 p. 3. Harrisons Principle if internal medicine (seventeenth Edition)/Fauci, Braunwald, Hasper and other. – Part 10, section 2, Chapter 252. 4. The Merck Manual of Diagnosis and Therapy (seventeenth Edition)/ Robert Berkow, Andrew J. Fletcher and others. – published by Merck Research Laboratories, 1999. Short theoretic material LUNG ABSCESS Essentials of Diagnosis • Development of pulmonary symptoms about 1-2 weeks after possible aspiration, bronchial obstruction, or previous pneumonia. • Septic fever and sweats, and periodic sudden expectoration of large amounts of purulent, foulsmelling, or "musty" sputum. Hemoptysis may occur. • X-ray density with central radiolucency and fluid level. General Considerations Lung abscess develops when necrosis and liquefaction occur in an area where necrotizing pneumonia is present. Symptoms and signs occur 1-2 weeks after the following events: (1) massive-aspiration of upper respiratory tract secretions and microbial flora, especially during profound suppression of cough reflex (eg, with alcohol, drugs, unconsciousness, anesthesia, brain trauma); (2) bronchial obstruction (eg, by atelectasis, foreign body, neoplasm); (3) presence of pneumonias, especially those caused by gram- negative bacteria or staphylococci; or (4) formation of septic emboli from other foci of infection, or, during bacteremia, with pulmonary infarcts. Abscess is more commonly in the lower dependent portions of the lung. The main etiologic organisms are related to the underlying condition, but a dense mixed anaerobic flora is often prominent, particularly when aspiration has occurred. Clinical Findings A. Symptoms and Signs: Onset may be abrupt or gradual. Symptoms include septic fever, sweats, cough, and chest pain. Cough is often nonproductive at onset. Expectoration of foul-smelling brown or gray sputum (anaerobic flora) or of purulent sputum without odor (pyogenic organism) may occur abruptly and in large quantity. Blood-streaked sputum is also common. Pleural pain, especially with coughing, is common because the abscess is often subpleural. Weight loss, anemia, and pulmonary osteoarthropathy may appear when the abscess becomes chronic (8-12 weeks after onset). Physical findings may be minimal. Consolidation due to pneumonitis surrounding the abscess is the most frequent finding. Rupture into the pleural space produces signs of fluid or pneumothorax. B. Laboratory Findings: Sputum cultures are usually inadequate in determining the bacterial cause of a lung abscess. Transtracheal aspirates should be obtained with the proper technique employed to culture anaerobic organisms in addition to the usual aerobic cultures. Special methods of transporting specimens are required for anaerobic organisms, and appropriate culture media and methods must be employed. Smear and cultures for the tubercle bacilli are required, especially in lesions of the upper lobe and in chronic abscess. C. X-Ray Findings: A dense shadow is the initial finding. A central radiolucency, often with a visible fluid level, appears as surrounding densities subside. Computerized tomography can supply the detailed localization of the abscess and may also reveal primary lesions (eg, bronchogenic carcinoma) and provide guidance for contemplated surgery. Various x-ray procedures also permit localization of pleural involvement to facilitate drainage. D. Instrumental Examination: Fiberoptic bronchoscopy may help to 'diagnose location and nature of obstructions (foreign body, tumor), obtain specimens for microbiologic and pathologic examination, and, occasionally, aid drainage. Differential Diagnosis Differentiate from other causes of pulmonary cavitation: tuberculosis, bronchogenic carcinoma, mycotic infections, and staphylococcal or gram-negative bacterial pneumonia. Treatment Postural drainage and bronchoscopy are important to promote drainage of secretions. A. Acute Abscess: Intensive antibacterial therapy is necessary to prevent further destruction of lung tissue. While cultures and sensitivity tests are pending, treatment should be started with penicillin G, 2-6 million units daily. In penicillin hypersensitivity clindamycin and chloramphenicol are alternatives. If the patient improves on antimicrobial drugs (and postural drainage), the drugs should be continued for 4—8 weeks. If the patient fails to respond significantly to the initial treatment, laboratory results may suggest other antimicrobials, eg, nafcillin for staphylococci, cefotaxime for Klebsiella, cefoxitin or metronidazole for mixed anaerobes. Postural drainage is important adjunctive treatment. Percutaneous catheter drainage has been used successfully in selected cases. Surgical therapy is indicated mainly for severe hemoptysis and for me infrequent abscesses that fail to respond to antimicrobial management. Failure of fever to subside after 2 weeks of therapy, abscess diameter of more than 6 cm, and very thick cavity waits are all factors that lessen the likelihood of success with nonsurgical treatment alone. B. Chronic Abscess: After acute systemic manifestations have subsided, the abscess may persist. Although many patients with chronic lung abscess can be cured with long-term treatment with antibacterial agents, surgery may occasionally be required. Complications Rupture of pus into the pleural space (empyema) causes severe symptoms: increase in fever, marked pleural pain, and sweating; the patient becomes “toxic" in appearance. Adequate drainage of empyema is mandatory. In chronic abscess, severe and even fatal hemorrhage may occur. Metastatic brain abscess is a well-recognized complication, and the infection may seed other organ sites. Bronchiectasis may occur as a sequela to lung abscess even when the abscess itself is cured. Prognosis The prognosis in acute abscess is excellent with prompt and intensive antibiotic therapy. About 80% of patients are healed within 7-8 weeks. The incidenee of chronic abscess is consequently low; In chronic cases, surgery is curative. BRONCHIECTASIS Essentials of Diagnosis: • Chronic cough with expectoration of large amounts of purulent sputum; hemoptysis. • Rales and rhonchi over lower lobes. • X-ray of chest reveals little; bronchograms show characteristic dilatations. General Considerations Bronchiectasis is a dilatation of small and medium-sized bronchi resulting from destruction of bronchial elastic and muscular elements. It may be, caused by pulmonary infections (eg, pneumonia, pertussis, tuberculosis) or by a bronchial obstruction (eg, foreign bodies or extrinsic pressure). In many patients, a history of onset following one or more episodes of pulmonary infection, usually in early childhood, is obtained. However,since infection does not regularly produce significant bronchiectasis, unknown intrinsic host factors presumably are present. The incidence of the disease has been reduced by treating pulmonary infections with antibiotics. Clinical Findings A. Symptoms and Signs: Most patients with bronchiectasis have a history of chronic cough with expectoration of large volumes of sputum, especially upon awakening. The sputum has a characteristic quality of "layering out" into 3 layers upon standing, a frothy top layer, a middle clear layer, and a dense particulate bottom layer. It is usually purulent in appearance and foul-smelling. Intermittent hemoptysis, occasionally in dangerous proportions, is often combined with intercurrent respiratory infections. Symptoms occur most often in patients with idiopathic bronchiectasis (ie, childhood respiratory infections). However, patients who have bronchiectasis secondary either to tuberculosis or chronic obstruction may not exhibit characteristic symptoms. Idiopathic bronchiectasis occurs most frequently in the middle and lower lobes and posttuberculous bronchiectasis in the upper lobes. Hemoptysis is thought to result from erosion of bronchiolar mucosa with resultant destruction of underlying blood vessels. Pulmonary insufficiency may result from progressive destruction of pulmonary tissue. Physical findings consist primarily of rales and rhonchi over the affected segments. If the condition is faradvanced,emaciation, cyanosis, and digital clubbing may appear. B. Laboratory Findings: There are no characteristic laboratory findings. If hypoxemia is chronic and severe, secondary polycythemia may develop. There may be either restrictive or obstructive pulmonary function defects associated with bronchiectasis. Hypoxemia and hypocapnia or hypercapnia may also be associated with the disease, depending on the severity of the underlying condition. . C.X-Ray Findings: Plain films of the chest often show increased bronchopulmonary markings in affected segments; in severe cases there may be areas of radiodensities surrounding portions of radiolucency. Early in the course of bronchiectasis, however, the chest x-ray may be normal. Iodized contrast media instilled into the bronchial tree (a bronchogram) demonstrates saccular, cylindric, or fusiform dilatation of small and medium bronchi with consequent loss of the normal branching pattern. Cylindric changes of bronchiectasis that may result from acute pneumonia will revert to normal after 6-8 weeks, but saccular dilatations represent long-standing damage and permanent disease. . Differential Diagnosis The differential diagnosis includes other disorders that lead to chronic cough, sputum production, and hemoptysis, ie, chrome bronchitis, tuberculosis, and bronchogenic carcinoma. The diagnosis of bronchiectasis is suggested by the patient's history and can be confirmed only by bronchographic examination or histopathologic examination of surgically removed tissue. Complications Recurrent infection in poorly drained pulmonary segments leads to chronic suppuration and may cause pulmonary insufficiency. Complications include hemoptysis, respiratory failure, chronic cor pulmonale, and amyloidosis. There is also an increased incidence of brain abscess, which is thought to be secondary to abnormal anastomoses between bronchial (systemic) and pulmonary venous circulation. These anastomoses produce right-to-left shunts and allow for the dissemination of septic emboli. Treatment A. General Measures and Medical Treatment: 1. Environmental changes- The patient should avoid exposure to all common pulmonary irritants such as smoke, fumes, and dust and should stop smoking cigarettes. 2. Control of bronchial secretions (improved drainage)a. Postural drainage often gives effective relief of symptoms and should be utilized in every case. The patient should assume the position that gives maximum drainage, usually lying on a bed in the prone, supine, or right or left lateral decubitus position with the hips elevated on several pillows and no pillow under the head. Any effective position should be maintained for 10 minutes, 2-4 times a day. The first drainage should be done upon awakening and tee last drainage at bedtime. Family members can be trained in the art of chest percussion to facilitate drainage of secretions. b. Liquefaction of thick sputum may be promoted by inhaling warm mists and, in some cases, mucolytic agents such as acetylcysteine or 5% sodium bicarbonate given by aerosol may also be helpful. 3. Control of respiratory infection-Exposure to respiratory infections should be minimized and the patient should be vaccinated against influenza and pneumococcal pneumonia. Antibiotic therapy is indicated for acute exacerbations (ie, increased production of purulent sputum, hemoptysis, etc). Long-term or prophylactic antibiotic therapy is controversial, since it has not been conclusively shown to be of lasting benefit. Therefore, it seems rational to treat acute exacerbations in order to control infection but minimize the emergence of resistant strains. Because the bacteria most commonly involved are H inftuenzae and S pneumoniae, the drug most commonly employed is ampicillin, 250-500 mg orally every 6 hours for 5 days. Alternative therapies for the penicillin-allergic patient are erythromycin, given in the same dosage schedule as ampicillin, or trimethoprim-sulfamethoxazole, 2 double-strength tablets twice a day for 5 days. B. Surgical Treatment: Surgical treatment is most often .employed when hemoptysis with bronchiectasis is recurrent and severe. Despite antibiotic therapy, localized bronchiectasis (eg, in a lower lobe or segment) with progressive uncontrolled infection and sputum production may be an indication for surgical removal of the affected segments. Other Considerations Bronchiectasis is also associated with mucoviscidosis. It is thought to be secondary to the thick viscid secretions that cannot be cleared by normal cough mechanisms and that lead to stasis of. sputum and chronic infection. This disorder, usually associated with sinusitis, may be accompanied by other manifestations of mucoviscidosis. Its most common organisms are S aureus or Pseudomonas aeruginosa. Bronchiectasis is also associated with certain abnormalities of cellular ciliary function, the most common of which is Kartagener's syndrome, a combination of sinusitis, situs in versus, and bronchiectasis. Patients with this disorder show immotile cilia secondary to ultrastructural abnormalities, stasis of sputum, failure to clear secretions, and chronic pulmonary infection that results in bronchiectasis. Antibiotic treatment of mucoviscidosis and Kartagener's syndrome must be guided by sensitivity studies of organisms cultured from sputum. Prepared by Orlovsky A. V., assistant, D.Ph., Murenets N. A., postgraduate Methodological Instruction to Lesson № 7. Anemia. Hours: 5. Working place: classroom, hospital wards. Questions. 1. To give definition of the term “Anemias” 2. Physiology of erythropoiesis and iron metabolism in organism. 3. Classifications of anemias. 4. Etiology and pathogenesis of IDA. 5. Clinic of IDA. 6. The laboratory diagnostic of IDA. 7. Diagnostic criteria of IDA. 8. Treatment of IDA. 9. Preparations of iron. Their dozes and circuits of use. 10. What is indication for iron transfusion. 11. Preventive maintenance of IDA. 12. To give definition of the term “B12 and folate deficiency anemias” 13. Etiology and pathogenesis of B12 and folate deficiency anemias. 14. Clinic of B12 and folate deficiency anemias. 15. Change of nervous system at these anemias. 16. The laboratory and instrumental diagnostic at these anemias. 17. Diagnostic criteria of B12 and folate deficiency anemias. 18. Treatment of B12 and folate deficiency anemias. 19. Features of treatment at changes of nervous system. 20. Criterion efficiency of treatment of B12 and folate deficiency anemias. 21. Preventive maintenance of B12 and folate deficiency anemias. 22. Clinic, Diagnostic and Treatment of megaloblastic anemias. 23. Concept of haemolytic and aplastic anemias 24. Etiology and pathogenesis of haemolytic anemias. 25. Classifications of inherent and acquired of haemolytic anemias. 26. Clinic of Thalassemias, Favism, hereditary spherocytosis (MinkowskyChauffard’s disease). 27. Clinic of acquired of haemolytic anemias. 28. The laboratory diagnostic of haemolytic anemias. 29. Clinic and Diagnostic of Hemoglobinopathies: Paroxysmal nocturnal hemoglobinuria, Sickle cell anemia. 30. Treatment of haemolytic anemias and their preventive maintenance. 31. Etiology and pathogenesis of aplastic anemias 32. Clinic and complications of aplastic anemias. 33. The laboratory diagnostic of aplastic anemias. 34. Diagnostic criteria of haemolytic and aplastic anemias. 35. Differential diagnostics of haemolytic and aplastic anemias. 36.Treatment of aplastic anemias and their preventive maintenance. 37.The indications to transplantation of bone marrow. Examples of tests 1. Name daily requirement of vitamin B 12: a. 1 – 3 μkg b. 2 – 7 μkg c. 15 – 20 μkg d. 30 – 50 μkg 2. Where the normal physiology absorption of vitamin B 12 may occur? a. in the stomach b. in the duodenum c. in the jejunem d. in the terminal ileum 3. Name daily requirement of folate: a. 100 μkg b. 300 μkg c. 500 μkg d. 700 μkg 4. Name systems that may disturb in patients with vitamin B 12 deficiency anaemia: a. hematopoietic system b. respiratory system c. nervous system d. digestive system Answers to tests: 1. 2. 3. 4. b d a a, c, d References. 1. Therapy: Manual. The course of lectures/V. M. Fedosyeyeva, A. A. Chrenov. – Simferopol, 2003. – 326 - 375 p. 2. Davidson’s Principles and practice of medicine (nineteenth edition)/Christopher Haslett, Edvin R. Chilvers and others. – Edinburgh, 2002. 3. Harrisons Principle if internal medicine (seventeenth Edition)/Fauci, Braunwald, Hasper and other. – Part 6, section 2, Chapter 98. 100 - 102. 4. The Merck Manual of Diagnosis and Therapy (seventeenth Edition)/ Robert Berkow, Andrew J. Fletcher and others. – published by Merck Research Laboratories, 1999. Short theoretic material Anemia - is the decreasing of hemoglobin and red blood cells amount in the unit of blood volume. From data of WHO: a hematocrit less than 40 in men and 37 in women, or hemoglobin less than 130 g/l in men and less than 120 g/l in women. Blood & Lymphocyte Development Actuality of theme: Anemia is very often met in 20% women of the developed countries and in 50% women of the non-developed countries; More than 50% patients with chronic diseases and tumors; Considerably worsens quality of life and capacity. Clinical classification of anemia is based on morphological prinsiple determination of mean corpuscular volume (MCV) of red blood cells MСV- is determined by automatic laboratory analyzers or by such formula: MСV = (hematocrit x10) / amount of RBC (in mln/l). Classification In the morphological approach, anemia is classified by the size of red blood cells; this is either done automatically or on microscopic examination of a peripheral blood smear. The size is reflected in the mean corpuscular volume (MCV): • If the cells are smaller than normal (under 80 fl), the anemia is said to be microcytic; • if they are normal size (80-100 fl), normocytic; • and if they are larger than normal (over 100 fl), the anemia is classified as macrocytic. Normocytic anemia (MCV - 80-100) • A loss or destruction of RBC is increased • Decreasing of RBC synthesis • Pathology of bone marrow (for example, action of medications, infection, aplastic anemia, myelodysplastic syndrome, plural mieloma and other infiltrative diseases). Causes of Normocytic anemia • acute blood loss • anemia of chronic disease • aplastic anemia (bone marrow failure). Microcytic anemia (MCV less than 80) Microcytic anemia is primarily a result of hemoglobin synthesis failure/insufficiency, which could be caused by: • Heme synthesis defect • Globin synthesis defect • Sideroblastic defect Makrocytic anemia (MCV more than 100 fl) - Megaloblastic anemia (vitamin В12 or folic acid deficiency ) - Toxic effect of chemotherapeutic agents (methotrexate) or other medications (zidovudine (AZT), phenytoin) - Pathology of bone marrow - Chronic abuse by alcohol (toxic effect) - Liver disease Anemia during pregnancy Anemia affects 20% of all females of childbearing age in the United States and Europe. Because of the subtlety of the symptoms, women are often unaware that they have this disorder, as they attribute the symptoms to the stresses of their daily lives. Possible problems for the fetus include increased risk of growth retardation, prematurity, intrauterine death, rupture of the amnion and infection. During pregnancy, women should be especially aware of the symptoms of anemia, as an adult female loses an average of two milligrams of iron daily. Therefore, she must intake a similar quantity of iron in order to make up for this loss. Additionally, a woman loses approximately 500 milligrams of iron with each pregnancy, compared to a loss of 4-100 milligrams of iron with each period. Depends on the level of hemoglobin in the blood anemia is divided on: - mild degree (Hb 110-90 g/l), - moderate degree (Hb 89-70 g/l), - severe degree (Hb less than 69 g/l). Depends on the size of RBC and their saturation by hemoglobin (from data of colour index - CI) anemia is divided on: -Normocytic normochromic anemia: colour of RBC is normal and CI is 0,86-1,1; -Microcytic anemia (can be hypo- or normochromic): microcytosis , anizopoykilocytosis, hypochromia, CI < 0,8; -Makrocytic anemia: makrocytosis, even megalocytosis, CI > 1,1. ANEMIA CAUSES • External bleeding: Loss of blood through heavy menstrual bleeding, wounds, as well as stomach ulcers can cause anemia. • Iron deficiency: The bone marrow needs iron to make red blood cells. • Anemia of chronic disease: Any long-term medical condition can lead to anemia. • Kidney disease: The kidneys help the bone marrow to make red blood cells. • Pregnancy: Water weight gain during pregnancy dilutes the red blood cells. • Poor nutrition: Vitamins and minerals are required to make red blood cells. • Alcoholism. • Uncommon causes of anemia: bleeding disorders, liver disease, thalassemia, infection, cancer, arthritis, enzyme deficiency, sickle cell disease, hypothyroidism, toxins, or hereditary conditions. Signs and symptoms Signs of anemia may include the following: •Black and tarry stools (sticky and foul smelling) •Maroon, or visibly bloody stools •Rapid heart rate •Rapid breathing •Pale or cold skin •Jaundice •Low blood pressure •Heart murmur •Enlargement of the spleen Symptoms of anemia may include the following: •Fatigue •Trouble breathing •Chest pain •Abdominal pain •Weight loss •Weakness •Dizziness and passing out, especially upon standing Diagnosis The only way to diagnose anemia is with a blood test. Generally, a full blood count is done. Apart from reporting the amount of red blood cells and the hemoglobin level, the automatic counters also measure the size of the red blood cells, which is an important tool in distinguishing between the causes. Occasionally, other tests are required to further distinguish the cause for anemia. These are discussed with the differential diagnosis (below). The doctor may also decide to take some other screening blood tests that might identify the cause of fatigue; glucose levels, ESR, ferritin, renal function tests and electrolytes may be part of such a workup. Doctor has a lot of questions in case of patient with anemia: 1. What is the reason of anemia? Is this anemia an independent disease or only syndrome, the complication of present patient`s pathology? Is this anemia the sign of the blood system disease? 2. What is the minimum of diagnostic measures, necessary for finding out of anemia character? 3. Do we need the consultation of hematologist? And if this so, what is their urgency? 4. What is the treatment? STANDARDS DIAGNOSTICS AND TREATMENT OF IRON DEFICIECY ANEMIA Iron deficiency is defined as a decreased total iron body content. Iron deficiency anemia occurs when iron deficiency is sufficiently severe to diminish erythropoiesis and cause the development of anemia. Iron deficiency is the most prevalent single deficiency state on a worldwide basis. In healthy people, the body concentration of iron (approximately 60 parts per million [ppm]) is regulated carefully by absorptive cells in the proximal small intestine, which alter iron absorption to match body losses of iron. Persistent errors in iron balance lead to either iron deficiency anemia or hemosiderosis. Both are disorders with potential adverse consequences. Principal reasons of IDA are: 1. Diseases of GIT. 2. Diseases of kidneys which are accompanied by mikro- and makrohematuria. 3. Diseases of the cardio-vascular system. 4. Breathing diseases. 5. Pathology of the blood system. 6. Hemorrhagic diatesis. 7. Meno- and metrorhagia 8. Pregnancy 9. Invasion of intestinal worms. 10. Malignant tumors Clinical symptoms of IDA A. Sideropenia. B. Circulatory-hypoxic syndrome. C. Anemic syndrome. CLINICAL CLASSIFICATION OF IRON DEFICIENCY ANEMIA І. Preclinical stage 1.1. Prelatent deficit of iron. 1.2. Latent deficit of iron (bleeding, unregulated participating in a donorship, increasing necessity in iron and others like that). ІІ. Clinical stage 2.1. No complicated form is caused by: 2.1.1. Chronic bleeding; 2.1.2. Increased necessity in iron (pregnancy, lactation, period of growth and ripening, for sportsmen); 2.1.3. An insufficient initial level of iron in organism; 2.1.4. Insufficient resorbtion of iron in a GIT; 2.1.5. Disturbances of transport and utilizations of iron (gipo- and atransferinemia, enzimopathia, autoimmunic processes); 2.1.6. Alimentary insufficiency of iron; 2.2. Complicated form is caused by: 2.2.1. Anemic hypoxia (signs: light, middle and severe, severe with the dystrophic changes of organs - hypoxic myocardial dystrophy, encephalopathia and others like that); 2.2.2. Sideropenic syndrome (signs : neurological disorders of emotional sphere, taste, sense of smell, dizuric disorders, changes of mucus shell of GIT, skin and its additions and others like that); 2.2.3. Metabolic endogenous intoxication. ІІІ. Mixed forms of iron deficiency anemia: 3.1. Dimorphic anemia (combination of iron deficiency anemia with vitamin В12 deficiency anemia); 3.2. Combination of iron deficiency anemia with the deficit of vitamins (group B, E, C); 3.3. Combination of iron deficiency anemia with the deficit of microelements; 3.4. Polydeficiency anemia (combination of iron deficiency anemia with the deficit of vitamins and microelements). Treatment of iron deficiency anemia - liquidation of reasons which caused the deficit of iron; - addition to the supplies of iron (therapy of satiation): using, mainly, peroral preparations of iron in day's dose of 2-3 mg of elementary (Fe++) iron on 1 kg of mass. Adopting iron is required simultaneously with ascorbic acid. More rapid getting up of indexes of red blood is observed at simultaneous application of antioxidants. Treatment iron is conducted 4-6 months: in a complete dose preparations appoint to normalization of indexes of red blood, whereupon a dose is diminished half. Basic modern drugs A. Monocomponent preparations - Arystiferon (ferrum sulfas) - Ferro-gradument (ferrum sulfas) - Ferronal (ferrum gluconas) - Ferrogluconat (ferrum gluconas) - Hemofer prolongatum (ferrum sulfas) - Heferol (ferrum fumaras) - Iron vine (ferrum sacharas) B. Combine preparations - Tardyferon-retard (ferrum sulfas, Vit C) - Gyno-tardyferon (ferrum sulfas, Vit C, folic acid) - Sorbifer-durulis (ferrum sulfas, Vit C) - Fenuls (ferrum sulfas, Vit C, B) - Makrofer (ferrum gluconas, folic acid) - Aktyferrin (ferrum sulfas, D,L-seryn) - Globiron (ferrum fumaras) - Ranferon (ferrum fumaras, Vit C, B12, B9, Zinci sulfas) C. Preparations for parenteral introduction • Ferbitol • Fercoven • Ferrum-lek • Venofer • Maltofer • Ferlecyt • Gektofer CRITERIA OF IRON DEFICIENCY ANAEMIA TREATMENT EFFICIENCY 7-10 days – retikulocytes` crisis, 3-4 weeks - normalization of hemoglobin level, amount of blood red corpuscles and hematokrit, 10-12 week - normalization of blood ferritin level. STANDARDS OF DIAGNOSTICS AND TREATMENT OF MEGALOBLASTIC ANEMIA Megaloblastic anemia is anemia, caused disturbances of DNA and RNA synthesis in erythroid cells which appear on the basis of vitamin of В12 and folic acid deficit. Reasons of megaloblastic anemia: • Addison-Birmer disease (autoimmune disease, caused by the presence of antibodies against the Kastl`s internal factor of); • State after the resection of stomach; • Stomach cancer; • Diseases of thin intestine; • Parasitizes diseases; • Initial deficit of transcobalamin II; • Alimentary insufficiency of vitamin В12. This image shows a large PMN with multiple discretely-identifiable nuclear lobes, usually seen in megaloblastic anemias. Normal PMN's have less than or equal to 5 lobes. This picture shows large, dense, oversized, red blood cells (RBCs) that are seen in megaloblastic anemia. Megaloblastic anemia can occur when there is a deficiency of vitamin B-12. Diagnostic search Conducted additionally: - sternal punction - megaloblastic type of erythropoesis; - fibrogastroskopia, biopsy of mucus stomach; - establishment of reason of vitamin В12 or folic acid deficit. Anamnesis: to pay attention to gradual development of disease, general weakness. Clinics - characteristic triad of syndromes: 1. Anemic (pallor of skin and mycoses, subikterosis of skin and sclera); 2. Damage of digestive organs (Genter`s tongue - in the first phase bright red, sickly, later - smooth, glossy; atrophic gastritis); 3. Neurological syndrome (funikularis myelosis). Characteristic changes: hyperchromic anemia (colored index > 1.0), leukopenia, can be thrombocytopenia, in blood analysis - makrocytosis, elliptocytosis, anisocytosis, bazofil grittiness appears in red corpuscles, red corpuscles with the Kebot`s rings and little Zholli`s bodie, gigantic neutrophiles with the hypersegmented kernel;analysis of gastric juice (histaminrezisten inacidity); increasing of indirect bilirubin. Reasons of folic acid deficit: - alcoholism; - liver cirrhosis; - violation of absorption of folic acid is in a thin bowel; -alimentary insufficiency of folic acid; -taking some medicines (antagonists of purins, sulfanilamides). Treatment of the vitamin В12 deficit: • vitamin В12 (cyanocobalamin) in a dose 500 mkg intramuscular daily during 2 weeks, and later - one time for a week to normalization of indexes of red blood; • dispansery supervision of hematologist - the vitamin В12 in a dose 500 mkg intramuscular one time on a month during all life; • patients with the expressed neurological syndrome during the first half-year get the dose of vitamin В12 on 50 % more high; • used the transfusion of red corpuscles concentrate only in extremely heavy cases at presence of cardio-vascular insufficiency. Treatment of the folic acid deficit: • folic acid in the dose of 5 mg - 1-3 times per a day реr оs during 2-3 weeks (if reason of deficit is not permanent). • in the case of ineffectiveness of the indicated therapy patients with the megaloblastic type of erythropoesis must be directed in a hematological center, hematological institute for authentication of diagnosis (eritroleukemia is possible or other pathology). Sickle cell anemia is an inherited blood disease in which the red blood cells produce abnormal pigment (hemoglobin). The abnormal hemoglobin causes deformity of the red blood cells into crescent or sickle-shapes, as seen in this photomicrograph. Elliptocytosis is a hereditary disorder of the red blood cells (RBCs). In this condition, the RBCs assume an elliptical shape, rather than the typical round shape. Spherocytosis is a hereditary disorder of the red blood cells (RBCs), which may be associated with a mild anemia. Typically, the affected RBCs are small, spherically shaped, and lack the light centers seen in normal, round RBCs. Sickle cell anemia is an inherited disorder in which abnormal hemoglobin (the red pigment inside red blood cells) is produced. The abnormal hemoglobin causes red blood cells to assume a sickle shape, like the ones seen in this photomicrograph. Red blood cells (RBCs) are normally round. In ovalocytosis, the cells are oval. Other conditions that produce abnormally shaped RBCs include spherocytosis and eliptocytosis. These crescent or sickle-shaped red blood cells (RBCs) are present with Sickle cell anemia, and stand out clearly against the normal round RBCs. These abnormally shaped cells may become entangled and block blood flow in the small blood vessels (capillaries). This photomicrograph of red blood cells (RBCs) shows both sickle-shaped and pappenheimer bodies. These abnormal red blood cells (RBCs) resemble targets. These cells are seen in association with some forms of anemia, and following the removal of the spleen (splenectomy). Prepared by Orlovsky A. V., assistant, D.Ph., Murenets N. A., postgraduate Methodological Instruction to Lesson № 8. Acute and chronic leukemias. Hours: 5. Working place: classroom, hospital wards. Questions. 1. To give definition of the term “HEMOBLASTOSIS” 2. Classifications of HEMOBLASTOSIS. 3. To give definition of the term “Acute leucosis (Acute Leukemias)” (AL). 4. Classifications of AL. 5. Etiology and pathogenesis of AL. 6. To list basic clinical syndromes at AL. 7. Laboratory diagnostic of AL. 8. Diagnostic criteria and Differential diagnostics of AL. 9. Treatment of AL. 10. That is complete remission of AL. 11. Diagnostic, Clinic and Treatment of hematosarcoma. 12. Classifications of myeloproliferative disease. 13. Diagnostic criteria of Chronic Myelocytic. 14. Treatment of Chronic Myelocytic. 15. Diagnostic criteria of Polycythemia. 16. Diagnostic, Clinic and Treatment of Myelofibrosis (Agnogenic Myeloid Metaplasia; Myelofibrosis with Myeloid Metaplasia). 17. Etiology and pathogenesis of Chronic Lymphocytic. 18. Laboratory diagnostic of Chronic Lymphocytic. 19. Diagnostic criteria and Differential diagnostics of Chronic Lymphocytic. 20. Differential diagnostics of Chronic leukemia and hematosarcomas. 21. Treatment of Chronic Lymphocytic. 22. To give definition of the term “leukemoid reaction”. 23. Tape of leukemoid reaction and Differential diagnostics with AL. 24. Treatment of leukemoid reaction. Examples of tests 1. Name etiology factors of leukaemias: A. exposure to ionizing radiation B. viral infection C. chromosomal tramslocation D. immunodeficiency disorder E. all named above 2. In which age could you mostly see acute lymphocytic leukaemia? A. in childhood B. in young adults C. in the middle age D. in old age 3. Name main cells in CBC you can see in patients with acute leukaemia: A. prolymphocytes B. plasmocytes C. blasts D. lymphocytes 4. Name the goal of treatment in patients with acute leukaemia: A. normal hematopoiesis with less than 20 % blast cells B. normal hematopoiesis with less than 15 % blast cells C. normal hematopoiesis with less than 10 % blast cells D. normal hematopoiesis with less than 5 % blast cells Answers to tests: 1. E, 2. A, 3. C, 4. D References. 1. Therapy: Manual. The course of lectures/V. M. Fedosyeyeva, A. A. Chrenov. – Simferopol, 2003. – 375 - 391 p. 2. Davidson’s Principles and practice of medicine (nineteenth edition)/Christopher Haslett, Edvin R. Chilvers and others. – Edinburgh, 2002. 3. Harrisons Principle if internal medicine (seventeenth Edition)/Fauci, Braunwald, Hasper and other. – Part 6, section 2, Chapter 104. 4. The Merck Manual of Diagnosis and Therapy (seventeenth Edition)/ Robert Berkow, Andrew J. Fletcher and others. – published by Merck Research Laboratories, 1999. Short theoretic material What is leukemia? Leukemia is a type of cancer. Cancer is a group of many related diseases. All cancers begin in cells, which make up blood and other tissues. Normally, cells grow and divide to form new cells as the body needs them. When cells grow old, they die, and new cells take their place. Sometimes this orderly process goes wrong. New cells form when the body does not need them, and old cells do not die when they should. Leukemia is cancer that begins in blood cells. Blood cells form in the bone marrow. Bone marrow is the soft material in the center of most bones. Immature blood cells are called stem cells and blasts. Most blood cells mature in the bone marrow and then move into the blood vessels. Blood flowing through the blood vessels and heart is called the peripheral blood. Blood & Lymphocyte Development The bone marrow makes different types of blood cells. Each type has a special function: White blood cells help fight infection Red blood cells carry oxygen to tissues throughout the body Platelets help form blood clots that control bleeding Leukemia (or leukaemia) is a cancer of the blood or bone marrow characterized by an abnormal proliferation of blood cells, usually white blood cells (leukocytes). It is part of the broad group of diseases called hematological neoplasms. Symptoms. Damage to the bone marrow, by way of displacing the normal marrow cells with increasing numbers of malignant cells, results in a lack of blood platelets, which are important in the blood clotting process. This means people with leukemia may become bruised, bleed excessively, or develop pinprick bleeds (petechiae). White blood cells, which are involved in fighting pathogens, may be suppressed or dysfunctional, putting the patient at the risk of developing infections. Finally, the red blood cell deficiency leads to anemia, which may cause dyspnea. All symptoms may also be attributable to other diseases; for diagnosis, blood tests and a bone marrow biopsy are required. Some other related symptoms: Fever, chills, and other flu-like symptoms Weakness and fatigue Loss of appetite and/or weight Swollen or bleeding gums Neurological symptoms (headache) Enlarged liver and spleen Leukemia is clinically and pathologically split into its acute and chronic forms Acute leukemia is a rapidly progressing disease that affects mostly cells that are unformed or immature (not yet fully developed or differentiated). These immature cells cannot carry out their normal functions. Acute forms of leukemia can occur in children and young adults. (In fact, it is a more common cause of death for children than any other type of malignant disease.) Immediate treatment is required in acute leukemias due to the rapid progression and accumulation of the malignant cells, which then spill over into the bloodstream and spread to other organs of the body. If left untreated, the patient will die within months or weeks. Chronic leukemia progresses slowly and permits the growth of greater numbers of more developed cells. In general, these more mature cells can carry out some of their normal functions. Typically taking months to years to progress, the cells are produced at a much higher rate than normal cells, resulting in many abnormal white blood cells in the blood. Chronic leukemia mostly occurs in older people, but can theoretically occur in any age group. Whereas acute leukemia must be treated immediately, chronic forms are sometimes monitored for some time before treatment to ensure maximum effectiveness of therapy. Furthermore, the diseases are classified according to the type of abnormal cell found most in the blood. When leukemia affects lymphoid cells (lymphocytes and plasma cells), it is called lymphocytic leukemia. When myeloid cells (eosinophils, neutrophils, and basophils) are affected, the disease is called myeloid or myelogenous leukemia. The major forms of leukemia are divided into four categories. The terms myelogenous or lymphocytic denote the cell type involved. Myelogenous and lymphocytic leukemia each have an acute or chronic form. Thus, the four major types of leukemia are acute or chronic myelogenous and acute or chronic lymphocytic leukemia. Prevalence of the four major types Acute lymphocytic leukemia (also known as Acute Lymphoblastic Leukemia, or ALL) is the most common type of leukemia in young children. This disease also affects adults, especially those age 65 and older Acute myelogenous leukemia (also known as Acute Myeloid Leukemia, or AML) occurs more commonly in adults than in children. This type of leukemia was previously called acute nonlymphocytic leukemia. Chronic lymphocytic leukemia (CLL) most often affects adults over the age of 55. It sometimes occurs in younger adults, but it almost never affects children. Chronic myelogenous leukemia (CML) occurs mainly in adults. A very small number of children also develop this disease. The most common forms in adults are AML and CLL, whereas in children ALL is more prevalent Leukemia.Causes and Risk Factors There is no single known cause for all of the different types of leukemia. The different leukemias likely have different causes, and very little is certain about what causes them. Researchers have strong suspicions about four possible causes: - natural or artificial ionizing radiation, - certain kinds of chemicals, - some viruses, and - genetic predispositions. Leukemia, like other cancers, result from somatic mutations in the DNA which activate oncogenes or deactivate tumor suppressor genes, and disrupt the regulation of cell death, differentiation or division. These mutations may occur spontaneously or as a result of exposure to radiation or carcinogenic substances and are likely to be influenced by genetic factors. Viruses have also been linked to some forms of leukemia. For example, certain cases of ALL are associated with viral infections by either the human immunodeficiency virus (HIV, responsible for AIDS) or human T-lymphotropic virus (HTLV-1 and -2, causing adult T-cell leukemia/lymphoma). Fanconi anemia is also a risk factor for developing acute myelogenous leukemia. Until the cause or causes of leukemia are found, there is no way to prevent the disease. Acute leukemia. Essentials of diagnosis. Short duration of symptoms, including fatigue, fever, and bleeding Cytopenia or pancytopenia More than 20 % blasts in the bone marrow Blasts in peripheral blood in 90 % Acute leukemia. Stages Beginning Developping Remission full – the level of blasts in the bone marrow les than 5 %, in the blood – absence, not full – clinical & hematology recovery but blasts are present Recidiv Terminal Acute leukemia. Clinics Anemic syndrome Hemmoragic syndrome (due to decreasing of platelets) Infective & ulcer-necrotic complications (due to decreasing of leukocytes) Extra-bone marrow localisation (lymphadenopathia, splenomegalia, leucemic infiltrationsin the skin, CNS, mammory glands, testis) Acute leukemia. Laboratory findings Pancytopenia with circulating blasts (in 10 % blasts may be absent – aleukemic leukemia) The level of leucocytes may be sometimes little increase The bone marrow is hypercellular & dominated by blasts Acute lymphoblastic leukemia (ALL) - is a cancer of the white blood cells, characterised by the overproduction and continuous multiplication of malignant and immature white blood cells (referred to as lymphoblasts) in the bone marrow. It is a hematological malignancy. It is fatal if left untreated as ALL spreads into the bloodstream and other vital organs quickly (hence "acute"). It mainly affects young children and adults over 50. This picture shows the darkly-stained lymph cells (lymphoblasts) seen in acute lymphocytic leukemia (ALL), the most common type of childhood leukemia. ALL. Classification Subtyping of the various forms of ALL is done according to the FAB (FrenchAmerican-British) classification, which is used for all acute leukemias (including acute myelogenous leukemia, AML). The FAB classification is: ALL-L1: small uniform cells ALL-L2: large varied cells ALL-L3: large varied cells with vacuoles (bubble-like features) ALL. Treatment The earlier acute lymphocytic leukemia is detected, the more effective the treatment. The aim is to induce a lasting remission, defined as the absence of detectable cancer cells in the body (usually less than 5% blast cells on the bone marrow). Treatment for acute leukemia can include chemotherapy, steroids, radiation therapy, intensive combined treatments (including bone marrow or stem cell transplants), and growth factors. ALL. Treatment Stages: Induction Consolidation CNS prophilaxis Maintaince treatment Prognosis Advancements in medical technology and research over the past four decades in the treatment of ALL has improved the overall prognosis significantly from 0 to 20-75 % survival rate, largely due to the continuous development of clinical trials and improvements in bone marrow transplantation (BMT) and stem cell transplanation (SCT) technology. The prognosis for ALL differs between individuals depending on a wide variety of factors: Sex: females tend to fare better than males. Ethnicity: Caucasians are more likely to develop acute leukemia than AfricanAmericans, Asians and Hispanics and tend to have a better prognosis than nonCaucasians. Age at diagnosis: children between 1-10 years of age are most likely to be cured. White blood cell count at diagnosis of less than 50,000 Whether the cancer has spread to the brain or spinal cord Morphological, immunological, and genetic subtypes Response of patient to initial treatment Genetic disorders such as Down's Syndrome Acute myeloid leukemia (AML) is a cancer of the myeloid line of white blood cells, characterized by the rapid proliferation of abnormal cells which accumulate in the bone marrow and interfere with the production of normal blood cells. AML is the most common acute leukemia affecting adults, and its incidence increases with age. While AML is a relatively rare disease overall, accounting for approximately 1.2% of cancer deaths in the United States, its incidence is expected to increase as the population ages Note multiple Auer rods which are found only in acute myeloid leukemias, either myeloblastic or monoblastic. These rods consist of clumps of azurophilic granule material. AML. Classification The two most commonly used classification schemata for AML, as of 2006, are the older French-American-British (FAB) system and the newer World Health Organization (WHO) system. French-American-British classification The French-American-British (FAB) classification system divided AML into 8 subtypes, M0 through to M7, based on the type of cell from which the leukemia developed and its degree of maturity. This is done by examining the appearance of the malignant cells under light microscopy and/or by using cytogenetics to characterize any underlying chromosomal abnormalities. The subtypes have varying prognoses and responses to therapy. The eight FAB subtypes are: M0 (undifferentiated AML) M1 (myeloblastic, without maturation) M2 (myeloblastic, with maturation) M3 (promyelocytic), or acute promyelocytic leukemia (APL) M4 (myelomonocytic) M4eo (myelomonocytic together with bone marrow eosinophilia) M5 monoblastic leukemia (M5a) or monocytic leukemia (M5b) M6 (erythrocytic), or erythroleukemia M7 (megakaryoblastic) Acute monocytic leukemia. These lesions are rarely found in chronic leukemia but are a common finding in acute forms. They appear as erythematous infiltrations of the skin, forming papules, macules, and plaques. Pruritus may be present. World Health Organization classification The World Health Organization (WHO) classification of acute myeloid leukemia attempts to be more clinically useful and to produce more meaningful prognostic information than the FAB criteria. The WHO subtypes of AML are: AML with characteristic genetic abnormalities, which includes AML with translocations between chromosome 8 and 21 [t(8;21)], inversions in chromosome 16 [inv(16)], or translocations between chromosome 15 and 17 [t(15;17)]. Patients with AML in this category generally have a high rate of remission and a better prognosis compared to other types of AML. AML with multilineage dysplasia. This category includes patients who have had a prior myelodysplastic syndrome (MDS) or myeloproliferative disease (MPD) that transforms into AML. This category of AML occurs most often in elderly patients and often has a worse prognosis. AML and MDS, therapy-related. This category includes patients who have had prior chemotherapy and/or radiation and subsequently develop AML or MDS. These leukemias may be characterized by specific chromosomal abnormalities, and often carry a worse prognosis. AML not otherwise categorized. Includes subtypes of AML that do not fall into the above categories. Acute leukemias of ambiguous lineage. Acute leukemias of ambiguous lineage (also known as mixed phenotype or biphenotypic acute leukemia) occur when the leukemic cells can not be classified as either myeloid or lymphoid cells, or where both types of cells are present. AML. Prognosis Acute myeloid leukemia is a curable disease; the chance of cure for a specific patient depends on a number of prognostic factors. The single most important prognostic factor in AML is cytogenetics, or the chromosomal structure of the leukemic cell. About half of AML patients have "normal" cytogenetics; they fall into an intermediate risk group. A number of other cytogenetic abnormalities are known to associate with a poor prognosis and a high risk of relapse after treatment. AML which arises from a pre-existing myelodysplastic syndrome or myeloproliferative disease (so-called secondary AML) has a worse prognosis, as does treatment-related AML arising after chemotherapy for another previous malignancy. Both of these entities are associated with a high rate of unfavorable cytogenetic abnormalities. In some studies, age >60 years and elevated lactate dehydrogenase level were also associated with poorer outcomes. As with most forms of cancer, performance status (i.e. the general physical condition and activity level of the patient) plays a major role in prognosis as well. Cure rates in clinical trials have ranged from 20-45%; however, it should be noted that clinical trials often include only younger patients and those able to tolerate aggressive therapies. The overall cure rate for all patients with AML (including the elderly and those unable to tolerate aggressive therapy) is likely lower. AML. Treatment Treatment of AML consists primarily of chemotherapy, and is divided into two phases: induction postremission (or consolidation) therapy. The goal of induction therapy is to achieve a complete remission by reducing the amount of leukemic cells to an undetectable level; the goal of consolidation therapy is to eliminate any residual undetectable disease and achieve a cure. Chronic myelogenous leukemia (CML) is a form of chronic leukemia characterized by increased and unregulated clonal production of predominantly myeloid cells in the bone marrow. CML is a myeloproliferative disease associated with a characteristic chromosomal translocation called the Philadelphia chromosome. Historically, it has been treated with chemotherapy, interferon and bone marrow transplantation, although targeted therapies introduced at the beginning of the 21st century have radically changed the management of CML. The Philadelphia chromosome as seen by metaphase FISH CML. Essentials of diagnosis Strikingly elevated white blood count Markedly left-shifted myeloid series but with a low percentage of promyelocytes and blasts Presence of Philadelphia chromosome or bcr-abl gene Oil immersion field demonstrating myeloid cells of all degrees of maturity This high-power microscopic view of a blood smear from a person with classical CML shows predominantly normal-appearing cells with intermediate maturity CML. Phases CML is often divided into three phases based on clinical characteristics and laboratory findings. In the absence of intervention, CML typically begins in the chronic phase, and over the course of several years progresses to an accelerated phase and ultimately to a blast crisis. Blast crisis is the terminal phase of CML and clinically behaves like an acute leukemia. One of the drivers of the progression from chronic phase through acceleration and blast crisis is the acquisition of new chromosomal abnormalities (in addition to the Philadelphia chromosome). Some patients may already be in the accelerated phase or blast crisis by the time they are diagnosed. Low power view showing marked hypercellularity with a broad-spectrum of myeloid and erythroid cell types and marked myeloid hyperplasia CML. Treatment General strategies for management include a variety of options: Leukapheresis, also known as a peripheral blood stem cell transplant, with stem cell cryopreservation (frozen storage) prior to any other treatment. The patient's blood is passed through a machine that removes the stem cells and then returns the blood to the patient. Leukapheresis usually takes 3 or 4 hours to complete. The stem cells may or may not be treated with drugs to kill any cancer cells. The stem cells then are stored until they are transplanted back into the patient. CML. Treatment HLA (human leukocyte antigen) typing of all patients under age 60, as well as typing of siblings, parents, and children, if available. This procedure will determine whether a compatible donor is available for stem cell transplantation. Pre-treatment fertility measures (e.g., cryopreservation of semen prior to treatment; completion of a pregnancy prior to treatment) in young patients who have not completed their families. Interferon-alpha (INF-a) therapy Chemotherapy with drugs such as hydroxyurea (Hydrea®), busulfan (Myleran®) or imatinib mesylate (Gleevec™). In general, CML treatment options are divided into 2 groups: - those that do not increase survival - and those that do. CML. Prognosis The prognosis of CML depends on a number of different parameters. Two different scoring systems are in use: one by Sokal et al (1984) and one by Hasford et al (1998). In the past, median survival was 3-4 years. With interferon-based therapy, this was increased to 5-6 years. Chronic lymphocytic leukemia (CLL) is a type of leukemia in which too many lymphocytes are produced. Although the malignant lymphocytes in CLL may look normal and mature, they are not and these cells may not cope effectively with infection. CLL is the most common form of leukemia in adults. Men are twice as likely to develop CLL as women. However, the key risk factor is age. Over 75% of new cases are diagnosed in patients over age 50. More than 7,000 new cases of CLL are diagnosed in the U.S. each year. CLL. Essentials of diagnosis. Most patients asymptomatic at presentation Splenomegaly typical Lymphocytosis > 5000/l Mature appearance of lymphocytes Co-expression of CD19, CD5 Peripheral blood smear showing CLL cells This is a microscopic view of bone marrow from a person with chronic lymphocytic leukemia; it shows predominantly small, mature lymphocytes The Rai or Binet staging systems These systems consider: The elevation of blood and marrow lymphocyte counts; The size and distribution of lymph nodes; The spleen size; The degree of anemia and the extent of the decrease of the blood platelet count. The Rai staging system O stage – lymphocytosis only I stage - lymphocytosis +lymphadenopathy II stage - organomegaly III stage - anemia IV stage - trombocytopenia The Binet staging system A – lymphadenopathy in less than 3 areas B – lymphadenopathy in more than 3 areas C – anemia, trombocytopenia CLL. Treatment Indications for treatment are: falling hemoglobin or platelet count progression to a later stage of disease painful, disease-related overgrowth of lymph nodes or spleen lymphocyte doubling time (an indicator of lymphocyte reproduction) of fewer than 12 months CLL. Treatment CLL treatment focuses on controlling the disease and its symptoms rather than on an outright cure. CLL is treated by chemotherapy, radiation therapy, biological therapy, or bone marrow transplantation. Symptoms are sometimes treated surgically (splenectomy removal of enlarged spleen) or by radiation therapy ("debulking" swollen lymph nodes). oThe myeloproliferative diseases ("MPD"s) are a group of diseases of the bone marrow in which excess cells are produced. They are related to, and may evolve into, myelodysplastic syndrome and acute myeloid leukemia, although the myeloproliferative diseases on the whole have a much better prognosis than these conditions. The concept of myeloproliferative disease was first proposed in 1951 by the eminent hematologist William Dameshek. The myeloproliferative diseases are: •Chronic myelogenous leukemia (CML) •Polycythemia vera (PCV) •Essential thrombocytosis (ET) •Myelofibrosis (increased connective tissue with decreased room for production of normal blood cells). Prepared by Orlovsky A. V., assistant, D.Ph., Murenets N. A., postgraduate Methodological Instruction to Lesson № 9. Multiple myeloma. Lymphomas Hours: 5. Working place: classroom, hospital wards. Questions. 1. To give definition of the term “Multiple myeloma” (MM). 2. Etiology and pathogenesis of MM. 3. Clinic of MM. 4. Laboratory and instrumental diagnostic of MM. 5. Stage of MM. 6. Diagnostic criteria and MM. 7. Differential diagnostics of MM with Waldenström's Macroglobulinemia. 8. Treatment of MM. 9. The basic preparations for treatment of MM. 10. Radial therapy of MM. Examples of tests 1. What is this multiple myeloma? A. the lymphomas B. the paraproteinaemias C. the leukaemias D. the haemolytic anaemia 2. Multiple myeloma is malignant proliferation of which cells in bone marrow? A. Lymphocytes B. Monocytes C. Basophiles D. Plasmatic cells 3. Name laboratory changes of Multiple myeloma asymptomatic stage. A. increased ESR, leucocytosis, trombocytopenia B. increased ESR, M-protein, proteinuria C. never changes D. leucocytosis, anaemia 4. Which symptoms will be present in case of effected bones in patients with Multiple myeloma? A. Bone pain B. neoplasm C. Fracture D. All named above 5. What could you see on bone marrow aspirate or trephine biopsy? A. Leucocytes infiltration B. Plasma cell infiltration C. T-lymphocyte infiltration D. B- lymphocyte infiltration Answers to tests: 1. B, 2. D, 3. B, 4. D, 5. B References. 1. Davidson’s Principles and practice of medicine (nineteenth edition)/Christopher Haslett, Edvin R. Chilvers and others. – Edinburgh, 2002. 2. Harrisons Principle if internal medicine (seventeenth Edition)/Fauci, Braunwald, Hasper and other. – Part 6, section 2, Chapter 105, 106. 3. The Merck Manual of Diagnosis and Therapy (seventeenth Edition)/ Robert Berkow, Andrew J. Fletcher and others. – published by Merck Research Laboratories, 1999. Short theoretic material Multiple Myeloma(Myelomatosis; Plasma Cell Myeloma) Multiple myeloma is a cancer of plasma cells that produce monoclonal immunoglobulin and invade and destroy adjacent bone tissue. Common manifestations include bone pain, renal insufficiency, hypercalcemia, anemia, and recurrent infections. Diagnosis requires demonstration of M-protein (sometimes present in urine and not serum) and either lytic bone lesions, lightchain proteinuria, or excessive marrow plasma cells. A bone marrow biopsy is usually needed. Specific treatment includes conventional chemotherapy with the addition of bortezomib, lenalidomide, thalidomide, corticosteroids, and high-dose melphalan followed by autologous peripheral blood stem cell transplantation. The incidence of multiple myeloma is 2 to 4/100,000. Male:female ratio is 1.6:1, and the median age is about 65 yr. Prevalence in blacks is twice that in whites. Etiology is unknown, although chromosomal and genetic factors, radiation, and chemicals have been suggested. Pathophysiology The M-protein produced by the malignant plasma cells is IgG in about 55% of myeloma patients and IgA in about 20%; of patients producing either IgG or IgA, 40% also have Bence Jones proteinuria, which is free monoclonal κ or λ light chains in the urine. In 15 to 20% of patients, plasma cells secrete only Bence Jones protein. IgD myeloma accounts for about 1% of cases. Diffuse osteoporosis or discrete osteolytic lesions develop, usually in the pelvis, spine, ribs, and skull. Lesions are caused by bone replacement by expanding plasmacytomas or by cytokines that are secreted by malignant plasma cells that activate osteoclasts and suppress osteoblasts. The osteolytic lesions are usually multiple; occasionally, they are solitary intramedullary masses. Enhanced bone loss may also lead to hypercalcemia. Extraosseous solitary plasmacytomas are unusual but may occur in any tissue, especially in the upper respiratory tract. Renal failure (myeloma kidney) occurs in many patients at diagnosis or during the course of the disorder due to many causes, most commonly from deposition of light chains in the distal tubules and hypercalcemia. Patients also often develop anemia usually from kidney disease or suppression of erythropoiesis by cancer cells. Susceptibility to bacterial infection may occur in some patients. Viral infections, especially herpetic infections, are increasingly occurring as a result of newer treatment modalities. Secondary amyloidosis (see Amyloidosis: Secondary amyloidosis (AA)) occurs in 10% of myeloma patients, most often in patients with Bence Jones proteinuria of λ-type. Variant expressions of multiple myeloma occur: Plasma Cell Disorders: Variant Expressions of Multiple Myeloma ). Symptoms and Signs Persistent bone pain (especially in the back or thorax), renal failure, and recurring bacterial infections are the most common problems on presentation, but many patients are identified when routine laboratory tests show an elevated total protein level in the blood or show proteinuria. Pathologic fractures are common, and vertebral collapse may lead to spinal cord compression and paraplegia. Symptoms of anemia predominate or may be the sole reason for evaluation in some patients, and a few patients have manifestations of hyperviscosity syndrome (see Plasma Cell Disorders: Symptoms and Signs). Peripheral neuropathy, carpal tunnel syndrome, abnormal bleeding, and symptoms of hypercalcemia (eg, polydipsia) are common. Patients may also present with renal failure. Lymphadenopathy and hepatosplenomegaly are unusual. Diagnosis • CBC with platelets, peripheral blood smear, ESR, chemistry panel (BUN, creatinine, Ca, uric acid, LDH) • Serum and urine protein electrophoresis, followed by immunofixation • X-rays (skeletal survey) • Bone marrow examination Multiple myeloma is suspected in patients > 40 yr with persistent unexplained bone pain, particularly at night or at rest, other typical symptoms, or unexplained laboratory abnormalities, such as elevated blood protein or urinary protein, hypercalcemia, renal insufficiency, or anemia. Laboratory evaluation includes routine blood tests, protein electrophoresis, x-rays, and bone marrow examination. Routine blood tests include CBC, ESR, and chemistry panel. Anemia is present in 80% of patients, usually normocytic-normochromic anemia with formation of rouleau, which are clusters of 3 to 12 RBCs that occur in stacks. WBC and platelet counts are usually normal. ESR usually is > 100 mm/h; BUN, serum creatinine, LDH, and serum uric acid are frequently elevated. Anion gap is sometimes low. Hypercalcemia is present at diagnosis in about 10% of patients. Protein electrophoresis is done on a serum sample and on a urine sample concentrated from a 24-h collection to quantify the amount of urinary M-protein. Serum electrophoresis identifies M-protein in about 80 to 90% of patients. The remaining 10 to 20% are usually patients with only free monoclonal light chains (Bence Jones protein) or IgD. They almost always have Mprotein detected by urine protein electrophoresis. Immunofixation electrophoresis can identify the immunoglobulin class of the M-protein and can often detect light-chain protein if the serum immunoelectrophoresis is falsely negative; immunofixation electrophoresis is done even if the serum test is negative if multiple myeloma is strongly suspected. Light-chain analysis with delineation of κ and λ ratios helps confirm the diagnosis. Light-chain analysis can also be used to follow efficacy of therapy and provide prognostic data. Serum level of β2-microglobulin is measured if diagnosis is confirmed or very likely; it frequently is elevated, and albumin may be decreased. A new international staging system uses the levels of serum albumin and β2microglobulin to indicate severity of disease and subsequent prognosis. X-rays include a skeletal survey. Punched-out lytic lesions or diffuse osteoporosis is present in 80% of cases. Radionuclide bone scans usually are not helpful. MRI can provide more detail and is obtained if specific sites of pain or neurologic symptoms are present. Bone marrow aspiration and biopsy are done and reveal sheets or clusters of plasma cells; myeloma is diagnosed when > 10% of the cells are of this type. However, marrow involvement is patchy; therefore, some samples from patients with myeloma may show < 10% plasma cells. Still, the number of marrow plasma cells is rarely normal. Plasma cell morphology does not correlate with the class of immunoglobulin synthesized. Chromosomal studies on bone marrow may reveal specific karyotypic abnormalities in plasma cells associated with differences in survival. In patients without serum M protein, myeloma is indicated by Bence Jones proteinuria > 300 mg/24 h, osteolytic lesions (without evidence of metastatic cancer or granulomatous disease), and sheets or clusters of marrow plasma cells. Prognosis The disease is progressive and incurable, but median survival has recently improved to > 5 yr as a result of advances in treatment. Unfavorable prognostic signs at diagnosis are lower serum albumin and higher β2-microglobulin levels. Patients presenting with renal failure also do poorly unless kidney function improves with therapy. Because multiple myeloma is ultimately fatal, patients are likely to benefit from discussions of end-of-life care that involve their doctors and appropriate family and friends. Points for discussion may include advance directives, the use of feeding tubes, and pain relief. Treatment • Chemotherapy for symptomatic patients • Thalidomide SOME TRADE NAMES THALOMID , bortezomib SOME TRADE NAMES VELCADE , or lenalidomide with corticosteroids and/or chemotherapy • Possibly maintenance therapy • Possibly stem cell transplantation • Possibly radiation therapy • Treatment of complications (anemia, hypercalcemia, renal insufficiency, infections, skeletal lesions) Treatment of myeloma has improved in the past decade, and long-term survival is a reasonable therapeutic target. Therapy involves direct treatment of malignant cells in symptomatic patients and the treatment of the complications. Asymptomatic patients probably do not benefit from treatment, which is usually withheld until symptoms or complications develop. However, patients with evidence of lytic lesions or bone loss (osteopenia or osteoporosis) should be treated with monthly infusions of zoledronic acid SOME TRADE NAMES ZOMETA or pamidronate SOME TRADE NAMES AREDIA to reduce the risk of skeletal complications. Treatment of malignant cells: Until recently, conventional chemotherapy consisted only of oral melphalan SOME TRADE NAMES ALKERAN and prednisone SOME TRADE NAMES DELTASONE given in cycles of 4 to 6 wk with monthly evaluation of response. Recent studies show superior outcome with the addition of either bortezomib SOME TRADE NAMES VELCADE or thalidomide SOME TRADE NAMES THALOMID . Other chemotherapeutic drugs, including other alkylating drugs (eg, cyclophosphamide SOME TRADE NAMES CYTOXAN, doxorubicin SOME TRADE NAMES ADRIAMYCIN and its newer analog liposomal pegylated doxorubicin SOME TRADE NAMES ADRIAMYCIN ) also are more effective when combined with thalidomide SOME TRADE NAMES THALOMID or bortezomib SOME TRADE NAMES VELCADE . Many other patients are effectively treated with bortezomib SOME TRADE NAMES VELCADE , thalidomide SOME TRADE NAMES THALOMID , or lenalidomide plus glucocorticoids and/or chemotherapy. Chemotherapy response is indicated by decreases in serum or urine M-protein, increases in RBCs, and improvement in renal function among patients presenting with kidney failure. Autologous peripheral blood stem cell transplantation may be considered for patients who have adequate cardiac, hepatic, pulmonary, and renal function, particularly those whose disease is stable or responsive after several cycles of initial therapy. Allogeneic stem cell transplantation after non-myeloablative chemotherapy (eg, low-dose cyclophosphamide SOME TRADE NAMES CYTOXAN and fludarabine SOME TRADE NAMES FLUDARA ) or low-dose radiation therapy can produce myeloma-free survival of 5 to 10 yr in some patients. However, allogeneic stem cell transplantation remains experimental because of the high morbidity and mortality from graft vs. host disease. In relapsed or refractory myeloma, combinations of bortezomib SOME TRADE NAMES VELCADE , thalidomide SOME TRADE NAMES THALOMID, or its newer analog lenalidomide with chemotherapy or corticosteroids may be used. These drugs are usually combined with other effective drugs that the patient has not yet been treated with, although patients with prolonged remissions may respond to retreatment with the same regimen that led to the remission. Maintenance therapy has been tried with nonchemotherapeutic drugs, including interferonα, which prolongs remission but does not improve survival and is associated with significant adverse effects. Following a response to corticosteroid-based regimens, corticosteroids alone are effective as a maintenance treatment. Thalidomide SOME TRADE NAMES THALOMID may also be effective as a maintenance treatment, and studies are evaluating maintenance therapy with bortezomib SOME TRADE NAMES VELCADE and lenalidomide among patients who have responded to these drugs alone or in combination therapeutic regimens. Treatment of complications: In addition to direct treatment of malignant cells, therapy must also be directed at complications, which include anemia, hypercalcemia, renal insufficiency, infections, and skeletal lesions. Anemia can be treated with recombinant erythropoietin (40,000 units sc q wk) in patients whose anemia is inadequately relieved by chemotherapy. If anemia produces cardiovascular or significant systemic symptoms, packed RBCs are transfused. Plasmapheresis is indicated if hyperviscosity develops (see Plasma Cell Disorders: Symptoms and Signs). Hypercalcemia is treated with saluresis, IV bisphosphonates, and sometimes with prednisone SOME TRADE NAMES DELTASONE . Most patients do not require allopurinol SOME TRADE NAMES ZYLOPRIM . However, allopurinol SOME TRADE NAMES ZYLOPRIM is indicated for patients with high levels of serum uric acid or high tumor burden and a high risk of tumor lysis syndrome with treatment. Renal compromise can be ameliorated with adequate hydration. Even patients with prolonged, massive Bence Jones proteinuria (≥ 10 to 30 g/day) may have intact renal function if they maintain urine output > 2000 mL/day. Dehydration combined with high-osmolar IV contrast may precipitate acute oliguric renal failure in patients with Bence Jones proteinuria. Infection is more likely during chemotherapy-induced neutropenia. In addition, infections with the herpes zoster virus are occurring more frequently in patients treated with newer antimyeloma drugs. Documented bacterial infections should be treated with antibiotics; however, prophylactic use of antibiotics is not routinely recommended. Prophylactic use of antiviral drugs may be indicated for patients receiving specific drugs. Prophylactic IV immune globulin may reduce the risk of infection but is generally reserved for patients with recurring infections. Pneumococcal and influenza vaccines are indicated to prevent infection. Skeletal lesions require multiple supportive measures. Maintenance of ambulation and supplemental Ca and vitamin D help preserve bone density. Analgesics and palliative doses of radiation therapy (18 to 24 Gy) can relieve bone pain. However, radiation therapy may impair the patient's ability to receive cytotoxic doses of systemic chemotherapy. Most patients, especially those with lytic lesions and generalized osteoporosis or osteopenia, should receive a monthly IV bisphosphonate (either pamidronate SOME TRADE NAMES AREDIA or zoledronic acid SOME TRADE NAMES ZOMETA). Bisphosphonates reduce skeletal complications and lessen bone pain and may have an antitumor effect. Prepared by Orlovsky A. V., assistant, D.Ph., Murenets N. A., postgraduate Methodological Instruction to Lesson № 10. Bleeding Disorder (Hemorrhagic diathesis) Hours: 5. Working place: classroom, hospital wards. Questions. 1. To give definition of the term “Hemorrhagic diathesis” (HD). 2. Classification of HD. 3. Homeostasis system and it physiology. 4. Types of a bleeding at HD. 5. Diagnostic criteria of Hemophilia. 6. Treatment and preventive maintenance of Hemophilia. 7. Diagnostic criteria of Willebrand's Disease. 8. Diagnostic criteria of Thrombocytopenic purpura. 9. Treatment of Werlhof’s disease. 10. Diagnostic criteria of Thrombocytopathy and Glanzmann's disease. 11. Variants of hemorrhagic vasculitis and clinic depending on variant of illness. 12. Differential diagnostics of hemorrhagic vasculitis. 13. Diagnostic criteria of Rendu-Osler-Weber Syndrome. Examples of tests 1. The hemorrhagic diathesis which are caused by changes of abnormal blood vessels is all but one: a. Henoch-Schönlein Purpura d. Hemorrhagic vasculitis b. Rendu-Osler-Weber Syndrome e. Willebrand's Disease c. Hemangioma 2. The hematomic type of hemorrhagic is at: a. Hemorrhagic vasculitis d. Hemophilia b. Werlhof’s disease e. Glanzmann's disease c. Hemorrhagic telangiectasia 3. The petechialic type of hemorrhagic is at: a. Thrombocytopenic and thrombocytopathy b. Rendu-Osler-Weber Syndrome c. Hemorrhagic vasculitis d. Hemophilia e. Werlhof’s disease 4. The patient 35 years during 5 years has nasal bleeding, ecchymosis on a skin. Two weeks back after nasal of a bleeding there was a weakness, faint. The patient has pallor, ecchymosis on a skin. The analysis of blood: er. – 4.2*1012/l, Hb – 90 g/l, chromatic parameter – 0.7, L. – 6.4* 109/l, stab n.- 3%, seg. – 67%, e. – 2%, l. – 23%, m – 5%, thrombocytes – 10*109/l , ESR – 15mm/ hour. With is diagnosis at the patient? a. Aplastic anemia d. Iron deficiency Anemias b. Hemorrhagic vasculitis e. Thrombocytopenic purpura c. Hemophilia References. 4. Davidson’s Principles and practice of medicine (nineteenth edition)/Christopher Haslett, Edvin R. Chilvers and others. – Edinburgh, 2002. 5. Harrisons Principle if internal medicine (seventeenth Edition)/Fauci, Braunwald, Hasper and other. – Part 6, section 2, Chapter 109, 110. 6. The Merck Manual of Diagnosis and Therapy (seventeenth Edition)/ Robert Berkow, Andrew J. Fletcher and others. – published by Merck Research Laboratories, 1999. Short theoretic material Classification of hemorrhagic diathesis Thrombocytopenia and platelet dysfunction: Idiopatic thrombocytopenic purpura (ITP); Thrombocytopenia other causes; Thrombocytopenia due splenic sequestration; Thrombotic thrombocytopenic purpura (TTP); Hemolitic uremic syndrom (HUS); Hereditary disorders of platelet function Coagulation disorders: Circulating anticoagulants; Disseminated intravascular coagulation (DIC); Hemophilia; Uncomon hereditary coagulation disorders Bleeding due to abnormal blood vessels: Autoerythrocyte sensitization; Disprteinemias causing vascular purpura; Hereditary hemorrhagic teleangiectasia; Purpura simplex; Senile purpura Unusual or excessive bleeding includes unexplained nosebleeds (epistaxis), excessive or prolonged menstrual blood loss (menorrhagia), prolonged bleeding after minor cuts or trauma, easy bruising into tissues (ecchymoses) or skin (petechial or purpuric lesions), and unexplained gingival bleeding after tooth brushing; Systemic bleeding can result from defects in blood vessels (connective tissue diseases, vitamin C deficiency, hereditary hemorrhagic telangiectasia) or, more commonly, quantitative or qualitative disorders of platelets or of coagulation. Etiology and Pathophysiology of Thrombocytopenia Platelets are cell fragments that function in the clotting system. Thrombopoietin, primarily produced in the liver in response to decreased numbers of marrow megakaryocytes and circulating platelets, stimulates the bone marrow to synthesize platelets from megakaryocytes. Platelets circulate for 7 to 10 days. About 1⁄3 are always transiently sequestered in the spleen. red in the spleen. The platelet count is normally 140,000 to 440,000/μL. The risk of bleeding is inversely proportional to the platelet count. When the platelet count is < 50,000/μL, minor bleeding occurs easily and the risk of major bleeding increases. Counts between 20,000 and 50,000/μL predispose to bleeding with trauma, even minor trauma; with counts < 20,000/μL, spontaneous bleeding may occur; with counts < 5000/μL, severe spontaneous bleeding is more likely. However, patients with counts < 10,000/μL may be asymptomatic for years. Symptoms and Signs Platelet disorders result in a typical pattern of bleeding: multiple petechiae in the skin, typically most evident on the lower legs; scattered small ecchymoses at sites of minor trauma; mucosal bleeding (epistaxis, bleeding in the GI and GU tracts, vaginal bleeding); and excessive bleeding after surgery. Heavy GI bleeding and bleeding into the CNS may be life threatening. However, massive bleeding into tissues (eg, deep visceral hematomas or hemarthroses) does not commonly occur and suggests a coagulation disorder (hemophilia). Treatment In patients with thrombocytopenia or platelet dysfunction, drugs that further impair platelet function should be avoided, particularly aspirin and other NSAIDs. Patients may require platelet transfusion, but only in limited situations. Prophylactic transfusions are used sparingly because they may lose their effectiveness with repeated use due to the development of platelet alloantibodies. In platelet dysfunction or thrombocytopenia caused by decreased production, transfusions are reserved for active bleeding or severe thrombocytopenia (eg, platelet count < 10,000/μL). In thrombocytopenia caused by platelet destruction, transfusions are reserved for lifethreatening or CNS bleeding. Hereditary Intrinsic Platelet Disorders Von Willebrand's Disease Von Willebrand's disease is a hereditary deficiency of von Willebrand's factor (VWF), which causes platelet dysfunction. Von Willebrand's factor (VWF) is synthesized and secreted by vascular endothelium to form part of the perivascular matrix. VWF promotes the platelet adhesion phase of hemostasis by binding with a receptor on the platelet surface membrane (glycoprotein Ib-IX), which connects the platelets to the vessel wall. VWF is also required to maintain normal plasma factor VIII levels. Disorders of amplification of platelet activation are the most common hereditary intrinsic platelet disorders and produce mild bleeding. They may result from decreased of adenosine diphosphate in the platelet granules (storage pool deficiency), from an inability to generate thromboxane A2 from arachidonic acid, or from an inability of platelets to aggregate in response to thromboxane A2. Thrombasthenia (Glanzmann's disease) is a rare autosomal recessive disorder producing a defect in the platelet glycoprotein IIb-IIIa complex; platelets cannot aggregate. Patients may experience severe mucosal bleeding (eg, nosebleeds that stop only after nasal packing and transfusions of platelet concentrates). Bernard-Soulier syndrome is another rare autosomal recessive disorder. It impairs platelet adhesion via a defect in the glycoprotein Ib-IX complex. Bleeding may be severe. Platelets are unusually large. They do not aggregate with ristocetin but aggregate normally with ADP, collagen, and epinephrine. Large platelets associated with functional abnormalities also occur in the May-Hegglin anomaly, a thrombocytopenic disorder with abnormal WBCs, and in the Chédiak-Higashi syndrome Symptoms and Signs of Von Willebrand's Disease Bleeding manifestations are mild to moderate and include easy bruising; bleeding from small skin cuts that may stop and start over hours; sometimes, increased menstrual bleeding; and abnormal bleeding after surgical procedures (eg, tooth extraction, tonsillectomy). Diagnosis of Von Willebrand's Disease VWD is suspected in patients with bleeding disorders, particularly those with a family history of the disorder. Definitive diagnosis requires measuring total plasma VWF antigen; VWF function, as determined by the ability of the plasma to support agglutination of normal platelets by ristocetin (ristocetin cofactor activity); and plasma factor VIII level. Treatment of Von Willebrand's Disease Patients are treated only if they are actively bleeding or are undergoing an invasive procedure (surgery, dental extraction). Treatment involves replacement of VWF by infusion of pasteurized intermediate-purity factor VIII concentrates which contain components of VWF. These concentrates are virally inactivated and therefore do not transmit HIV infection or hepatitis. Because they do not cause transfusion-transmitted infections, these concentrates are preferred to the previously common use of cryoprecipitate. High-purity factor VIII concentrates are prepared by immunoaffinity chromatography and contain no VWF. Idiopathic Thrombocytopenic Purpura (ITP) Idiopathic (immunologic) thrombocytopenic purpura is a bleeding disorder caused by thrombocytopenia not associated with a systemic disease. Typically, it is chronic in adults but is usually acute and selflimited in children. Spleen size is normal. Diagnosis requires that other disorders be excluded through selective tests. Idiopathic thrombocytopenic purpura (ITP) usually results from development of an antibody directed against a structural platelet antigen (an autoantibody). In childhood ITP the autoantibody may be triggered by binding of viral antigen to megakaryocytes. Symptoms, Signs, and Diagnosis spleen is of normal size unless it is enlarged by a coexistent childhood viral infection. ITP is suspected in patients with unexplained thrombocytopenia. Peripheral blood is normal except for reduced platelet numbers. Bone marrow is examined if blood counts or blood smear reveals abnormalities in addition to thrombocytopenia. Bone marrow examination reveals normal or possibly increased numbers of megakaryocytes in an otherwise normal marrow. Because diagnostic findings are nonspecific, diagnosis requires exclusion of other thrombocytopenic disorders suggested by clinical or laboratory test data. Because HIV-associated thrombocytopenia may be otherwise indistinguishable from ITP, HIV testing is performed if the patient has risk factors for HIV infection. Treatment includes of ITR Corticosteroids (prednisone 1 mg/kg once/day) initially. In the patient who responds, the platelet count rises to normal within 2 to 6 wk). Splenectomy (can achieve a remission in about 2⁄3 of these patients), Immunosuppressive treatment (cyclophosphamide, azathioprine, rituximab), Platelet transfusions, IV immune globulin. In a child or adult with ITP and life-threatening bleeding, rapid phagocytic blockade is attempted by giving IV immune globulin 1 g/kg once/day for 1 to 2 days. This usually causes the platelet count to rise within 2 to 4 days but only for 2 to 4 wk. Thrombocytopenia: Other Causes Acute respiratory distress syndrome Blood transfusions Connective tissue and lymphoproliferative disorders Drug-induced immunologic destruction (Quinidine, sulfa preparations, carbamazepine, methyldopa, aspirin, oral antidiabetic drugs, gold salts, and rifampin, heparin) Gram-negative sepsis HIV Thrombocytopenia Due to Splenic Sequestration Increased splenic platelet sequestration can occur in various disorders that produce splenomegaly. Sequestration is expected in patients with congestive splenomegaly caused by advanced cirrhosis. The platelet count usually is > 30,000/μL unless the disorder producing the splenomegaly also impairs platelet production (eg, in myelofibrosis with myeloid metaplasia). Thrombotic Thrombocytopenic Purpura (TTP) and Hemolytic-Uremic Syndrome (HUS) unexplained thrombocytopenia and microangiopathic hemolytic anemia are sufficient evidence for a presumptive diagnosis. TTP-HUS is suspected in patients with suggestive symptoms, thrombocytopenia, and anemia. If the disease is suspected, urinalysis, peripheral blood smear, reticulocyte count, serum LDH, renal functions, serum bilirubin (direct and indirect), and Coombs' test are obtained. The diagnosis is suggested by thrombocytopenia and anemia, with fragmented RBCs on the blood smear (helmet cells, triangular-shaped RBCs, distortedappearing RBCs-these changes describe microangiopathic hemolysis); evidence of hemolysis (falling Hb level, polychromasia, elevated reticulocyte count, elevated serum LDH); and negative direct antiglobulin (Coombs') test. Prognosis and Treatment Epidemic HUS in children associated with enterohemorrhagic infection usually spontaneously remits and is treated with supportive care and not plasma exchange. In other cases, untreated TTP-HUS is almost always fatal. With plasma exchange, however, about 85% of patients recover completely. Plasma exchange is continued daily until evidence of disease activity has subsided, which may be several days to many weeks Corticosteroids and antiplatelet drugs (aspirin) have also been used but are controversial. Coagulation Disorders Caused by Circulating Anticoagulants (CA) CA are usually autoantibodies that neutralize specific clotting factors in vivo (autoantibody against factor VIII or factor V) or inhibit protein-bound phospholipid in vitro; antibodies bind to prothrombin-phospholipid complexes, inducing hypoprothrombinemia; these patients may bleed excessively; Factor VIII autoantibodies also arise occasionally in nonhemophilic patients, eg, in a postpartum woman as a manifestation of underlying systemic autoimmune disease or in elderly patients without overt evidence of other underlying disease. Patients with a factor VIII anticoagulant can develop life-threatening hemorrhage. Therapy with cyclophosphamide and corticosteroids may suppress autoantibody production in patients without hemophilia. Disseminated Intravascular Coagulation(DIC) (Consumption Coagulopathy; Defibrination Syndrome) DIC involves abnormal, excessive generation of thrombin and fibrin in the circulating blood. During the process, increased platelet aggregation and coagulation factor consumption occur. DIC that evolves slowly (over weeks or months) causes primarily venous thrombotic and embolic manifestations; DIC that evolves rapidly (over hours or days) causes primarily bleeding. Etiology and Pathophysiology of DIC Complications of obstetrics—eg, abruptio placentae, saline-induced therapeutic abortion, retained dead fetus or products of conception, or amniotic fluid embolism. Infection, particularly with gram-negative organisms. Malignancy, particularly mucin-secreting adenocarcinomas of the pancreas and prostate and acute promyelocytic leukemia. Shock from any cause. severe tissue damage from head trauma, burns, frostbite, or gunshot wounds; complications of prostate surgery; venomous snake bites in which enzymes enter the circulation that activate one or several coagulation factors and generate thrombin or directly convert fibrinogen to fibrin; profound intravascular hemolysis; aortic aneurysms or cavernous hemangiomas (Kasabach-Merritt syndrome) associated with vessel wall damage and areas of blood stasis. Symptoms and Signs of DIC In slowly evolving DIC, symptoms of venous thrombosis and pulmonary embolism may be present. In severe, rapidly evolving DIC, skin puncture sites (eg, IV or arterial punctures) bleed persistently, ecchymoses form at sites of parenteral injections, and serious GI bleeding may occur. Delayed dissolution of fibrin polymers by fibrinolysis may result in the mechanical disruption of RBCs and mild intravascular hemolysis. Occasionally, microvascular thrombosis and hemorrhagic necrosis produce dysfunction and failure in multiple organs. Diagnosis of DIC decreasing plasma fibrinogen; increased plasma d-dimer (an indication of in vivo fibrin deposition and degradation); thrombocytopenia, a normal to minimally prolonged PT (results are typically reported as INR); factor VIII is reduced in DIC because of the thrombin-induced generation of activated protein C, which proteolyses factor VIII. Treatment of DIC Immediate correction of the underlying cause is the priority (eg, broadspectrum antibiotic treatment of suspected gram-negative sepsis, evacuation of the uterus in abruptio placentae). If treatment is effective, DIC should subside quickly. If bleeding is severe, adjunctive eplacement therapy is indicated, consisting of platelet oncentrates to correct thrombocytopenia; cryoprecipitate to replace fibrinogen and factor VIII; and fresh frozen plasma to increase levels of other clotting factors and natural anticoagulants (antithrombin, proteins C and S). Hemophilia Hemophilias are common hereditary bleeding disorders caused by deficiencies of either clotting factor VIII or IX. Hemophilia A (factor VIII deficiency), which affects about 80% of hemophilic patients, and hemophilia B (factor IX deficiency) have identical clinical manifestations, screening test abnormalities, and Xlinked genetic transmission. Because these genes are located on the X chromosome, hemophilia affects males almost exclusively. Daughters of hemophilic males are obligate carriers, but sons are normal. Each son of a carrier has a 50% chance of having hemophilia, and each daughter has a 50% chance of being a carrier. Diagnosis Patients with hemophilia bleed into tissues (eg, hemarthroses, muscle hematomas, retroperitoneal hemorrhage), and the bleeding may be delayed after trauma. Hemarthroses can lead to synovitis and arthropathy family history PTT is prolonged, but the PT and platelet count are normal. Decrease of Factor VIII and IX. Prevention and Treatment should avoid aspirin and NSAIDs. The COX-2 inhibitors have little antiplatelet activity, may produce fewer GI erosions than aspirin or other NSAIDs, and can be used with caution in hemophilia. To avoid surgical operations. Drugs should be given orally or IV. In hemophilia A, factor VIII. In hemophilia B, factor IX. Desmopressin (SOME TRADE NAMES DDAVP, STIMATE) may temporarily raise factor VIII levels. An antifibrinolytic agent (ε- aminocaproic acid SOME TRADE NAMES AMICAR 2.5 to 4 g po qid for 1 wk or tranexamic acid SOME TRADE NAMES CYKLOKAPRON 1.0 to 1.5 g po tid or qid for 1 wk) should be given to prevent late bleeding after dental extraction or other oropharyngeal mucosal trauma (tongue laceration). BLEEDING DUE TO ABNORMAL BLOOD VESSELS Bleeding may result from abnormalities in platelets, coagulation factors, or blood vessels. Vascular bleeding disorders are caused by defects in blood vessels, typically producing petechiae, purpura, and bruising but seldom leading to serious blood loss. Bleeding may result from deficiencies of vascular and perivascular collagen in Ehlers-Danlos syndrome and in other rare hereditary connective tissue disorders (pseudoxanthoma elasticum, osteogenesis imperfecta, Marfan syndrome). Hemorrhage may be a prominent feature of scurvy or of Henoch-Schönlein purpura, a hypersensitivity vasculitis common during childhood. In vascular bleeding disorders, tests of hemostasis are usually normal. Diagnosis is clinical. Henoch-Schönlein Purpura (HSP) Henoch-Schönlein purpura is vasculitis that affects primarily small vessels. It occurs most often in children. Common manifestations include palpable purpura, arthralgias, GI symptoms and signs, and glomerulonephritis. Diagnosis is clinical in children but usually warrants biopsy in adults. Disease is usually self-limited. Corticosteroids can relieve arthralgias and GI symptoms but do not alter the course of the disease. Progressive glomerulonephritis may require highdose corticosteroids and cyclophosphamide. Symptoms and Signs of HSP The disease begins with a sudden palpable purpuric rash typically occurring on the feet, legs, and arms and as a strip across the buttocks. The purpura may start as small areas of urticaria that become indurated and palpable. Crops of new lesions may appear over days to several weeks. Many patients also have fever and polyarthralgia with periarticular tenderness and swelling of the ankles, knees, hips, wrists, and elbows. GI symptoms are common and include colicky abdominal pain, abdominal tenderness, and melena. Symptoms usually remit after about 4 wk. In most patients, the disorder subsides without serious sequelae; however, some patients develop chronic renal failure. Diagnosis of HSP Biopsy of skin lesions The diagnosis is suspected in patients, particularly children, with typical skin findings. It is confirmed by biopsy of skin lesions when leukocytoclastic vasculitis with IgA in the vessel walls is identified. Urinalysis is done; hematuria, proteinuria, and RBC casts indicate renal involvement. If renal function is deteriorating, renal biopsy may help define the prognosis. Diffuse glomerular involvement or crescent formation in most glomeruli predicts progressive renal failure. Treatment of HSP treatment is symptomatic. Corticosteroids (prednisone 2 mg/kg up to a total of 50 mg po once/day) may help control abdominal pain and are occasionally needed to treat severe joint pain or renal disease. Pulse IV methylprednisolone followed by oral and cyclophosphamide can be given to attempt to control inflammation when the kidneys are severely affected. However, the effects of corticosteroids on renal manifestations are not clear. Autoerythrocyte Sensitization (Gardner-Diamond Syndrome) Autoerythrocyte sensitization is a rare disorder affecting women. It is characterized by local pain and burning preceding painful ecchymoses that occur primarily on the extremities. In women with autoerythrocyte sensitization, intradermal injection of 0.1 mL of autologous RBCs or RBC stroma may result in pain, swelling, and induration at the injection site. Diagnosis is based on examination of the site of intradermal injection of autologous RBCs and of a separate control injection site (without RBCs) 24 to 48 h after injection. Dysproteinemias Causing Vascular Purpura Amyloidosis causes amyloid deposition within vessels in the skin and subcutaneous tissues, which may increase vascular fragility, producing purpura. In some patients, coagulation factor X is adsorbed by amyloid and becomes deficient, but this usually is not the cause of bleeding. Periorbital purpura or a purpuric rash that develops in a nonthrombocytopenic patient after gentle stroking of the skin suggests amyloidosis. Hereditary Hemorrhagic Telangiectasia (Rendu-Osler-Weber Syndrome) Hereditary hemorrhagic telangiectasia is a hereditary disease of vascular malformation transmitted as an autosomal dominant trait affecting men and women. telangiectatic lesions on the face, lips, oral and nasal mucosa, and tips of the fingers and toes. Some patients have pulmonary arteriovenous fistulas. These fistulas may produce significant right-to-left shunts, which can result in dyspnea, fatigue, cyanosis, or polycythemia. However, the first sign of their presence may be a brain abscess, transient ischemic attack, or stroke as a result of infected or noninfected emboli. Cerebral or spinal arteriovenous malformations occur in some families and may cause subarachnoid hemorrhage, seizures, or paraplegia. Treatment Treatment for most patients is supportive, but accessible telangiectases (in the nose or GI tract via endoscopy) may be treated with laser ablation. Arteriovenous fistulas may be treated by surgical resection or embolotherapy. Iron therapy Prepared by Orlovsky A. V., assistant, D.Ph., Murenets N. A., postgraduate