Critically evaluate the relevant importance of histology, cytology and immunohistochemistry in the diagnosis and management of non-malignant diseases of the respiratory tract.
INTRODUCTION
The diagnosis and treatment of most respiratory disorders depend heavily on understanding the basic physiologic principles of respiration and gas exchange. Some respiratory diseases result from inadequate ventilation, whereas others result from abnormalities of diffusion through the pulmonary membrane or abnormal transport in the blood from the lungs to the tissues. The therapy is often entirely different for these diseases, so it is no longer satisfactory simply to make a diagnosis of “respiratory insufficiency” (Guyton & Hall, 2000).
In the normal respiratory system, the volume and pattern of ventilation are determined by the neural output from the respiratory center located near the ventrolateral surface of the medulla. This output is influenced by afferent information from several sources, including higher centers in the brain, peripheral chemoreceptors, central chemoreceptors, and neural impulses from moving tendons and joints.
Deviation from the normal range, and consequent respiratory insufficiency, can result from malfunction of the respiratory system at any point in the respiratory pathway. It is important to appreciate this when ordering and interpreting pulmonary function tests. Disturbances of different points can usually be measured specifically when the tests available and the patterns of pathophysiologic disturbances are understood.
Diagnosis and management of pulmonary disorders requires a history, a physical examination, and usually chest x-rays. Pulmonary function testing, arterial blood gas analysis, chemical or microbiologic tests, or special studies (eg, endoscopy, bronchoalveolar lavage, biopsy, radionuclide scanning) may be needed.
Among the most fundamental of all tests of pulmonary performance are determinations of the blood PO2, CO2 and pH. Several simple and rapid methods have been developed to make these measurements within a few minutes, using no more than a few drops of blood (Guyton & Hall, 2000).
Blood pH is measured using a glass of pH electrode of the type used in all chemical laboratories. However, the electrodes used for this purpose are miniaturized. A glass electrode pH meter can also be used to determine blood CO2. The concentration of oxygen in a fluid can be measured by a technique called polarography. Electric current is made to flow between a small negative electrode and the solution (Guyton & Hall, 2000).
Non malignant respiratory diseases that will be discussed in this paper will include pulmonary hypertension, asthma, chronic obstructive pulmonary disease (COPD), pneumonia, cystic fibrosis, and allergic pulmonary diseases. The importance of histology, cytology and immunohistochemistry in the diagnosis and management of these non-malignant diseases of the respiratory tract will be discussed.
PULMONARY HYPERTENSION
Primary pulmonary hypertension is a rare disease of unknown etiology, whereas secondary pulmonary hypertension is a complication of many pulmonary, cardiac and extrathoracic conditions. Chronic obstructive pulmonary disease, left ventricular dysfunction and disorders associated with hypoxemia frequently result in pulmonary hypertension. Regardless of the etiology, unrelieved pulmonary hypertension can lead to right-sided heart failure. Signs and symptoms of pulmonary hypertension are often subtle and nonspecific. The diagnosis should be suspected in patients with increasing dyspnea on exertion and a known cause of pulmonary hypertension (Stites, 2001).
All patients with documented pulmonary hypertension should undergo a comprehensive laboratory evaluation to clarify the etiology. The goal is to identify or exclude treatable causes. Initial tests include complete blood count, prothrombin time, partial thromboplastin time, hepatic profile and autoimmune panel (Stites, 2001). HIV testing should be considered in all patients, especially those with a compatible history or risk factors.
Treatment of pulmonary hypertension is directed at the underlying etiology. For example, patients with emphysema should be treated with long-term oxygen therapy, bronchodilators and steroids to reduce the pulmonary artery pressure. Afterload reduction and diuretics are part of the therapy in patients with left ventricular dysfunction causing pulmonary venous disease. A patient with mitral valve disease may need valve repair or replacement to reduce the chronically elevated left atrial pressure. A patient with chronic thromboembolic pulmonary hypertension will need to be treated indefinitely with anticoagulation therapy, an inferior vena cava filter and a thromboendarterectomy to open the lumen (Brooke Huffman, 2001).
CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Chronic obstructive pulmonary disease (COPD) is a disease state characterized by the progressive development of airflow limitation that is not fully reversible. The airflow limitation is associated with an abnormal inflammatory response of the lungs to noxious particles or gases (Daryanani, 2004).
COPD is an umbrella term for two diseases, chronic bronchitis and emphysema, both of which are characterized by irreversible obstruction to air flow on exhalation. Asthma is another obstructive lung disease; however, it is classified separately from COPD because the person with asthma usually has periods during which air flow returns to normal. While many persons with COPD also have some degree of airway reactivity (or bronchospasm) and are thus said to have an asthmatic component to their disease, their air flow never returns to normal. Both COPD and asthma are also inflammatory processes; however, inflammation in COPD differs markedly from that seen in asthma, with different cells, mediators, and responses to treatment (Locke, 2004).
In COPD, definite diagnosis depends on (1) demonstration of physiologic evidence of airways obstruction which persists despite intensive and maximum medical management, and (2) exclusion of any specific disease as a cause of this physiologic abnormality.
Individuals with a family history of lung disease and those with an early onset of emphysema should be tested for α1-antitrypsin deficiency to determine the serum levels. Phenotyping should be done if the level is low. The normal phenotype is constituted by the MM genetic pattern. The most common abnormal phenotype associated with α1-antitrypsin deficiency is the ZZ pattern. Persons with the MZ phenotype are carriers of the disease, but do not appear to have an increased risk of developing COPD (Locke, 2004).
β-2 agonists, corticosteroids, anticholinergics, and methylxanthines have been the mainstay of COPD therapy. New agents, classes, and combinations of drugs are being developed for the treatment of COPD. In February 2004, tiotropium, a long-acting anticholinergic bronchodilator, was approved by FDA. Three combination products are available: ipratropium/albuterol as a metered-dose inhaler (MDI); ipratropium/albuterol as a solution for inhalation via a nebulizer; and fluticasone/salmeterol, in the 250/50 mcg strength for the treatment of COPD associated with chronic bronchitis (Daryanani, 2004). Phosphodiesterase-4 (PDE4) inhibitors are a newer class of drugs under investigation for the treatment of COPD that may also be available in the near future. With the growing number of pharmacologic options for the treatment of COPD, it is important to use evidence-based clinical data to determine which agents are most beneficial.
Emphysema
In the degenerative and potentially fatal pulmonary disease called emphysema, the lungs lose their elasticity as a result of disruption of elastic tissue and the walls between the alveoli break down so that the alveoli are replaced by large air sacs.
The most common cause of emphysema is excessive cigarette smoking. The smoke causes an increase in the number of pulmonary alveolar macrophages, and these macrophages release a chemical substance that attracts leukocytes to the lungs. The leukocytes in turn release proteases including elastase, which attacks the elastic tissue in the lungs. At the same time, α1-antitrypsin, a plasma protein that normally inactivates elastase and other proteases, is itself inhibited (Ganong, 2001). The α1-antitrypsin is inactivated by oxygen radicals, and these are released by the leukocytes. The final result which can be seen in biochemical and histological tests is a protease-antiprotease imbalance with increased destruction of lung tissue.
Chronic Bronchitis
Chronic bronchitis is an inflammatory condition clinically defined as a chronic cough that exists for 3 months of the year for 2 consecutive years. While the diagnosis of bronchitis is based on clinical criteria, distinctive pathologic features of the airways are associated with the hypersecretion of mucus (Locke, 2004). Again, as in emphysema, certain proteases are involved. In chronic bronchitis, these proteases are potent stimulants of mucus secretion as the size and number of mucus-secreting goblet cells in the airway epithelium increase.
Mucosal inflammation is characterized by edema, which further narrows the airways. These inflammatory airway changes occur secondary to chronic stimulation from irritants such as cigarette smoke. The presence of thick and tenacious mucus in the airways also promotes adherence of bacteria, which can reproduce rapidly in this environment. Impaired ciliary function, caused by cigarette smoking, further compromises the lung’s defense mechanisms and increases the patient’s susceptibility to infection (Locke, 2004).
ASTHMA
Asthma is characterized by episodic or chronic wheezing, cough, and a feeling of tightness in the chest as a result of bronchoconstriction. Three abnormalities are present: airway obstruction that is at least partially reversible, airway inflammation, and airway hyper-responsiveness to a variety of stimuli. A link to allergy has long been recognized, and plasma IgE levels are often elevated as found out in biochemical tests.
The sputum in a patient with uncomplicated asthma is highly distinctive. Grossly, it is tenacious, rubbery and whitish. In the presence of infection, particularly in adults, the sputum may be yellowish. Examination of the blood and the sputum of a patient with asthma commonly shows eosinophilia regardless of whether allergic factors can be shown to have an etiologic role in the disease. Blood eosinophilia > 250 to 400 cells/cu mm is the rule; in many asthmatics, the degree of the eosinophilia may correlate with the severity of the asthma. The extent to which blood eosinophilia can be suppressed with corticosteroids has been used as an index of the therapeutic efficacy of these agents.
Proteins released from eosinophils in the inflammatory reaction may damage the airway epithelium and contribute to the hyper-responsiveness. Leukotrienes are released from eosinophils and mast cells, and leukotrienes cause bronchoconstriction. Numerous other amines, neuropeptides, chemokines, and interleukins have effects on bronchial smooth muscle or produce inflammation, and they may be involved in asthma (Ganong, 2001).
Many eosinophils are found histologically, frequently arranged in sheets; large numbers of histiocytes and polymorphonuclear leukocytes are also present. Eosinophilic granules from disrupted cells may be seen throughout the sputum smear. Elongated dipyramidal crystals (Charcot-Leyden) originating from eosinophils are commonly found. When infection is present, and particularly when there is a bronchotic element, polymorphonuclear leukocytes and bacteria predominate. In uncomplicated asthma, sputum cultures rarely reveal pathogenic bacteria.
In the treatment of asthma, inhibitors of leukotriene synthesis such as zilueton and CysLT1 receptor blockers such as montelukast are found to be effective. β-Adrenergic receptors mediate bronchodilation, and treatment with inhaled β-Adrenergic agonists is a standard therapy for asthma.
PNEUMONIA
In diagnosing lower respiratory tract infections, histology and immunohistochemistry are important. Most of the clinical manifestations of the various pneumonias overlap. Some investigators demonstrated that chest radiography is not helpful for differentiating bacterial from nonbacterial pneumonia. Therefore, microbiologic means should be used to identify the causative agent in pneumonia (Thomson, 1991). Identification of the causative agent and knowledge of its antimicrobial susceptibility are important in determining the approach to treatment. Consequently, gram stain and culture of lower respiratory secretions should be performed.
Immunologic diagnosis of community-acquired pneumonia in adults can be attempted using methods that detect bacterial antigen in tissue fluids and microorganism-specific antibody (IgM or IgG) in serum. Detection of Haemophilus influenzae and Streptococcus pneumoniae antigens has been evaluated using counter-immunoelectrophoresis, latex agglutination, coagglutination and enzyme immunoassay (Thomson, 1991).
The following tests can help with diagnosis and treatment of pneumonia: (1) Chest X-ray, indicated for anyone with suspected pneumonia to aid diagnosis, gain insight into the cause and severity of pneumonia, detect associated lung diseases, and assess the patient’s response to treatment. (2) Blood work, including complete blood cell count and differential; serum creatinine, urea nitrogen, glucose, electrolyte, bilirubin, and liver enzyme levels; possibly HIV status; Sao^sub 2^ levels; and blood cultures. (3) Sputum tests, including Gram’s stain, culture and sensitivity, and possibly tuberculosis and Legionella testing. Negative results help confirm the presence of viral pneumonia. (4) Thoracentesis with culture and stain, pH, white blood cell count and differential, and possibly cytologic testing (Schultz, 2002).
The goal of empiric therapy is to choose a regimen that will be effective against the most likely pathogen. When rapid diagnostic techniques are not available, therapy should be started based on the knowledge of the susceptibility pattern of the common respiratory pathogens in the community. A reasonable attempt should be made to obtain a Gram stain of respiratory secretions before antimicrobial therapy is started (Thomson, 1991).
With the aid of the Gram stain results, the physician can initiate treatment based on a suspected pathogen. When gram-positive cocci in chains or pairs are found as the predominant organism, S. pneumoniae is the most likely causative organism. When the smear indicates gram-positive cocci in clusters, staphylococcal infection must be considered. The finding of gram-negative coccobacilli in the smear is compatible with H. influenzae. Gram-negative diplococci suggest M. catarrhalis, and gram-negative rods are indicative of Enterobacteriaceae, Pseudomonas and anaerobic organisms. When mixed gram-positive and gram-negative organisms are seen, aspiration of oral flora should be suspected (Thomson, 1991).
CYSTIC FIBROSIS
Cystic fibrosis is another condition that leads to repeated pulmonary infections and progressive, eventually fatal destruction of the lungs. In this congenital recessive disorder, a Cl- channel in the apical membrane of airway epithelial cells is not activated in a normal fashion by cyclic adenosine monophosphate (cAMP).
Histologically, the gene that is abnormal in cystic fibrosis is located in the long arm of chromosome 7. This gene encodes a Cl- channel called the cystic fibrosis transmembrane conductance regulator (CFTR) (Ganong, 2001). Functional abnormalities in the CFTR protein result in a paucity of salt and water in secretions from epithelial cells. Consequently, airway secretions are tenacious and difficult to clear, leading to airway obstruction and subsequent bacterial infection. Recurrent bacterial infections and subsequent inflammation damage the lungs and account for much of the irreversible pulmonary disease in patients with cystic fibrosis (Worth, 1996).
Sweat testing (using pilocarpine iontophoresis) is a standard quantitative test in the diagnosis of cystic fibrosis. A chloride level greater than 60 mEq per L is a positive test. False-negative and false-positive results are rare, but they do occur. A positive sweat test in combination with typical pulmonary manifestations, pancreatic malabsorption or a history of cystic fibrosis in the immediate family is considered diagnostic (Worth, 1996). Similarly, eosinophilia and elevated serum Ige levels lend confirmatory evidence but cannot establish the diagnosis. This test is usually performed at age 1 to 2 weeks when cystic fibrosis is suspected at birth, but can be done at any age.
A complete microbiological assessment of expectorated sputum, including antibiotic susceptibility testing, should be performed at least on an annual basis, and preferably on a quarterly basis. Oropharyngeal swab cultures, which are commonly obtained from children who do not produce sputum, have not been fully studied in adults. Multiply-resistant Gram-negative organisms, such as Burkholderia cepacia, Stenotrophomonas maltophilia, and Achromobacter xylosoxidans, are found in up to one third of adults with cystic fibrosis (David, 2004).
ALLERGIC PULMONARY DISEASES
Hypersensitivity (allergic) diseases of the lungs include hypersensitivity pneumonitis (extrinsic allergic alveolitis), allergic bronchopulmonary aspergillosis, and many drug reactions. Other eosinophilic pneumonias and the pulmonary granulomatoses are of suspected allergic origin.
Most data suggest that Th1 responses are required for viral clearance but Th1 cytokines such as interferon-[gamma] can also enhance the inflammatory response. Allergic airway responses are characterized by Th2 cytokines, increased production of total and allergen-specific IgE, tissue eosinophilia, and elevated exhaled nitric oxide (NO) in the lower airway, and are thought to be ineffective against viral infection and perhaps even detrimental (Varner, 2002).
Inhaled corticosteroids are the primary treatment for rhinitis and are thought to suppress Th2-like inflammation but not Th1 responses. Yet, nondiscriminate suppression of Th2 responses leads to a reduction in eosinophils, anti-inflammatory Th2 cytokines, and exhaled NO, and thus may enhance susceptibility to or severity of viral infection. Indeed, inhaled steroids are less effective against viral-induced wheezing than other triggers of asthma exacerbations and increase adverse sequelae of viral infection, such as otitis media in children, when used in the upper airway (Varner, 2002).
SUMMARIZATION/CONCLUSION
There are already significant advancements in the diagnosis and management of non-malignant diseases of the respiratory tract. These advancements are in the field of histology, cytology and immunohistochemistry.
Most non-malignant diseases of the respiratory tract can be diagnosed using cell and tissue specimens of respiratory organs. Cytological and histological examinations would be helpful in diagnosing these diseases. Diseases usually show abnormal patterns and characteristics in cell and tissue cultures that will be examined.
Histology, cytology and immunohistochemistry can help in confirming diseases, as sometimes chest X-rays and other procedures are not totally exact in diagnosing non-malignant diseases of the respiratory tract.
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