Denise H. Rhoney, PharmD, FCCP, FCCM

• Ron and Nancy McFarlane Distinguished Professor and Chair, Division of Practice Advancement and Clinical Education, UNC Eshelman School of Pharmacy, Chapel Hill, North Carolina

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It is important to remember that staging disease in sarcoidosis does not reflect disease progression antifungal japan buy 100mg sporanox free shipping, i fungus gnats walls purchase sporanox 100 mg overnight delivery. Pathology Sarcoidosis is characterized by the formation of noncaseating granulomas antifungal wash for dogs generic sporanox 100mg with amex. These granulomas are infiltrated by Th1 lymphocytes and macrophages fungus gnats in my house cheap sporanox online, which fuse to form multinucleated epithelioid cells fungus on tongue buy on line sporanox. Often these granulomas resolve, leading to spontaneous remission; however, in 10­20% the persistent inflammation results in interstitial fibrosis. Management Treatment If the patient has hilar lymphadenopathy and no lung involvement, then no treatment is required. If infiltration has occurred for more than 6 weeks, treat with corticosteroids (20­40 mg/day for 4­6 weeks, then reduced dose for up to 1 year). If shadowing is present on chest Clinical features the clinical presentation of sarcoidosis is dependent on the organ involved; however, the majority of patients (>90%) have pulmonary involvement causing: · Dyspnoea. They tend to be multiorgan diseases primarily affecting the kidney, lungs, joints and skin. The course of the disease is variable: some patients resolve completely, whereas others proceed to renal failure. Vasospasm is also a common feature and patients are at risk of developing myocardial infarction, pulmonary embolism or deep vein thrombosis. In the lung, mucosal thickening and ulceration occur, producing the clinical features of rhinorrhoea, cough, haemoptysis and dyspnoea. Rheumatoid arthritis Rheumatoid arthritis is a chronic inflammatory condition characterized by a symmetrical deforming polyarthropathy. In all, 10­15% of patients with rheumatoid arthritis have lung involvement and usually these patients have severe disease. Ankylosing spondylitis Ankylosing spondylitis is a chronic inflammatory condition of the spine and sacroiliac joints, which predominantly affects men. Systemic sclerosis Systemic sclerosis is a severe autoimmune connective tissue disorder. Pulmonary involvement is a sign of severe disease and is associated with a poor prognosis. Patients typically develop pulmonary fibrosis and rapidly progressive pulmonary hypertension, which leads to cor pulmonale. Approximately 500 mL of the respiratory tree by volume is described as anatomical dead space in a 75-kg man. Filtering of air by the nasopharynx removes fine particulate matter from inspired air. Blood vessels at the lung bases are subjected to a lower hydrostatic pressure than those at the apices. The pressure in the pulmonary circulation is normally equal to that of the systemic circulation. The pressure in the pulmonary circulation is normally greater than that of the systemic circulation. An 80-year-old woman with severe pneumonia and extensive consolidation of the right lung desaturates whenever the nurses turn her on to her right side. Increased ventilation of the right lung increasing ventilation:perfusion mismatch. Once oxygen is bound to the haem group of haemoglobin, the ferrous (Fe2þ) ion changes to the ferric state (Fe3þ). During exercise an individual will hyperventilate in order to blow off carbon dioxide. Increase in carbon dioxide and decrease in pH enhance dissociation of oxygen from oxyhaemoglobin. Renal compensation returns the blood gases and pH to normal in respiratory acidosis. Volume of air that can be breathed in by a maximum inspiration following a maximum expiration. Volume of air that can be expelled by a maximum effort at the end of a normal expiration. Volume of air breathed in by a maximum inspiration at the end of a normal expiration. An elderly man attends the outpatient clinic complaining of breathlessness on exertion and weight loss. The bicarbonate buffer system is important in the acid­base balance because its pK is very close to physiological pH. The British Thoracic Society guidelines on the management of asthma state that: A. Patients should not be stepped down the algorithm as their disease will likely worsen. On examination there is markedly reduced chest expansion of the left side with hyperresonant percussion and absent breath sounds on that side. A 60-year woman with a new diagnosis of breast cancer attends A&E with a 4-day history of increasing shortness of breath. On examination there is markedly reduced chest expansion on the left side with stony dull percussion and absent breath sounds at the left base. A 49-year-old smoker with a 6-month history of weight loss attends A&E with shortness of breath and a dry cough. On examination there is reduced chest expansion on the right side with dull percussion and absent breath sounds at the right base. Which of these investigations is the gold standard for diagnosis of a pulmonary embolism Which of these tests assesses breathlessness by having patients walk a 10-metre distance during increasingly short time intervals Which of the following is not a pathophysiological step in pulmonary hypertension He is managed with 35% oxygen on facemask, nebulized bronchodilators, antibiotics and steroids. The patient develops type 2 respiratory failure and his most recent blood gas demonstrates pH 7. Which of these is the gold standard investigation for idiopathic pulmonary fibrosis Which of these is not a commonly recognized cause of extrinsic allergic alveolitis Over the past 2 days he has developed a productive cough, fevers and progressive dyspnoea. Sequential chest X-rays show a rapidly progressive left-sided consolidation with evidence of cavitation. A 55-year-old man with a history of alcoholism is admitted to A&E with a reduced Glasgow Coma Scale. A 25-year-old male is admitted to A&E with a dry cough and worsening dyspnoea over several weeks. A 67-year-old retired plumber presents with progressive shortness of breath and right-sided chest pain. A 63-year-old woman has been diagnosed with mesothelioma 5 years ago, likely due to her previous factory work in her 30s and 40s. She needs to seek legal representation to clarify whether her former employer was negligent. She is eligible for compensation under the Industrial Injuries Disability Benefit scheme. Which of the following is the most common causative organism in community-acquired pneumonia A 67-year-old smoker presenting with weight loss and malaise is found to have a unilateral pleural effusion on chest X-ray. These muscles are attached to the inferior border of a rib and the superior border of the rib below. The central part of this domed muscle is tendinous and the outer margin is muscular. These muscles play the greatest role in preventing chest wall recession during quiet inspiration. In addition to the diaphragm and scalene muscles, these muscles raise the ribs anteroposteriorly to produce movement at the manubriosternal joint during forced inspiration. This structure has no contractile element and contains loose submucosa and glands. These structures have perforations between cells to communicate with adjacent similar structures. A disorder because of difficulty expanding the lungs, such as due to stiffening of the lung tissue or weakness of the respiratory muscles. The volume of air that can be breathed in by a maximum inspiration following a maximum expiration. The volume of air that can be expelled by a maximum effort at the end of a normal expiration. The drug prescribed to an asthmatic adult who uses a reliever (but no other medications) more than once a day. A long-term asthmatic woman suffering from sideeffects of her medication including osteoporosis, diabetes and recurrent infections. A mild asthmatic complaining that his medication causes oral candidiasis and a hoarse voice. A 48-year-old woman who is being managed for diabetes and hypertension complains of a constant dry cough. A 60-year-old woman, who smokes 25 cigarettes per day, presents with a 5-week history of cough, malaise and weight loss. A patient whom you suspect to have asthma is asked to keep a diary of peak flow measurements. A camera that is passed through the upper airways to visualize pathology directly and take samples for histology in a lifelong smoker complaining of a new-onset cough with haemoptysis. Saline that is squirted through a bronchoscope and then sucked back up again to collect cells for cytology in a lifelong smoker complaining of new-onset cough with haemoptysis. A sealed box the size of a telephone box, in which the patient whom you suspect of having an interstitial lung disease is asked to sit and perform respiratory manoeuvres. A test of exercise capacity whereby the patient complaining of reduced exercise tolerance is asked to walk up and down between two cones, placed 10 metres apart, in a set period of time. The time in which the patient is allowed to complete the course is progressively reduced. On examination you notice a raised jugular venous pressure and fine inspiratory crackles on auscultation. On examination there is reduced chest expansion on the left side with dull percussion and reduced breath sounds at the left base. On examination there is reduced chest expansion on the left side with dull percussion and reduced breath sounds with coarse crackles at the left base. On examination there is reduced chest expansion on the left side with hyperresonant percussion and absent breath sounds. On examination there is reduced chest expansion bilaterally and fine inspiratory crackles are audible at both apices of the lungs. Select the appropriate response from the options above for the following statements: 1. Match the category of pulmonary hypertension to its description in the following clinical scenarios: 1. A 70-year-old woman has suffered with recurrent deep vein thrombosis and pulmonary emboli secondary to antiphospholipid syndrome. A 65-year-old man with a long history of ankle swelling and worsening left ventricular function on echocardiography. A 67-year-old with a history of heavy smoking complains of shortness of breath on lying flat and general fatigue. A 46-year-old woman with pulmonary hypertension but no evidence of any medical condition despite comprehensive investigation for her shortness of breath. The cough is productive and is present most days of the year, particularly during the winter months. During the admission an echo is performed which shows a mildly dilated right ventricle and pulmonary artery pressure of 50 mmHg. A 62-year-old woman has suffered with some weight loss and is found to be anaemic. An 87-year-old woman is found to have a suspected primary small-cell carcinoma with multiple metastases. A 55-year-old woman who is a heavy smoker is found to have cytological findings of hyperdense nuclei with minimal cellular cytoplasm. A 45-year-old man returns from a business conference with shortness of breath, a dry cough and diarrhoea and vomiting. A 19-year-old develops shortness of breath and a dry cough following a week of flu-like symptoms. A 70-year-old smoker is admitted to hospital with shortness of breath and a productive cough following a week of flu-like symptoms. A 70-year-old male is admitted to hospital with confusion, fevers and a productive cough. A 56-year-old man with multiple, large well-circumscribed nodules throughout both lung fields. The chest X-ray of a 67-year-old man shows a thickened diaphragm with a lumpy appearance. A 34-year-old man who presented with a swollen thigh appears to have a large, well-circumscribed nodule in his left lung. A 70-year-old lifelong smoker is found to have a mass originating from his right main bronchus. A 48-year-old immigrant from Bangladesh with a 3-month history of fevers, productive cough and weight loss. A 19-year-old with shortness of breath and a dry cough following a week of flu-like symptoms. A man with hepatic failure has small bilateral transudative effusions on diagnostic tap. Match the correct letter above to its description in the following clinical scenarios: 1.

Measure the distance (using your fingers) between the sternal notch and the cricoid cartilage fungus gnats lifespan discount sporanox 100 mg with mastercard. Less than 3 fingers is indicative of air flow limitation (common in chronic obstructive pulmonary disease) fungus gnats ncsu sporanox 100mg order on-line. This is repeated throughout the chest both front and back quinsana plus antifungal powder generic 100 mg sporanox otc, comparing opposite zones fungus root word purchase sporanox 100 mg. The vibrations produced by this manoeuvre are transmitted through the lung parenchyma and felt by the hand fungus on neck discount 100 mg sporanox. Tactile vocal fremitus is increased by consolidation of the lungs and decreased by pleural effusions and pleural thickening. Displacement of the apex beat normally signifies cardiomegaly but other respiratory conditions may cause the apex beat to become displaced, including: · · · · Pulmonary fibrosis. Finally, in palpation you may find it useful to perform tactile vocal fremitus by placing the ulnar edge of your hand Percussion is an extremely useful tool in the respiratory examination, as the percussion note provides information about the consistency of the lung matter underlying the chest wall, i. Percussion is performed by placing the middle finger of your non-dominant hand on the chest wall palm downwards in an intercostal space. You then strike this finger with the terminal phalanx (fingertip) of the middle finger of your dominant hand. In order to achieve a good percussion note, the striking finger should be partially flexed and struck at right angles to the other finger. Kyphosis increased forward curvature of the spine (osteoporosis/ankylosing spondylitis). Begin percussion at the apices by percussing (gently) on to the clavicles directly and then move down the chest wall, remembering to compare both sides directly. A normal percussion note is described as resonant; in the presence of lung pathology the percussion note may be described as dull, stony dull or hyperresonant. Map out any abnormality you find but do not confuse the cardiac borders or liver edge with lung pathology; they will sound dull normally. Auscultation Normal breath sounds are described as vesicular and have a rustling quality heard in inspiration and the first part of expiration. Auscultate in a logical order, comparing the two sides (as for percussion) and ask the patient to breathe through an open mouth. It is important to remember that added sounds that disappear when the patient coughs are not significant. Vocal resonance is increased by consolidation and reduced by conditions such as pleural effusion and pneumothoraces. Whispering pectoriloquy Whispering pectoriloquy is a variation of vocal resonance that can be used to confirm the presence of consolidation. Summary Once you have finished your examination, sum up the positive findings in a clear and concise manner. Normally, to complete the respiratory examination you would inform the examiner that you would like to: · Examine a sputum pot. Vocal resonance Vocal resonance is the auscultatory equivalent of tactile vocal fremitus. It is performed using the diaphragm of the stethoscope on the chest and asking the patient to 89 Examination of the respiratory system. As you read this chapter, you should bear in mind that some of the investigations below are performed only rarely in specialized pulmonary laboratories whilst others are performed by patients at home every day. The investigations that are most commonly performed, and which you should have a thorough knowledge of, include: · · · · · Arterial blood gas analysis. If malignancy is suspected, you should also perform liver function tests and test alkaline phosphatase as an indicator of metastases. In addition, endocrine tests should be performed for paraneoplastic manifestations, such as syndrome of inappropriate antidiuretic hormone (see Ch. Tests of blood gases Arterial blood gas analysis Blood gas analysis of an arterial blood sample is mandatory in all acute pulmonary conditions. The analysis should always be performed initially on room air and then repeated soon after starting oxygen therapy to assess response to treatment. A heparinized sample of arterial blood is tested using a standard automated machine, which measures: · PaO2. Blood pH, standard bicarbonate and base excess are either given on the standard readout or can be calculated. Other, less commonly performed investigations will be discussed in less detail in this chapter. However, the arterial blood gas results can then help you identify the underlying abnormality, as well as its severity. Different underlying pathologies will cause different patterns on the arterial blood gas. It is also important to remember that a metabolic disturbance (such as high lactate from shock) can be partially or completely compensated for by the respiratory system, which may be seen clinically as an increased 92 Routine investigations. This is particularly useful in the identification of tuberculosis, which can take several weeks to grow on conventional media. Pulse oximetry this is a simple, non-invasive method of monitoring the percentage of haemoglobin that is saturated with oxygen. The patient wears a probe on a finger or earlobe and this is linked to a unit which displays the readings. The unit can be set to sound an alarm when saturation drops below a certain level (usually 90%). The pulse oximeter works by calculating the absorption of light by haemoglobin, which alters depending on whether it is saturated with oxygen or desaturated. A more accurate assessment of oxygen saturation, if necessary, can be obtained by arterial blood gas analysis. Blood culture A blood culture should always be performed in patients with fever and lower respiratory tract infection. Collect a large volume of blood and divide it equally in to two bottles of nutrient media, one for aerobic and the other for anaerobic bacteria. Again, it is important to collect an initial set of cultures before starting antibiotic therapy. Upper respiratory specimens Microbiology Microbiological examination is possible with samples of sputum, bronchial aspirate, pleural aspirate, throat swabs and blood. The microbiological findings should be interpreted in view of the whole clinical picture. Bacteriology Sputum Testing of sputum for the presence of bacteria is the most common microbiological test performed in respiratory medicine. Obtain the sample, preferably of induced sputum, before antibiotic treatment is started. Request Gram stain, Ziehl­Neelsen stain (for tuberculosis) and anaerobic cultures. A sputum sample is valuable in diagnosing suspected pneumonia, tuberculosis and aspergillosis, or if the patient presents with an unusual clinical picture. Resistance to commonly used antibiotics is often found in bacteria responsible for respiratory tract infections; therefore, antibiotic sensitivity testing is vital. Microscopy is generally unhelpful because of the abundant commensals of the upper respiratory tract which contaminate samples. Avoid contact with the tongue and saliva, as this can inhibit identification of group A streptococci. However, this can often be a commensal organism and not the underlying cause of symptoms. Common pathogens of sinuses are Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus and anaerobes. Coxiella burnetii, Mycoplasma pneumoniae and Legionella are difficult to culture; therefore, results of serology must be used. Lower respiratory specimens Techniques used to collect samples include expectoration, cough induction with saline, bronchoscopy, bronchial alveolar lavage, transtracheal aspiration and direct aspiration through the chest wall. Patients may be lightly sedated to reduce anxiety and suppress the cough mechanism. Serological diagnoses are obtained when viruses are difficult to isolate and grow in cell culture. Specimens should be collected early in the acute phase because viral shedding for respiratory viruses lasts 3­7 days; however, symptoms commonly persist for longer. Viral serology also identifies the virus and its strain or serotype, and is able to evaluate the course of infection. Viral serology is not commonly used in clinical practice as antiviral therapies are relatively ineffective and not commonly used to treat viral respiratory tract infections. However, they can be useful from an epidemiological perspective, such as in the identification of different strains of the influenza virus for the development of vaccines. Bronchoalveolar lavage Sterile saline (usually around 100 mL) is infused down the flexible bronchoscope and then aspirated. This technique is commonly used to look for evidence of neoplasms or opportunistic infections in immunocompromised patients. If this is done in the acute setting and the patient is unwell, a smaller volume of saline is used to avoid airway compromise, known as bronchial washing. Cell culture Specimens for cell cultures are obtained from nasal washings, throat swabs, nasal swabs and sputum. Fungal testing Fungal infections may be serious, especially in immunocompromised patients, where they can cause systemic infection; invasive fungal infections require blood culture. Repeated specimens from the site need to be taken to rule out contaminants in cultures. Microscopic identification may be difficult for Aspergillus because it is common in the environment. Culture is rarely helpful in identifying Aspergillus; the Aspergillus precipitins test is of more use. It is important to remember that fungal infections are uncommon in healthy individuals. Transbronchial biopsy Transbronchial biopsy provides samples from outside the airways. The technique is performed using biopsy forceps attached to a flexible bronchoscope. The bronchoscopist cannot directly visualize the biopsy site and may be assisted by fluoroscopic imaging. Percutaneous fine-needle aspiration this technique is used to sample peripheral lesions under the guidance of radiography. Open and thoracoscopic lung biopsy In some cases of diffuse lung disease, or where a lesion cannot easily be reached, more extensive lung biopsy is required for diagnosis. Open-lung biopsy is performed through a thoracotomy with the patient under general anaesthesia. However, video-assisted thorascopic techniques are increasingly used as a less invasive alternative. Histopathological examination of biopsy material the histopathological examination is a vital test in cases of suspected malignancy, allowing a definitive diagnosis to be made. Biopsy material is obtained by the techniques described above, in addition to: · Pleural biopsy. Histological features of malignant neoplasms are: · Loss of cellular differentiation. Other uses of histopathology include diagnosing interstitial lung diseases such as cryptogenic fibrosing alveolitis. Pleural tap (thoracocentesis) this is the drainage of a small amount of fluid from a pleural effusion. The sample can appear serous, bloody (haemothorax, usually after trauma) or pus-filled (empyema). Any sample extracted can be analysed in several different ways to help identify the pathology. This includes microscopy, cytopathology, culture and biochemical analysis of its contents. Cytological examination of sputum Cytological examination is useful in diagnosing bronchial carcinoma and has the advantage of being a non-invasive, quick test; however, it is dependent upon adequate sputum production. Sputum is obtained by: · · · · Induction/inhalation of nebulized hypertonic saline. These two types of disorder have characteristic patterns of lung function which can be measured using the tests below. Peak flow meters can be issued on prescription and used at home by patients to monitor their lung function. A patient would normally be asked to do this for a couple of weeks in order to obtain a peak flow diary, which could then be analysed to look at the type of airways disease. Asthma patients can be given an information sheet telling them what to do if their peak flow is lower than normal, depending on how severe the reduction is. This can help reduce the severity and length of exacerbations (by starting treatment earlier) and also ensure that the sickest patients seek medical help sooner. Alex, a 9-year-old boy, was becoming wheezy and short of breath after mild exertion. The spirometer works by converting volumes of inspiration and expiration in to a single line trace. Each time the subject breathes, the volume inspired or expired is converted in to the vertical position of a float. The position of the float is recorded on a rotating drum by means of a pen attachment. The measurement of lung volume by displacement of a float within a sealed chamber is recorded on a paper roll by a pen. Whereas in obstructive diseases: · High intrathoracic pressures generated by forced expiration cause premature closure of the airways with trapping of air in the chest. Flow­volume loops are graphs constructed from maximal expiratory and inspiratory manoeuvres performed on a spirometer.

A number of mechanisms have been implicated in xenobiotic-mediated antibody binding to erythrocytes (Arndt and Garratty fungus gnats gravel cheap 100mg sporanox with mastercard, 2005) antifungal doterra proven 100mg sporanox. Some drugs fungus deck discount 100mg sporanox with mastercard, of which penicillin is a prototype fungus definition order sporanox no prescription, appear to bind to the surface of the cell topical antifungal yeast infection discount 100 mg sporanox amex, with the "foreign" drug acting as a hapten and eliciting an immune response. The antibodies that arise in this type of response only bind to drug-coated erythrocytes. Other drugs, of which quinidine is a prototype, bind to components of the erythrocyte surface and induce a conformational change in one or more components of the membrane. This type of interaction can give rise to a confusing array of antibody specificities. Some of the antibodies recognize only the drug­membrane component complex; others are specific for the membrane component, but only when drug is present; while still others may recognize the membrane component in the presence or absence of the drug. A third mechanism, for which -methyldopa is a prototype, results in production of a drug-induced autoantibody that cannot be distinguished from the antibodies arising in idiopathic autoimmune hemolytic anemia. The mechanism for induction of this group of antibodies is not understood, but may be related to development of an autoimmune response. A variant of this type of response is the augmentation of autoimmune hemolytic anemia that may occur during therapy of some lymphoproliferative disorders. Treatment of these disorders with some drugs has been associated with worsening of the hemolytic anemia (Gonzalez et al. It has been hypothesized that therapy further disrupts regulation of the autoimmune phenomenon, allowing increased antibody production. Some xenobiotics are associated with nonspecific deposition of proteins on erythrocytes. This was first associated with cephalosporins but has also been seen with other drugs, including cisplatin and the -lactamase inhibitors sulbactam and clavulanate (Arndt and Garratty, 2005). Immunoglobulin and complement proteins may be among the proteins deposited on the erythrocyte surface. These proteins may cause a positive direct antiglobulin test, suggesting a drug-induced antibody response. This form of antibody deposition is generally not associated with hemolysis, although the possibility of hemolysis related to this type of reaction has been raised. The clinical picture of extravascular hemolysis depends on the rate of hemolysis but is usually less dramatic. Serologic studies usually show evidence of IgG and/or complement on the surface of erythrocytes, although it may be difficult to document that antibody binding is drug-dependent. The mainstay of therapy in patients with druginduced hemolytic anemia is removal of the offending agent and avoidance of reexposure. They include granulocytes, which may be subdivided in to neutrophils, eosinophils, and basophils; monocytes; and lymphocytes. Granulocytes are defined by the characteristics of their cytoplasmic granules as they appear on a blood smear stained with a polychromatic (Romanovsky) stain. Neutrophils, the largest component of blood leukocytes, are highly specialized in the mediation of inflammation and the ingestion and destruction of pathogenic microorganisms. The turnover of neutrophils is enormous and increases dramatically in times of inflammation and infection, elevating the number of these cells released from the bone marrow. Eosinophils and basophils modulate inflammation through the release of various mediators and play an important role in other homeostatic functions. All these are influenced by cellular and humoral immune responses, as discussed in greater detail in Chap. In the world of clinical and experimental toxicology, the neutrophil is the focus of concern when evaluating granulocytes as possible targets for drug and nontherapeutic chemical effects. Eosinophils and basophils are far more difficult to study, with changes in these populations most frequently associated with reactions to other target organ or systemic toxicity. Examples include the eosinophilia observed with the toxic oil syndrome that resulted from exposure to rapeseed oil denatured in aniline utilized in northwestern Spain (Kilbourne et al. Peripheral eosinophilia is often but not reliably observed with hypersensitivity reactions to drugs (Roujeau, 2005), while tissue eosinophilia can be diagnostic, in the context of a suggestive clinical course, in conditions such as drug-induced cutaneous vasculitis (Bahrami et al. This variability in systemic response can be genetically predisposed, as demonstrated in studies using transgenic mice on genetic restrictions in people afflicted by the aforementioned toxic oil syndrome (Gallardo et al. The time course of the reaction can also influence whether eosinophilia can be demonstrated in hypersensitivity disease (Roujeau, 2005). Evaluation of Granulocytes the most informative test to assess the neutrophil compartment is the blood neutrophil count. Accurate interpretation requires an understanding of neutrophil kinetics and the response of this tissue to physiologic and pathologic changes. In the blood, neutrophils are distributed between circulating and marginated pools, which are of equal size in humans and in constant equilibrium (Athens et al. A blood neutrophil count assesses only the circulating pool, which remains between 1800 and 7500/µL in a healthy adult human (Dale, 2006). This constancy is remarkable, considering that as many as 1011 neutrophils are released from the marrow daily, that this circulating pool represents only 1% of the total body neutrophils (Semerad et al. The latter is downregulated by the phagocytosis of apoptotic neutrophils in the tissues, which provides an important negative feedback loop. The upregulation and downregulation of chemokine receptors further controls the release of neutrophils from the bone marrow (as discussed below) and their return following senescence (Martin et al. Pharmaceutical companies are currently developing recombinant proteins that function as agonists and inhibitors of these mediators, which have great potential as exciting new therapies. Many will also be shown to cause unacceptable immunotoxicity and hematotoxicity, which portends exciting times for the academic and industrial hematopathologist and toxicologist. Neutrophil kinetics and response to disease will vary substantially among animal species (Feldman et al. Thus, a thorough understanding of these features in any animal model used in investigative toxicology is required before informed interpretations can be made. In humans, clinically significant neutropenia occurs when the blood neutrophil count is less than 1000/µL, but serious recurrent infections do not usually occur until counts fall below 500/µL (Dale, 2006). Morphologic assessment of peripheral blood granulocytes can be helpful in characterizing neutropenia. In humans and most healthy animal species, mature (segmented) and a few immature (band) neutrophils can be identified on blood films stained with Wright or Giemsa stain. During inflammation, a "shift to the left" may occur, which refers to an increased number of immature (nonsegmented) granulocytes in the peripheral blood, which may include bands, metamyelocytes, and occasionally myelocytes. During such times, neutrophils may also show "toxic" granulation, Döhle bodies, and cytoplasmic vacuoles. These morphologic changes may be prominent in sepsis or as a result of drug or chemical intoxication. In order to fully characterize such changes or understand the pathogenesis of the abnormality, bone marrow must be examined using marrow aspirates and biopsies. These provide information on rates of production, bone marrow reserves, and abnormalities in cell distribution, and occasionally specific clues as to etiology. The latter can be collected and re-engrafted to form new functioning bone marrow (Broxmeyer et al. The ability to manipulate this system, as in the above experiments and through the many recombinant proteins under development, will continue to provide important research, diagnostic, and therapeutic tools for the hematologist, oncologist, and toxicologist. Toxic Effects on Granulocytes the toxicologist is concerned with the effect of xenobiotics on granulocytes as relates to proliferation (granulopoiesis) and kinetics, the extent to which a drug or chemical contaminant can impair the vital functions these cells perform, and how neutrophils mediate or exacerbate inflammatory disease or other target organ toxicity. However, it is difficult to separate effects on granulopoiesis and neutrophil kinetics from that of function. Both are complex and highly regulated, as discussed above, through an array of growth factors, chemokines, cytokines, and interactions with monocytes, dendritic cells, and lymphocytes in a bidirectional, multicompartmental manner (Nathan, 2006). Such complexity is not surprising, given the daunting task these cells perform, which is elegantly described in a review by Nathan (2006): "The [neutrophil] must remain non-sticky as it hurtles through the arterial and arteriolar circulation; then it must squeeze through capillaries smaller in diameter than itself, without allowing collision, friction, or distortion to activate it. A fraction of the population must adhere tightly enough to the normal endothelium of post-capillary venules to resist being washed away in the circulation, but loosely enough to roll while scouting for evidence of tissue damage and microbial infection. If such evidence is received, the cell must crawl to a boundary between endothelial cells, penetrate the junctions and the underlying basement membrane without damaging these structures, move up the chemotactic gradient, and decide whether its original information remains valid. If it cannot locate microbes quickly, it must attempt to destroy them at a distance by releasing every weapon at its disposal. Effects on Proliferation and Kinetics As with other hematopoietic tissue, the high rate of proliferation of neutrophils makes their progenitor and precursor granulocyte pool particularly susceptible to inhibitors of mitosis. Such effects by cytotoxic drugs are generally nonspecific, as they similarly affect cells of the dermis, gastrointestinal tract, and other rapidly dividing tissues. Agents that affect both neutrophils and monocytes pose a greater risk for toxic sequelae, such as infection (Dale, 2006). Such effects tend to be dose-related, with mononuclear phagocyte recovery preceding neutrophil recovery (Arneborn and Palmblad, 1982). Myelotoxicity in clinical medicine and preclinical safety studies today is most commonly seen with cytoreductive cancer chemotherapy agents. However, this is changing, as more cancer cell­targeted, normal-tissue-sparing anticancer agents are being developed. In fact, most published reviews today on drug-induced neutropenia and agranulocytosis do not even address that associated with such cytotoxic agents. Accordingly, the term commonly refers to idiosyncratic reactions, most often secondary to accelerated immune-mediated destruction of neutrophils and their progenitors, as discussed below. The toxicity associated with cytotoxic drugs, however, remains important in that it is often dose-limiting (even with some of the newer drugs) with serious manifestations that include febrile neutropenia associated with life-threatening infections (Kuderer et al. These drugs vary in terms of their mechanism, the kinetics of the cytopenias they induce, and how individual patients or animals respond. While cytoreductive drugs such as alkylating agents, cisplatin, and nitrosureas can be toxic to both resting and actively dividing cells, nonproliferating cells such as metamyelocytes, bands, and mature neutrophils are relatively resistant (Friberg and Karlsson, 2003). Generally, stem cells cycle slowly and are therefore minimally affected by a single administration of a cytotoxic drug such as 5-fluorouricil; however, such exposure can stimulate cycling activity, making these cells more vulnerable to doses administered three to five days later (Harrison and Lerner, 1991). Cytokines have long been thought to enhance these effects by driving cells in to the S phase (Smith et al. Sustained exposure to drugs affecting slowly cycling stem cells is believed to cause more prolonged myelosuppression, similar to that observed with idiosyncratic toxic neutropenia (Tannock, 1986). Recent studies suggest that these features are shared by cancer stem cells, which is the basis for the more sophisticated cancer interventions and regimens under development today (Eramo et al. Finally, there is considerable variation among individuals as regards susceptibility to bone marrow toxicity; this can relate to how the drug is metabolized as with 5-fluorouracil (Sundman-Engberg et al. Based on these and other data, including plasma drug concentrations, "semi-mechanistic" pharmacokinetic/pharmacodynamic models of myelosuppression have been developed to tailor doses and treatment regimens to individual patients (Friberg and Karlsson, 2003). Pharmacokinetic monitoring is now routinely performed with some anticancer treatment regimens, particularly high-dose methotrexate (Chabner et al. Two innovations have had a dramatic impact on cancer chemotherapy and the dose-limiting myelotoxicity associated with these drugs: (1) the aforementioned development of drugs with cancer cell­specific molecular targets that are relatively bone marrow sparing, such as those that target aberrant growth factor receptor signaling, apoptosis, angiogenesis, and other metabolic, immune, inflammatory, and mutation-promoting pathways that selectively advantage tumor cells (Hanahan and Weinberg, 2011); and (2) the use of hematopoietic growth factors, the cotreatment with which mitigates or successfully rescues patients from the effects of myelosuppression (Andres et al. Treatment with these recombinant proteins can substantially reduce the incidence, severity, and duration of neutropenia and its complications (Rader, 2006). Cytokine-induced differentiation therapy of leukemias is another exciting treatment modality (Leung et al. The prospect of exaggerated pharmacology and off-target effects of these sophisticated interventions should provide the preclinical toxicologist and oncologist with interesting hematotoxicologic challenges. Lindane, an insecticide used to treat seeds and soil, has been associated with leukopenia (Parent-Massin et al. An example of chemicals affecting mature cells is methyl methacrylate monomer, which has been used in orthopedic surgical procedures and is cytotoxic to both neutrophils and monocytes at clinically relevant concentrations (Dahl et al. Chemicals that affect granulocyte kinetics can cause neutropenia or neutrophilia that has variable toxicologic significance. The effects of epinephrine and glucocorticoids on granulocyte kinetics were discussed previously. Dexamethasone has long been known to cause neutrophilia through enhanced release of mature neutrophils from the bone marrow and demargination, with the latter being the largest contributor to the expanded circulating pool (Nakagawa et al. It is now clear that the reduced margination of neutrophils is mediated by multiple effects, including altered chemotaxis, expression of adhesion molecules, and the release of mediators from other cells (Barnes, 2006; Caramori and Adcock, 2005). It is widely assumed that inhibition of margination and homing are among the important mechanisms of the anti-inflammatory and immunosuppressive effects of these widely used drugs. The development of drugs with more selective effects on neutrophils is among the most active areas of investigative pharmacology and toxicology today. The latter could lead to the release of lysosomal enzymes and the destruction of neutrophils as "bystanders" (Hincks et al. In addition to glucocorticoids, several drugs and nontherapeutic chemicals have been shown to inhibit neutrophil chemotaxis. More common is the activation of neutrophils with the potential for proinflammatory consequences, specifically through increased phagocytosis, O2- production, or both. Examples include the environmental contaminants sodium sulfite, mercuric chloride, chlordane, and toxaphene (Girard, 2003). This toxicologic potential of xenobiotics will be discussed in more detail in Chap. Examples include ethanol and glucocorticoids, which impair phagocytosis and microbe ingestion in vitro and in vivo (Brayton et al. Iohexol and ioxaglate, components of radiographic contrast media, have also been reported to inhibit phagocytosis (Lillevang et al. Superoxide production, required for microbial killing and chemotaxis, has been reported to be reduced in patients using parenteral heroin as well Idiosyncratic Toxic Neutropenia Of greater concern are chemicals that unexpectedly damage neutrophils and granulocyte precursors-particularly to the extent of inducing agranulocytosis, which is characterized by a profound depletion in blood neutrophils to less than 500/µL (Pisciotta, 1973). The term was first used by Schultz in 1922 in patients with severe sore throat associated with a marked reduction of granulocytes, followed by sepsis and death (Schultz, 1922).

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