on 28-Mar-2021 (Sun)

A consensus statement of the American Thoracic Society defines dyspnea in the following way [1]:

"Dyspnea is a term used to characterize a subjective experience of breathing discomfort that is comprised of qualitatively distinct sensations that vary in intensity. The experience derives from interactions among multiple physiological, psychological, social, and environmental factors, and may induce secondary physiological and behavioral responses."

Dyspnea is considered acute when it develops over hours to days and chronic when it occurs for more than four to eight weeks.

Most patients with breathing discomfort can be categorized into one of two groups: respiratory system dyspnea or cardiovascular system dyspnea. Respiratory system dyspnea includes discomfort related to disorders of the central controller, the ventilatory pump, and the gas exchanger (table 1), while cardiovascular system dyspnea includes cardiac diseases (eg, acute ischemia, systolic dysfunction, valvular disorders, pericardial diseases), anemia, and deconditioning (figure 1)

Factors that stimulate the respiratory centers in the brainstem lead to increased ventilation and breathing discomfort in a variety of settings; these often are secondary to derangements in other parts of the system, such as hypoxia or hypercapnia due to ventilation/perfusion mismatching in the gas exchanger, or stimulation of pulmonary receptors as occurs with interstitial inflammation or edema

In addition, drugs such as aspirin (at a toxic dose) or progesterone and conditions such as pregnancy or diabetic ketoacidosis can produce dyspnea through central effects independent of problems in the ventilatory pump or gas exchanger.

Typically, dyspnea associated with stimulation of the respiratory controller is described as a sensation of "air hunger" or an "urge or need to breathe" [2-4]

To some degree, the breathing pattern may also reflect what are presumed to be attempts by the controller to reduce breathing discomfort. Thus, patients with severe airflow obstruction generally adapt a relatively slow, deep breathing pattern to minimize the pleural pressures needed to overcome airways resistance. Alternatively, patients with interstitial fibrosis or kyphoscoliosis and reduced lung or chest wall compliance have a characteristic rapid, shallow breathing pattern which minimizes the work needed to expand the thorax

When the respiratory controller is stimulated (eg, by exercise), airflow obstruction may heighten the sensation of air hunger. The increase in respiratory rate during exercise in the setting of expiratory flow limitation can lead to exercise-induced air-trapping, a process known as dynamic hyperinflation. Dynamic hyperinflation is associated with a reduced inspiratory reserve and increased dyspnea. For those in whom hyperinflation is substantial, such that inspiratory capacity at rest or during exercise is limited by total lung capacity, dyspnea is further exacerbated, and patients may also complain of an inability to get a deep breath.

For patients with restrictive lung disease, the adoption of breathing patterns with either an increase or decrease in tidal volume from their average resting tidal volume results in increased dyspnea [5]. Breathing with a rapid, shallow pattern, the patient experiences an increase in the ratio of dead space to tidal volume (since anatomic dead space is relatively fixed), which leads to a need for greater total ventilation (hence, the increase in respiratory rate); this adds to respiratory work-load and may contribute to the development of hypercapnia. In contrast, an increase in tidal volume requires a significant increase in respiratory work due to the stiffness of the lung. Since most patients with restrictive lung disease tend to use a rapid, shallow breathing pattern, we conclude that this pattern, relative to alternatives, must produce less dyspnea

The "ventilatory pump" comprises the ventilatory muscles, the peripheral nerves which transmit signals to them from the controller, the bones of the chest wall to which the respiratory muscles are connected, the pleura which transforms movement of the chest wall to negative pressure inside the thorax, and the airways that serve as a conduit for the flow of gas from the atmosphere to the alveoli and back again. The most common derangements of the ventilatory pump result in a sense of increased "work of breathing" [6-10].

When hyperinflation results in an end-inspiratory volume that approximates total lung capacity, patients often complain of an inability to get a deeper satisfying breath [9]. A sensation of chest tightness may also be present in patients in whom acute bronchoconstriction is the cause of airflow obstruction [6,7,12,13].

Neuromuscular weakness (eg, myasthenia gravis, Guillain-Barré syndrome) leads to a condition in which the patient must exert near maximal inspiratory effort to produce a normal negative pleural pressure [11]. Patients with reduced compliance of the chest wall (eg, kyphoscoliosis) or lungs (eg, interstitial fibrosis) must perform more work than normal to move air into the lungs. Obstructive lung disease is associated with increased resistance to flow and, in patients with significant hyperinflation, reduced compliance as breathing occurs on the stiff portion of the pressure-volume curve of the respiratory system

The "gas exchanger" consists of the alveoli and the pulmonary capillaries across which oxygen and carbon dioxide diffuse. Most of the common cardiopulmonary disorders leading to dyspnea are associated with some derangement of the gas exchanger due either to destruction of the diffusing membrane (eg, emphysema, pulmonary fibrosis) or the addition of fluid or inflammatory material into the lungs such that ventilation to alveoli is reduced regionally. To a lesser degree, the distance for diffusion may also contribute in these conditions or in the greatly dilated pulmonary capillaries seen in some patients with hepatopulmonary syndrome. Diseases affecting the gas exchanger are typically characterized by hypoxemia, either at rest or with exercise, and by chronic hypercapnia in more severe cases

For this system to work optimally and avert breathing discomfort, one must have a pump that functions without generating high pulmonary capillary pressures. There must also be sufficient hemoglobin to carry oxygen and appropriate enzymes to utilize oxygen in the tissues.

Symptoms of heart failure fall into two major classes: those due to a reduction in cardiac output (fatigue, weakness, and dyspnea on exertion) and those due to increased pulmonary or systemic venous pressure and fluid accumulation (dyspnea at rest and exertion, edema, hepatic congestion, and ascites)

When heart failure causes an increase in pulmonary venous pressure, it can lead to dyspnea either by producing hypoxemia or by stimulating pulmonary vascular and/or interstitial receptors (eg, unmyelinated J-receptors, also called C-fibers)

In patients with low cardiac output, oxygen delivery to the tissues is reduced, which may lead to changes in tissue metabolism with associated accumulation of products of anaerobic energy generation leading to stimulation of metabo- or ergoreceptors [14,15], which can lead to dyspnea.

Anemia can severely impair oxygen delivery because the bulk of oxygen carried in the blood is hemoglobin-bound (see "Structure and function of normal hemoglobins"). Nevertheless, the exact mechanism by which anemia produces dyspnea is not known.

Individuals usually complain of respiratory discomfort when they engage in vigorous physical activity, even in the presence of a normal cardiovascular and respiratory system and normal hematocrit. More fit individuals experience less discomfort for any given workload; cardiovascular fitness is determined by the ability of the heart to increase maximal cardiac output and by the ability of the peripheral muscles to utilize oxygen efficiently for aerobic metabolism.

It is common for patients with chronic cardiopulmonary disease to assume a sedentary lifestyle in an effort to avoid breathing discomfort. However, the end result over a span of months to years is that the individual becomes progressively deconditioned (ie, reduced maximal cardiac output, reduced capillary density in the muscles, and reduced mitochondrial capacity to sustain aerobic metabolism) and ultimately may be limited more by poor cardiovascular fitness than by the underlying disease [16].

Dyspnea due to deconditioning is typically described as "heavy breathing" or a sense of "breathing more" [8], and with careful questioning, one can determine that the patient is actually limited by fatigue or leg discomfort rather than breathing discomfort.

While clinical history is often insufficient to make a secure diagnosis, it provides guidance in narrowing the diagnostic possibilities and selecting diagnostic tests. In one study of 85 patients presenting to a pulmonary unit with a complaint of chronic dyspnea, the initial impression of the etiology of dyspnea based upon the patient history alone was correct in only 66 percent of cases [17]. Thus, a systematic diagnostic approach to these patients is necessary.

The temporal pattern of breathlessness and association with certain triggers can provide important clues. Breathing discomfort arising over the course of minutes to hours is due to a relatively limited number of conditions (table 2). These entities typically have associated symptoms and signs that provide clues to the appropriate diagnosis

Chronic exertional dyspnea and paroxysmal nocturnal dyspnea (PND) are both associated with heart failure, although nocturnal dyspnea is more specific to heart failure. Asthma is also associated with exertional and nocturnal dyspnea, but unlike PND does not usually improve with sitting or standing.

Orthopnea, the development of or worsening of dyspnea in the supine position, is also associated with heart failure and increased pulmonary capillary pressure due to the increased venous return to the heart in this position. Central obesity, however, with a large protuberant abdomen, may also lead to orthopnea; increased intra-abdominal pressure associated with large abdominal girth impairs movement of the diaphragm during inhalation. Finally, patients with inspiratory muscle weakness may also complain of orthopnea due to the increased work of breathing associated with moving the diaphragm against high intra-abdominal pressure.

Bendopnea, the worsening of dyspnea when leaning forward, is described in patients with decompensated heart failure [18].

Dyspnea that is not exacerbated by exertion is more often due to a functional or perceptual problem than to cardiopulmonary disease.

Intermittent dyspnea associated with cold air or animal dander exposure suggests asthma; work-related dyspnea may suggest occupational asthma; and dyspnea following upper respiratory infections may be due to asthma or chronic obstructive pulmonary disease (COPD).

In addition to asthma, intermittent symptoms that resolve completely between episodes can be seen with recurrent aspiration; recurrent pulmonary emboli and heart failure can also wax and wane, but generally are characterized by a baseline level of dysfunction. The presence of specific, reproducible inciting events such as exercise or cold air exposure is common with airways hyperreactivity.

The rapidity with which symptoms develop during exercise can also provide useful diagnostic information. For example, patients who develop shortness of breath and wheezing after walking 50 to 100 feet often have acute elevations in pulmonary capillary wedge pressure (usually due to cardiac diastolic dysfunction) or pulmonary hypertension. In contrast, symptoms of exercise-induced asthma usually are precipitated by more intense activity, beginning three minutes into exercise, peaking within 10 to 15 minutes, and resolving by 60 minutes.

Respiratory muscle weakness generally leads to gradually progressive dyspnea, sometimes with an acute worsening at a time of illness, particularly a respiratory infection.

For patients with chronic dyspnea, formal assessment of the severity of dyspnea can help create a baseline for future comparisons [19]. A number of instruments are available to help assess the severity of dyspnea, such as the Baseline Dyspnea Index, the Modified Medical Research Council (mMRC) dyspnea scale (table 3), and the Borg scale (table 4) [20-24]. It is important to note that scales like the mMRC do not measure dyspnea directly; rather, they assess the intensity of exercise that provokes dyspnea and, indirectly, the degree of disability resulting from dyspnea.

Attention to the quality or descriptor that a patient associates with the breathing discomfort often provides clues to the underlying diagnosis [25]. This observation comes from studies in which dyspnea questionnaires (table 5) were presented to patients with breathing discomfort from a variety of cardiopulmonary disorders [6-8,26].

While some clusters of phrases were common to a number of disease categories (eg, increased work or effort of breathing was found with COPD, asthma, and neuromuscular disease), each disease had a relatively unique set of clusters associated with it.

The sensation of "air hunger" has been associated with acute bronchoconstriction and hyperinflation in asthma and COPD, heart failure, pulmonary embolism, and restricted thoracic motion, as well as acute hypercapnia from any cause [3,4,27].

Acute bronchoconstriction leads to a series of sensations as the degree of obstruction worsens, from "chest tightness" to an increased "effort to breathe" to a sensation of "air hunger" [6-9,12,13]. The sensation of "tightness" appears to be independent of the work of breathing [28]. Attention to the use of verbal descriptors of dyspnea may help the clinician avoid underestimation of the severity of airflow limitation when objective measurements of lung function are not possible.

Report of "increased work of breathing" is associated with COPD, moderate to severe asthma, myopathy, and pulmonary fibrosis.

Patients with COPD and dynamic hyperinflation sometimes complain of a sensation of "unsatisfying breaths" or a sense that they "cannot get a deep breath" [9].

● A sensation of rapid, shallow breathing may correspond to interstitial lung disease or reduced chest wall compliance.

● Heart failure is also associated with a sensation of "suffocation" [6].

● A sense of heavy breathing is typical of deconditioning.

The absence of cigarette smoking argues strongly against a diagnosis of COPD, unless the patient has a history of tuberculosis or use of biomass cooking fuels. In one study, a history of smoking cigarettes had a positive predictive value for COPD of 0.4; COPD is uncommon among patients who have never smoked or have smoked less than 10 pack years [37].

A complete physical examination is essential. In particular, attention should be directed at the presence or absence of stridor, wheezing, crackles, tachycardia, arrhythmia, heart murmurs, gallop, peripheral edema, muscle weakness, dysphonia, and evidence of rheumatic disease. However, the absence of physical findings tends to have a greater negative predictive value, than the positive predictive value of any identified signs [17].

Abdominal rounding, the protruding of the central abdomen with diminished transverse diameter during exhalation, has been associated with acute heart failure [38].

Clues to the need for an urgent evaluation include heart rate >120 beats/minute, respiratory rate >30 breaths/minute, pulse oxygen saturation (SpO₂) <90 percent, use of accessory respiratory muscles, difficulty speaking in full sentences, stridor, asymmetric breath sounds or percussion, diffuse crackles, diaphoresis, and cyanosis

The majority of patients with chronic dyspnea of unclear etiology have one of five diagnoses, although the spectrum of potential causes is broad and more than one etiology may be present (table 7) [17,37,39].

The five most common causes of chronic dyspnea are the following:

● Asthma (see 'Respiratory' above)

● Chronic obstructive pulmonary disease (COPD) (see 'Respiratory' above)

● Interstitial lung disease (see 'Respiratory' above)

● Myocardial dysfunction (see 'Cardiovascular' above)

● Obesity/deconditioning (see 'Cardiovascular' above)

The optimal sequence of diagnostic testing for chronic dyspnea has not been determined. We typically follow an algorithm that utilizes three tiers of testing: initial testing (table 8), follow-up testing based on results of initial tests (table 9A and table 9B and table 9C), and advanced testing if the diagnosis remains uncertain (table 10).

One study found that the most informative tests for adults (age 45 to 84) with dyspnea and no known cardiopulmonary disease were the forced expiratory volume in one second (FEV₁) obtained by spirometry, the N-terminal pro-brain natriuretic peptide (NT-proBNP), and percent emphysema on chest computed tomography [40].

If the clinical evaluation doesn’t allow narrowing of the differential we usually obtain the following "initial tests" (table 8):

● Complete blood count (to exclude anemia): The degree of dyspnea associated with anemia may depend on the rapidity of blood loss and the degree of exertion that the patient undertakes. (See 'Cardiovascular' above.)

● Glucose, blood urea nitrogen, creatinine, electrolytes.

● Thyroid stimulating hormone (TSH).

● Spirometry pre and post inhaled bronchodilator OR full pulmonary function tests (PFTs) if the clinical evaluation does not suggest asthma or COPD.

● Pulse oximetry during ambulation at a normal pace over approximately 200 meters and/or up two to three flights of stairs.

● Chest radiograph.

● Electrocardiogram.

● Plasma BNP or NT-pro BNP

Typically in asthma, airflow limitation is reversible, although a large component of airways edema and inflammation may need a course of inhaled or oral glucocorticoid therapy to achieve complete reversibility

Patients with a smoking history longer than 20 years and irreversible airflow limitation on spirometry are usually managed with a presumptive diagnosis of chronic obstructive pulmonary disease (COPD). However, other causes of irreversible airflow limitation (eg, bronchiectasis, bronchiolitis, central airway obstruction) should be considered if the patient does not respond to empiric therapy for asthma or COPD

The second phase of the evaluation of dyspnea is aimed at clarifying abnormalities that were noted on initial testing, but were not diagnostic (table 9A and table 9C and table 9B)

A restrictive pattern may be caused by interstitial lung disease, pleural disease (eg, trapped lung), chest wall disease (eg, kyphoscoliosis), or ventilatory muscle weakness (eg, diffuse or due to diaphragmatic paralysis). Respiratory muscle weakness can be evaluated further with maximal inspiratory and expiratory pressures at the mouth, maximal voluntary ventilation in one minute, and supine spirometry that is compared with sitting spirometry results

Alternatively, if total lung capacity and residual volume are normal or increased, the decrease in vital capacity may be an indicator of reduced elastic recoil or air trapping and the patient may have emphysema or bronchiolitis without airflow limitation that is measurable on spirometry

Bronchoprovocation testing (eg, with methacholine, histamine, or mannitol) is typically obtained in patients with recurrent, episodic dyspnea suggestive of asthma who have normal or near normal spirometry. A trial of therapy for asthma is an alternative, but bronchoprovocation is preferred to enable a precise determination of asthma. Studies have shown that up to 30 percent of patients with a clinical diagnosis of asthma do not have airway reactivity on formal testing [41,42].

Pulmonary vascular disease (eg, pulmonary hypertension, chronic thromboembolic disease, pulmonary veno-occlusive disease) is suggested by the combination of normal spirometry and lung volumes, but abnormal gas transfer manifest by a decrease in DLCO and pulse oxygen saturation on exertion (eg, ≥5 percent).

A low resting oxygen saturation (eg, ≤95 percent) or a significant decline in oxygen saturation during exercise (≥5 percent) warrants further evaluation. The differential diagnosis includes COPD, interstitial lung disease, pulmonary vascular disease, bronchiolitis obliterans, intrapulmonary or intracardiac shunt, and heart failure. Thus, such patients typically need high resolution computed tomography (HRCT) and a transthoracic echocardiogram, possibly with a bubble study

Obesity is associated with reductions in expiratory reserve volume and function residual capacity and, in some patients, a decrease in total lung capacity (restrictive ventilatory defect) [43]. However, the changes in lung volumes do not necessarily correlate with dyspnea and it can be difficult to know whether this pattern of reduced lung volumes is due to obesity or another respiratory disease. In a population study (NHANES III), subjects in the highest quintile of body mass index (BMI), had the lowest risk for significant airflow obstruction, so obesity by itself is less commonly a cause of classical airflow obstruction [44].

Suspected interstitial lung disease is evaluated by HRCT, and central masses and suspected large airway obstruction (eg, tumor) are best evaluated by CT with contrast and direct visualization. On the other hand, vascular redistribution and abnormal heart size are best evaluated by measurement of a serum N-terminal pro-brain natriuretic peptide (NT-pro BNP) or transthoracic echocardiography.

A small percentage of patients with interstitial lung disease may have a normal chest radiograph on presentation; HRCT scan clearly is more sensitive for detecting subtle ground glass or reticular opacities [45,46]. Thus, patients with crackles on physical examination, reduced lung volumes on pulmonary function testing, or a decreased DLCO should have HRCT scans even if the chest radiograph is normal

If LV ejection fraction and end-diastolic volume are normal, echocardiography can identify features of diastolic dysfunction (heart failure with preserved ejection fraction [HF-PEF]), such as LV hypertrophy (LVH), concentric remodeling, and left atrial enlargement.

Among older adults with unexplained chronic dyspnea after an initial evaluation (eg, history, physical examination, pulmonary function tests, and a chest radiograph), nearly two-thirds have evidence of diastolic dysfunction [48], which can manifest as dyspnea with relatively minimal exertion.

Constrictive pericarditis can be difficult to diagnose in patients who present with chronic dyspnea, although patients generally have peripheral edema. Findings on echocardiography that may suggest constrictive pericarditis include increased pericardial thickness, dilation of the inferior vena cava with absent or diminished inspiratory collapse, abnormal filling of the ventricles in diastole, and pronounced respiratory variation in ventricular filling. When occult constrictive pericarditis is suspected, right heart catheterization is performed with measurement of hemodynamics before and after infusion of a liter of warm saline

When elevated pulmonary artery pressures are suggested by Doppler echocardiography and are supported by an elevated brain natriuretic peptide (BNP) and oxygen desaturation on exertion, the next step in the evaluation of suspected pulmonary hypertension is pulmonary artery catheterization to confirm an elevated mean pulmonary artery pressure (mPAP >20 mmHg at rest) and exclude diastolic dysfunction (unlikely with pulmonary artery wedge pressure [PAWP] <15 mmHg)

In particular, CPET may help identify patients with mitochondrial disorders (eg, McArdle’s myophosphorylase deficiency, isolated mitochondrial myopathy) by demonstrating a reduction in maximum oxygen uptake (VO₂ max), reduced peripheral oxygen extraction (increased mixed venous oxygen), and an increase in blood lactate after exercise.

A CPET may be helpful in providing support for the presence of deconditioning or in detecting a low threshold for respiratory discomfort. Patients with a low threshold for respiratory discomfort typically terminate the test at mild workloads because of dyspnea, but have no evidence of cardiopulmonary abnormality.

For patients who report dyspnea but have normal or near normal testing, we explain the reassuring nature of testing in detail, advise a conditioning program, and ask the patient to return in 6 to 12 months for re-evaluation.

For a given physiologic derangement that may cause dyspnea, perceptual responses vary widely among individuals. Anxiety, anger, pain, and depression may be associated with dyspnea intensity out of proportion to the physiologic impairment [55-58]. Increased ventilation associated with anxiety, anger, or pain may push an individual with a limited pulmonary reserve at baseline closer to his or her ventilatory limits and increase the perceived respiratory discomfort for any given activity.

Patients with hyperventilation syndrome typically experience a sensation of air hunger or an inability to take a deep breath in the absence of cardiopulmonary disease. These individuals may have panic and/or anxiety disorders, and on examination are often observed to breathe with very large tidal volumes despite the complaint that they cannot take a deep enough breath. (See "Hyperventilation syndrome in adults".)

Airway, breathing, and circulation are the emergency clinician's primary focus when beginning management of the acutely dyspneic patient. Once these are stabilized, further clinical investigation and treatment can proceed.

A chief complaint of dyspnea or shortness of breath accounts for 3.4 million visits (2.4 percent) of the more than 145 million visits to United States EDs in 2016. Other dyspnea-related chief complaints (eg, cough, chest discomfort) comprised 8.8 percent [2]

Epidemiologically, the most common diagnoses among older adult patients presenting to an ED with a complaint of acute shortness of breath and manifesting signs of respiratory distress (eg, respiratory rate >25, oxygen saturation [SpO2] <93 percent) are decompensated heart failure, pneumonia, chronic obstructive pulmonary disease (COPD), pulmonary embolism (PE), and asthma [4]

Tracheal foreign objects – Common objects include food, coins, bones, dentures, medication tablets, and a multitude of other objects that can be placed in the mouth and become lodged in the upper and lower airways. This is an uncommon cause of acute dyspnea in adults but is more common in children

Angioedema can cause significant swelling of the lips, tongue, posterior pharynx, and most dangerously the larynx; this can occur over minutes to hours and may cause severe dyspnea. The affected skin may be erythematous or normal in color but is usually not pruritic. Although first described over a century ago, the pathophysiology, origin, and treatment of angioedema are not completely understood. Etiologies include idiopathic, allergic, medication-related (eg, nonsteroidal antiinflammatory drug [NSAID], angiotensin-converting enzyme [ACE] inhibitor, angiotensin receptor blocker), and complement-related (eg, C1-esterase inhibitor deficiency or a nonfunctional allele). Patients who receive intravenous (IV) tissue plasminogen activator (tPA) for acute ischemic stroke are also at risk for developing angioedema, which tends to be hemilingual and contralateral to the ischemic hemisphere [5].

Anaphylaxis – Often triggered by foods, insect bites, and various medications, anaphylaxis may cause severe swelling of the upper airway and tongue, and possibly airway occlusion. Symptoms and signs develop over minutes to hours and may include skin and mucosal findings (eg, hives, flushing, oropharyngeal swelling), respiratory compromise (eg, wheezing, stridor, hypoxia), cardiovascular compromise (eg, hypotension, tachycardia, syncope), and gastrointestinal complaints (eg, abdominal pain, vomiting, and diarrhea).

Infections of the pharynx and neck – A number of oropharyngeal infections can cause acute dyspnea [6-9]. Epiglottitis generally presents with rapidly progressive sore throat, dysphagia, hoarseness ("hot potato" voice), and fever. Although once a predominately pediatric disease, epiglottitis now occurs more often in adults in whom airway obstruction may not be a prominent symptom. Pertussis may present with severe paroxysms of cough but can be difficult to diagnose clinically. Deep space infections of the neck from Ludwig's angina, severe tonsillitis, peritonsillar abscess, and retropharyngeal abscess can cause swelling and pain, which may manifest in part as acute dyspnea.

Airway trauma – Blunt or penetrating injuries of the head or neck can cause hemorrhage, swelling, and anatomic distortion, which can compromise the airway and cause acute dyspnea. Suspect a larynx fracture in patients complaining of dyspnea in the setting of severe neck pain and dysphonia following blunt trauma. Patients who have sustained facial burns or smoke inhalation are at risk for rapidly progressive airway compromise and must be evaluated urgently. Early endotracheal intubation is often indicated.

Pulmonary embolism (PE) – The diagnosis of PE should be considered in any patient with acute dyspnea. Risk factors include a history of deep venous thrombosis or PE, prolonged immobilization, recent trauma or surgery (particularly orthopedic), pregnancy, malignancy, stroke or paresis, oral contraceptive or other estrogen use, smoking, and a personal or family history of hypercoagulability. Presentation varies widely, but dyspnea at rest and tachypnea are the most common signs. A large minority of patients have no known risk factor at the time of diagnosis. Other embolic phenomena include fat embolism, especially after a long bone fracture or associated with the acute chest syndrome of sickle cell disease; and amniotic fluid embolism.

Chronic obstructive pulmonary disease (COPD) – Exacerbations of COPD can present with acute shortness of breath. Most often, a viral or bacterial respiratory infection exacerbates the patient's underlying illness. Pulmonary emboli may be responsible for up to 25 percent of apparent "COPD exacerbations" and should be suspected when the patient fails to improve with standard COPD treatment

Asthma – Asthma exacerbations generally present with dyspnea and wheezing. Signs of severe disease include the use of accessory muscles, brief fragmented speech, profound diaphoresis, agitation, and failure to respond to aggressive treatment. The chest may be silent in the face of severe bronchospasm. Extreme fatigue, cyanosis, and depressed mental status portend imminent respiratory arrest.

Pneumothorax and pneumomediastinum – Any simple pneumothorax can develop into a life-threatening tension pneumothorax. In addition to trauma and medical procedures (eg, central venous catheter placement, intubation, and barotrauma), a number of medical conditions increase the risk for developing a pneumothorax. (

Risk factors for primary spontaneous pneumothorax include smoking, a family history, and Marfan syndrome. Patients are generally in their 20s and complain of sudden-onset dyspnea and pleuritic chest pain that began at rest. (See "Pneumothorax in adults: Epidemiology and etiology".)

Patients with certain pulmonary diseases (including COPD, cystic fibrosis, tuberculosis, and AIDS patients with pneumocystis pneumonia) are at risk for secondary spontaneous pneumothorax. (See "Treatment of secondary spontaneous pneumothorax in adults".)

Patients who have sustained chest trauma or who have been coughing vigorously may develop a pneumothorax and present with dyspnea, sharp pleuritic chest pain, and subcutaneous emphysema over the supraclavicular area and anterior neck from pneumomediastinum associated with a pneumothorax.

Pulmonary infection – Lung infections such as severe bronchitis or pneumonia can cause shortness of breath and hypoxia. Productive cough, fever, and pleuritic chest pain are common but insensitive signs. The onset of dyspnea in these patients is generally subacute unless underlying chronic pulmonary disease is present. A chest radiograph is generally necessary for diagnosis but may be unrevealing early in the disease course.

Noncardiogenic pulmonary edema (acute respiratory distress syndrome [ARDS]) – ARDS can complicate a wide range of conditions and is characterized by rapidly progressive dyspnea, hypoxia, and bilateral infiltrates on plain chest radiograph (CXR). It can be difficult to distinguish from acute decompensated heart failure purely on clinical grounds. Brain natriuretic peptide (BNP) and echocardiography can be helpful in differentiating the two. Even though a low BNP is helpful in differentiating ARDS from heart failure, an elevated BNP may occur with ARDS as well as with heart failure, and thus, clinical correlation is needed. Potential causes of ARDS include sepsis, shock, severe trauma, toxic inhalations (eg, aspiration, thermal injury, anhydrous ammonia, chlorine), infections (eg, hantavirus, severe acute respiratory syndrome [SARS], dengue, Middle East respiratory syndrome), blood transfusion, and drug overdose (eg, cocaine, opioids, aspirin).

High altitude pulmonary edema (HAPE) – HAPE is a form of noncardiogenic pulmonary edema that typically occurs in patients who have ascended rapidly to elevations over 2500 m (8000 feet). Symptoms often begin with a nonproductive cough, dyspnea on exertion, and fatigue, generally between two to four days after ascending to a high altitude. This may progress quickly to dyspnea at rest. Pulmonary symptoms are often accompanied by a headache and on occasion cerebral edema. The diagnosis of HAPE should be suspected in any patient with dyspnea who has ascended to a high altitude.

E-cigarette or vaping-associated lung injury (EVALI) – EVALI is an emerging cause of respiratory distress and lung injury, found especially among males (70 percent) less than 35 years of age (80 percent), although it can be seen in patients of any gender or age. It is primarily associated with vaping tetrahydrocannabinol (THC) products, but our understanding of this condition is evolving rapidly [10,11]. EVALI is characterized by a recent history of e-cigarette use; symptoms of shortness of breath, cough, chest pain, and gastrointestinal complaints; and diffuse hazy or consolidative opacities on plain radiograph.

Acute coronary syndrome (ACS) – Patients, particularly older adults, suffering from a myocardial infarction (MI) may present with dyspnea as their sole symptom. Clinicians are more likely to miss an MI in the patient whose chief complaint is dyspnea, rather than chest pain

Acute decompensated heart failure (ADHF) – Symptomatic ADHF can be caused by volume overload, heart failure with preserved ejection fraction (HFpEF [previously known as "diastolic dysfunction"]), heart failure with reduced ejection fraction (HFrEF [previously known as "systolic dysfunction"]), or outflow obstruction (eg, aortic stenosis, hypertrophic cardiomyopathy, severe systemic hypertension). Myocardial ischemia and arrhythmia are common precipitants. Symptoms range from mild dyspnea on exertion to severe pulmonary edema requiring emergency airway management. Common findings include tachypnea, pulmonary crackles, jugular venous distension (picture 1), S3 gallop, and peripheral edema. ADHF is among the most common causes of acute respiratory failure among patients over 65 years.

High-output heart failure – High-output heart failure may be precipitated by a number of conditions, including severe anemia, pregnancy, beriberi (thiamine deficiency), and thyrotoxicosis. Signs may include tachycardia, bounding pulses, a venous hum heard over the internal jugular veins, and carotid bruits. An elevated troponin may be seen secondary to demand ischemia.

Cardiomyopathy – The physiologic derangements associated with cardiomyopathy (primarily dilated cardiomyopathy) may result in pulmonary edema and manifest as dyspnea. Potential causes include cardiac ischemia, hypertension, alcohol abuse, cocaine abuse, and a number of systemic diseases (eg, sarcoidosis, systemic lupus erythematosus).

Cardiac arrhythmia – Cardiac rhythm abnormalities, such as atrial flutter, atrial fibrillation, second- and third-degree heart block, and tachyarrhythmias (eg, supraventricular tachycardia [SVT] and ventricular tachycardia) can result in dyspnea. Such abnormalities may stem from underlying disease, including myocardial ischemia or cardiac decompensation due to the elevated or slowed heart rate or uncoordinated contractions.

Valvular dysfunction – Aortic stenosis, mitral regurgitation, or ruptured chordae tendinae can present with acute dyspnea. A murmur may be appreciable, but the absence of an audible murmur does not exclude the diagnosis.

Cardiac tamponade – Whether due to trauma, malignancy, uremia, drugs, or infection, cardiac tamponade can present with acute dyspnea. The classically described findings of hypotension, distended neck veins, and muffled heart tones suggest the diagnosis but are often absent. The electrocardiogram (ECG) generally shows sinus tachycardia and low voltage and may uncommonly reveal electrical alternans.

Stroke – Although dyspnea is not the chief complaint of patients with an acute stroke, a number of respiratory abnormalities may result from a sufficiently severe injury or one affecting regions involved in respiration. Such abnormalities may include aspiration pneumonia, neurogenic pulmonary edema, and a number of abnormal respiratory patterns, including apnea, that can lead to severe hypoxia or hypocapnia. Invasive airway management may be required.

Neuromuscular disease – A number of neuromuscular diseases, including multiple sclerosis, Guillain-Barré syndrome, myasthenia gravis, amyotrophic lateral sclerosis, West Nile virus, and Enterovirus D68, seen primarily in children, can cause weakness of the respiratory muscles, leading to acute respiratory failure.

A number of specific causes of anemia diagnoses occur at increased frequency in individuals with malnutrition and/or malabsorption. These may include deficiencies of iron, vitamin B12, folate, and copper, which may occur in isolation or simultaneously. In individuals with severely reduced intake due to anorexia nervosa or starvation, the bone marrow is often affected.

● Gastric surgery – Gastric surgery, particularly bariatric surgery, is associated with malabsorption of vitamins and trace elements. This is particularly the case following Roux-en-Y procedures [32]. Rates of deficiencies with different procedures and details of routine supplementation are discussed separately. (See "Bariatric surgery: Postoperative nutritional management".)

● Zinc supplements – Zinc ingestion, as a dietary supplement or in zinc-containing denture adhesives, can cause copper deficiency by inhibiting copper absorption. (See "Causes and pathophysiology of the sideroblastic anemias", section on 'Copper deficiency'.)

● Starvation or anorexia nervosa – Anemia is seen in approximately one-third of individuals with severe malnutrition or anorexia nervosa, either alone or in combination with neutropenia or leukopenia [33]. The bone marrow may show gelatinous necrosis. Anemia will improve with restored food intake.

Iron deficiency causes microcytosis, while vitamin B12, folate, and copper deficiency cause macrocytosis. If both iron deficiency and one of the other deficiencies are present, the MCV may be in the normal range, often with an increased red cell distribution width (RDW)

Vitamin B12 and copper deficiency can cause other cytopenias; neutropenia commonly accompanies the anemia in copper deficiency. Vitamin B12 and copper deficiency both can produce posterior column neurologic abnormalities

The evaluation in all cases should include serum iron, transferrin/TIBC, ferritin, vitamin B12, and folate levels. Copper level should be measured in malnourished individuals with anemia accompanied by neutropenia and/or neuropathy, as well as those with anemia in the setting of gastric/bariatric surgery or a history of zinc ingestion. Individuals with any of these deficiencies should be evaluated for the underlying cause

Chronic anemia in patients with systemic illnesses may reflect anemia of chronic disease/inflammation (ACD/AI), particularly in disorders associated with inflammatory processes such as rheumatoid arthritis or systemic lupus erythematosus (SLE).

The reduction in hemoglobin is often mild to moderate. The red cells are typically normocytic, although there may occasionally be a moderate degree of microcytosis. Iron studies show decreased serum iron and normal or elevated ferritin concentrations. Serum erythropoietin is typically increased above the level seen in patients who are not anemic but to a lesser degree than would be observed in uncomplicated iron deficiency (figure 4). Serum hepcidin is not routinely available but would be expected to be elevated.

Underlying conditions commonly associated with ACD/AI include:

● Cancer

● Chronic kidney disease (may be associated with concomitant erythropoietin deficiency)

● Rheumatologic conditions

● Hypothyroidism

● Infections

There is debate about whether diabetes mellitus per se causes ACD/AI, or whether ACD/AI can only be caused by complications of diabetes.

Pancytopenia is the combination of anemia, thrombocytopenia, and neutropenia (or leukopenia).

Findings of particular concern that warrant hematologist involvement and bone marrow examination include:

● Severe pancytopenia.

● Blasts or immature myeloid/lymphoid forms, which suggest acute leukemia.

● Abnormal lymphocytes (hairy cells, large granular lymphocytes, prolymphocytes).

● Leukoerythroblastosis (picture 10) with or without teardrop cells (dacrocytes; (picture 11)).

● Pancytopenia with hemolysis or thrombosis.

● Pancytopenia or bicytopenia (anemia with leukopenia or anemia with thrombocytopenia) in an older individual with normal vitamin B12, folate, and copper levels.

Potential diagnoses are numerous (table 5). They include drug-induced pancytopenia (cytotoxic drugs, anti-infective drugs, anticonvulsants (table 6)), certain infections (viral [hepatitis, cytomegalovirus, Epstein Barr virus] and severe non-viral [clostridial sepsis, malaria, leishmaniasis, leptospirosis, babesiosis]), bone marrow failure (aplastic anemia), myelodysplasia, myelofibrosis, clonal disorders such as paroxysmal nocturnal hemoglobinuria (PNH), and hematologic malignancies.

Hypersplenism – Cirrhosis can cause pancytopenia due to sequestration of cells in the spleen (hypersplenism). Macrocytosis and target cells are often seen on the peripheral blood smear. The mean corpuscular volume (MCV) will typically be elevated to a moderate degree, usually no higher than 105 fL. Splenic imaging is appropriate if splenomegaly has not been previously documented.

Nutrient deficiency – Deficiency of vitamin B12, copper, and/or folate may also cause pancytopenia and should be evaluated, especially if the peripheral blood smear shows macroovalocytes (picture 12), hypersegmented neutrophils (picture 13), and/or if the MCV is >110 fL.

Autoimmune – Autoimmune cytopenias typically affect a single cell line but can affect more than one cell line simultaneously, especially if there is an underlying rheumatologic disorder such as systemic lupus erythematosus (SLE) or a lymphoid disorder such as chronic lymphocytic leukemia (CLL)

HLH – Hemophagocytic lymphohistiocytosis (HLH) may be primary (typically in children) or secondary to an infection, malignancy, or rheumatologic condition.

TMAs – Thrombotic microangiopathies (TMAs) such as thrombotic thrombocytopenic purpura (TTP) typically cause thrombocytopenia and microangiopathic hemolytic anemia, with a very low platelet count and schistocytes on the blood smear. Some types of drug-induced TMAs such as due to quinine can cause pancytopenia. Disseminated intravascular coagulation (DIC) can cause pancytopenia due to TMA plus bone marrow suppression, with coagulation abnormalities often prominent.

Reticulocyte count — Anemia can also be classified on the basis of reticulocyte production. This approach is most informative when the reticulocyte count is either very decreased or very elevated. Attention must be paid to the particular reticulocyte parameter reported (absolute count versus percentage) and is most helpful using a reticulocyte parameter that is corrected for the degree of anemia (table 2).

Reticulocytosis requires a normally functioning bone marrow replete with iron, folate, cobalamin (vitamin B12), and copper, and a normally functioning kidney that can sense a decrease in oxygen delivery and produce a compensatory increase in erythropoietin (EPO). Thus, a decreased reticulocyte count suggests underproduction of red blood cells (RBCs; bone marrow suppression), and an increased reticulocyte count usually suggests hemolysis or blood loss. If both bone marrow suppression and hemolysis or blood loss are present, the reticulocyte count will be inappropriately low

Anemia with a decreased (or inappropriately low) reticulocyte count may be due to:

- Deficiency of iron, vitamin B12, folate, or copper

- Medications that suppress the bone marrow

- Primary bone marrow disorders including myelodysplastic syndrome (MDS), myelofibrosis, or leukemia

- Very recent bleeding (within five to seven days, before bone marrow compensation has occurred)

Anemia with an increased reticulocyte count may be due to:

- Hemolysis

- Repletion of deficient iron, vitamin B12, folate, or copper (early phase of recovery)

- Recovery from bleeding

If the reticulocyte count is increased and the cause of anemia is not readily apparent, additional laboratory testing for hemolysis is appropriate (table 3).

An increase in reticulocyte count following treatment can also be very helpful in determining if the cause of anemia was determined accurately and completely. As examples:

• If anemia was attributed to a deficiency (iron, vitamin B12, folate), brisk reticulocytosis is expected to occur within one to two weeks of repletion.

• If the reticulocyte count does not increase with correction of a deficiency, this suggests an additional cause of anemia is interfering with bone marrow function. As an example, vitamin B12 or folate deficiency may occur concurrently with iron deficiency, causing a normocytic anemia (see 'Normocytic (normal MCV)' below). This combination of findings is often seen in malabsorption syndromes such as for celiac disease, autoimmune gastritis, or bariatric surgery.

Hemolytic anemia should be considered when there is a rapid fall in hemoglobin concentration with an increased reticulocyte count in the absence of blood loss (table 2). Other abnormal laboratory findings indicative of hemolysis are summarized in the table (table 3).

Schistocytes on the blood smear indicated likely hemolysis due to mechanical RBC destruction. Schistocytes plus thrombocytopenia indicate possible thrombotic microangiopathy (TMA), which may be life-threatening.

Chronic hemolysis may present with a stable hemoglobin, a high reticulocyte count, and a normal lactate dehydrogenase (LDH) and bilirubin. The combination of an increased LDH and reduced haptoglobin is 90 percent specific for acute hemolysis, while the combination of a normal LDH and a serum haptoglobin greater than 25 mg/dL is 92 percent sensitive for ruling out hemolysis [36,37].

Intramedullary hemolysis (within the bone marrow) due to ineffective erythropoiesis, as may be seen in thalassemia or vitamin B12 deficiency, may produce elevations of bilirubin and LDH without reticulocytosis

Causes of hemolysis are numerous and can be categorized in several ways, as summarized in the table (table 7) and discussed in more detail separately. (See "Diagnosis of hemolytic anemia in adults".)

Hereditary, non-immune:

• Hemoglobinopathies (sickle cell disease, thalassemias, unstable hemoglobins)

• Hereditary red cell enzyme deficiencies (glucose-6-phosphate dehydrogenase [G6PD], pyruvate kinase [PK], glucose phosphate isomerase, 5’ nucleotidase)

• Hereditary RBC membrane defects (hereditary spherocytosis [HS], elliptocytosis [HE], stomatocytosis [HSt])

Acquired, non-immune

• Membrane defects (liver disease, acquired acanthocytosis)

• Infections (malaria, babesiosis, clostridial sepsis, Bartonellosis, trypanosomiasis, visceral leishmaniasis)

• Drug-induced (oxidant stress)

• Severe burns

• Thrombotic microangiopathies (thrombotic thrombocytopenic purpura [TTP], hemolytic uremic syndrome [HUS], drug-induced TMA)

• Mechanical (intravascular devices, artificial heart valve, giant hemangioma, footstrike hemolysis)

• Hypersplenism (may have a component of phagocytosis but is not antibody mediated)

• Vasculitis

• Severe hypertension

• Heavy metals (Wilson disease, copper toxicity, arsine toxicity)

• Envenomation (snake, brown recluse spider, hobo spider)

• Hypophosphatemia

Acquired, immune-mediated

• Autoimmune (warm autoimmune hemolytic anemia [AIHA], cold agglutinin disease, paroxysmal cold hemoglobinuria)

• Hemolytic transfusion reactions

• Drug-induced

Many individuals with anemia will be otherwise well, and the clinical history and other initial findings on the complete blood count (CBC) may not be helpful for suggesting specific diagnoses leading to anemia. A diagnostic approach based on the mean corpuscular volume (MCV) is most useful in these cases, as illustrated in the flowchart (algorithm 1).

A decreased MCV (usually <80 fL) reflects a defect in cellular hemoglobin synthesis. These anemias are summarized in the table (table 8) and discussed in detail separately and briefly below.

Causes

• Iron deficiency – Restricted iron availability (iron deficiency and some cases of anemia of chronic disease/anemia of inflammation [ACD/AI], which can cause functional iron deficiency). (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults" and "Anemia of chronic disease/anemia of inflammation".)

• Decreased globin chains – Qualitative abnormalities in globin proteins such as thalassemia, hemoglobin (Hb) C, and HbE (but not HbS). (See "Pathophysiology of thalassemia" and "Clinical manifestations and diagnosis of the thalassemias" and "Overview of variant sickle cell syndromes".)

• Decreased heme – Abnormalities of the heme porphyrin ring, including sideroblastic anemias and lead poisoning. (See "Causes and pathophysiology of the sideroblastic anemias" and "Lead exposure and poisoning in adults".)

Very low MCV – Iron deficiency and thalassemia are the most likely causes of a very low MCV (<80 fL). The ratio of the MCV to the red blood cell (RBC) count (Mentzer index) is useful in predicting the likelihood of thalassemia trait versus iron deficiency. If the ratio of MCV (in fL) to RBC count (in millions of cells/microL) is less than 13, thalassemia is more likely than iron deficiency [38].

In practice, all individuals with a low MCV should have iron studies to evaluate iron status (and should have deficiency corrected if present), because the results of hemoglobin analysis can be altered by concomitant iron deficiency.

All patients – All patients with microcytic anemia should have serum iron, total iron binding capacity (TIBC)/transferrin, and serum ferritin concentrations measured, with calculated transferrin saturation (TSAT). Iron studies will identify iron deficiency (the most likely diagnosis for microcytic anemia) and ACD/AI in most cases. Mild microcytosis with iron studies showing low iron, low TIBC, and high-normal to high ferritin in the appropriate clinical context (eg, chronic inflammatory condition with normal MCV prior to its development) is consistent with ACD/AI.

Individuals with normal iron studies – Hemoglobin quantitation should be ordered in individuals with microcytic anemia who do not have iron deficiency or ACD/AI to identify beta thalassemia or other hemoglobinopathies. Globin gene studies may be needed to diagnose alpha thalassemia; the family history may be helpful in determining likelihood of these disorders. Minimal to mild anemia and microcytosis may indicate non-transfusion-dependent thalassemia (thalassemia trait). Basophilic stippling may also be seen with beta thalassemia [39].

Individuals with normal hemoglobin – Basophilic stippling (picture 14) suggests possible lead poisoning, and whole blood lead levels should be measured. The diagnosis of sideroblastic anemia requires a bone marrow examination.

Macrocytosis (high MCV) — An increased MCV (>100 fL) is typically attributed to asynchronous maturation of nuclear chromatin, although other causes may also be present. These anemias are summarized in the table (table 9) and discussed in detail separately and briefly below.

Megaloblastic anemia – Asynchronous nuclear maturation (megaloblastosis), in which the rate of cell division is reduced relative to cytoplasmic expansion. (See "Macrocytosis/Macrocytic anemia", section on 'Megaloblastic anemia'.)

Megaloblastic maturation can be due to:

- Vitamin B12 deficiency

- Folate deficiency

- Copper deficiency

- Myelodysplastic syndrome (MDS)

- Aplastic anemia

- Diamond Blackfan anemia

- Drugs that interfere with DNA synthesis

Membrane changes – In some cases, conditions that increase RBC membrane (such as liver disease or excess alcohol [even without liver disease]) and other underlying disorders such as hypothyroidism can cause increases in MCV. Stomatocytosis (hereditary or acquired) can also cause macrocytic anemia.

Reticulocytosis – Reticulocytes are larger than mature RBCs (picture 3), and reticulocytosis will increase the MCV. This will be associated with an increased red cell distribution width (RDW) and can often be suspected from examination of the peripheral blood smear.

Spurious – Increased concentrations of immunoglobulin or acute phase proteins such as occurs with inflammation or a polyclonal or monoclonal gammopathy may cause small rouleaux (picture 15) that are counted by electronic counters as single large cells. This is a laboratory artifact that can be assessed by viewing the peripheral blood smear.

All individuals – Serum vitamin B12 level should be measured in all patients with unevaluated macrocytosis. All individuals who are nutritionally compromised or who have had gastric surgery should also have serum folate measured. In patients without known nutritional/gastric issues who have MCV >110 fL and a normal vitamin B12 level, serum methylmalonic acid (MMA) and serum folate should be measured.

Individuals with normal vitamin B12 and folate

- Thyroid stimulating hormone (TSH) should be checked. (See "Macrocytosis/Macrocytic anemia", section on 'Hypothyroidism'.)

- Alcohol use should be assessed. The MCV typically is not >105 fL in alcohol-induced macrocytosis. (See "Hematologic complications of alcohol use", section on 'Anemia'.)

- Serum copper level should be checked, especially if neutropenia and/or neuropathy are present or if the history reveals zinc ingestion or other risk factors. (See "Copper deficiency myeloneuropathy", section on 'Causes of acquired copper deficiency'.)

- The peripheral blood smear (or report) should be reviewed. If the blood smear shows target cells, liver synthetic tests should be measured. The MCV in liver disease typically is not >105 fL. Other morphologic abnormalities such as stomatocytosis should be evaluated, if present. If the copper level is normal and the blood smear shows evidence of dysplasia such as bilobed or immature neutrophils or binucleate RBCs, or other cytopenias, refer to a hematologist for bone marrow and/or molecular (DNA) studies on bone marrow or peripheral blood.

A normal MCV (80 to 100 fL) is the most common finding in anemic men and postmenopausal women. Normocytic anemias can be more challenging to evaluate than anemias with an MCV that is obviously low or high. Causes are more numerous and may be multifactorial, an underlying condition may not be apparent, and other findings may be nonspecific

Often normocytic anemia is associated with a slightly elevated RDW, and the reticulocyte count is not substantially increased (and may be decreased). An increased RDW may indicate a population of microcytic or macrocytic RBCs that is too small to shift the MCV out of the normal range, or combined microcytic and macrocytic processes, such as iron deficiency plus vitamin B12 or folate deficiency [40]

Nutrient deficiency – Any of the causes of acquired microcytic or macrocytic anemia, especially early stages of deficiency of iron, vitamin B12, folate, or copper.

Multiple causes – Combined microcytic plus macrocytic anemia [40]. The most characteristic situation is simultaneous deficiency of vitamin B12 and iron in an individual with celiac disease or autoimmune gastritis.

• ACD/AI – Anemia of chronic disease/anemia of inflammation (ACD/AI). (See "Anemia of chronic disease/anemia of inflammation".)

• CDK – Anemia of chronic kidney disease (CKD). (See "Overview of the management of chronic kidney disease in adults", section on 'Anemia'.)

• HF – Anemia of heart failure (HF), including cardio-renal syndrome [41]. (See "Evaluation and management of anemia and iron deficiency in adults with heart failure" and "Cardiorenal syndrome: Definition, prevalence, diagnosis, and pathophysiology".)

• Endocrine – Anemia with endocrine deficiency, including hypothyroidism (most cases), androgen deficiency, or adrenal insufficiency (in adrenal insufficiency, anemia may be masked by volume contraction). (See 'Caveats for normal ranges' above and "Clinical manifestations of adrenal insufficiency in adults", section on 'Hematologic findings'.)

•

• Clonal hematopoietic stem cell disorders – Anemia due to a clonal disorder of erythropoiesis (myelodysplastic syndrome, aplastic anemia, or clonal cytopenias of uncertain significance [CCUS]) [42]. The strict definition of clonal hematopoiesis of indeterminate potential (CHIP) includes normal hemoglobin and other blood counts. (See "Clinical manifestations and diagnosis of myelodysplastic syndromes (MDS)" and "Idiopathic and clonal cytopenias of uncertain significance (ICUS and CCUS)".)

• Early blood loss – Blood loss that has not yet caused iron deficiency. (See "Evaluation of occult gastrointestinal bleeding".)

• PRCA – Pure red cell aplasia. (See "Acquired pure red cell aplasia in adults".)

• Partially treated anemia – Anemia in process of correction or following transfusion. A "dimorphic RBC population" (presence of two distinct populations of RBCs of different sizes) may be suspected when an increased RDW is present; it can be confirmed by examination of the peripheral blood smear, although the distinct populations may not always be recognized. This finding is traditionally taught as a clue to sideroblastic anemia [43]. However, it is more commonly seen during early treatment of iron deficiency or megaloblastic anemia, or following transfusion of a patient with microcytic or macrocytic anemia

Reticulocyte count and chemistry panel – All individuals with normocytic anemia of unknown cause should have a reticulocyte count and chemistry panel (or review of results of this testing) during the initial evaluation, and abnormalities of this testing should be pursued (algorithm 1).

• Iron studies and hemolysis labs – If the reticulocyte count and chemistry panel are unrevealing, determine serum iron concentration, serum TIBC/transferrin, and serum ferritin concentration measured and transferrin saturation (TSAT) calculated, in order to diagnose iron deficiency or ACD/AI. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults".)

If iron stores are normal, evaluate for hemolysis.

• Additional tests – If hemolysis is absent and there are no other obvious diagnoses, consider conditions listed above including cancer, endocrine disorders, blood loss, and nutrient deficiencies.

- Normocytic anemia with estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 sq m and no other identified cause is most probably the anemia of chronic kidney disease. (See "Overview of the management of chronic kidney disease in adults", section on 'Anemia'.)

- Evaluation for disorders common in older adults is generally reasonable, including testing for monoclonal gammopathies, clonal cytopenias, androgen deficiency (in men), and bone marrow evaluation for myelodysplasia and pure red cell aplasia.

Poisoning – A number of toxins can cause derangements in respiratory function, leading to dyspnea. Organophosphate poisoning causes an increase in airway secretions and bronchospasm. Petroleum distillates and paraquat can cause respiratory difficulty. Botulism may cause generalized descending muscle weakness involving the respiratory muscles.

Salicylate poisoning – Salicylate overdose leads to stimulation of the medullary respiratory center, initially causing hyperventilation and respiratory alkalosis followed by metabolic acidosis. In some cases, pulmonary edema may occur with severe poisoning. Prominent extrapulmonary signs include fever, tinnitus, vertigo, vomiting, diarrhea, and, in more severe cases, mental status changes.

Carbon monoxide poisoning – Carbon monoxide is a potentially lethal toxin that impairs oxygen transport. Carbon monoxide poisoning may present with tachypnea and acute dyspnea in moderate cases and pulmonary edema in severe cases. Extrapulmonary signs are generally more prominent and often nonspecific. They can include headache, malaise, chest discomfort, and altered mental status. Pulse oximetry readings are unaffected.

Toxin-related metabolic acidosis – Toxic ingestions, including methanol and ethylene glycol, may cause a metabolic acidosis and compensatory tachypnea that manifest as respiratory distress and may lead to respiratory failure.

Diabetic ketoacidosis – Diabetic ketoacidosis can cause tachypnea and dyspnea largely from the body's attempt to correct the metabolic acidosis. Patients with diabetic ketoacidosis may give a history of polyuria, polydipsia, polyphagia, and progressive weakness; signs of severe disease include hyperventilation, altered mental status, abdominal pain, and vomiting