Evaluation of acute pulmonary infiltrates

Key points

• Chest x ray findings are frequently non-specific, but diagnosis can often be made when combining these findings with a careful history, physical examination, and a limited number of easily available diagnostic studies
• If the combination of a clinical evaluation and simple diagnostic testing do not narrow the differential diagnosis of an acute pulmonary infiltrate, CT chest should be strongly considered as a helpful next diagnostic test
• If an infectious aetiology is suspected, it is helpful in thinking about the differential diagnosis to classify the patient as severely immunocompromised (eg AIDS, bone marrow transplant, or using strong immunosuppressive agents) or immunocompetent
• Acute pulmonary infiltrates can be categorised by their appearance on chest x ray, into unilateral versus bilateral, localised versus diffuse, and interstitial versus alveolar. This can help significantly in narrowing the differential diagnosis
• After an initial clinical evaluation, aetiology of acute pulmonary infiltrates can usually be categorised as cardiogenic pulmonary oedema, non-cardiogenic pulmonary oedema, infectious, or non-infectious, and this categorisation can help to drive initial clinical approach and treatment

Tips

• Lack of clinical response to treatment of infectious aetiologies should prompt aggressive investigation for atypical infection or non-infectious inflammatory aetiologies
• Pulmonary embolism commonly presents with a normal or near normal chest x ray
• Acute eosinophilic pneumonia (AEP) can be difficult to distinguish from severe acute bacterial pneumonia, with both presenting with acute consolidation on chest x ray, leukocytosis, fever, productive cough, hypoxia, and possibly respiratory failure. Acute eosinophilic pneumonia is characterised by systemic and pulmonary eosinophilia and response to systemic glucocorticoids.

WHAT ARE ACUTE PULMONARY INFILTRATES?
Acute pulmonary infiltrates can be defined simply as the new appearance of parenchymal opacities on a chest radiograph. The term "infiltrates" is used loosely, commonly to refer to airspace disease or parenchymal opacity on chest radiograph, and does not necessarily imply a pathological process of tissue invasion or destruction. While there is no standard definition of acute versus chronic infiltrates, in general, acute infiltrates are present for days to weeks, while chronic infiltrates have been present for weeks to months. Due to the heterogeneity among disease processes and with each individual disease, the definition of acute versus chronic is somewhat relative and arbitrary, but is relevant to acute versus chronic clinical symptoms, and can be a useful framework within which to discuss a differential diagnosis and diagnostic evaluation.

It is notable that many patients are diagnosed and treated for common acute pulmonary diseases without the assistance of chest radiography, even though a chest x ray, if it were to be obtained, would be expected to show acute infiltrates. This module will take the perspective of evaluating a patient who presents with acute radiographic opacities on chest x ray.

Limitations of the chest x ray as a diagnostic tool
The presence of acute pulmonary infiltrates can be a manifestation of one or several of a broad list of pulmonary and extrapulmonary processes. Very often, the findings on chest x ray are either nonspecific, such as with bilateral lower lobe alveolar consolidation, or they are specific for a very broad category of disorders, such as pulmonary oedema. In the evaluation of acute pulmonary infiltrates, the clinical history and examination are critical in making the diagnosis. While supportive testing can be very helpful, particularly for certain categories of diseases, often a clinical diagnosis is made with very little additional testing, and empirical therapy and close follow up are the most effective approach. This approach is successful a majority of the time.

Epidemiology
Any individual may develop acute pulmonary infiltrates, but age, demographics, and patient history can significantly help to narrow the differential. Pulmonary infiltrates are common, as the differential diagnosis includes such prevalent disorders as heart failure and community acquired pneumonia, but specific studies of the epidemiology of acute radiographic abnormalities, in general, are lacking.

Differential diagnosis
With some exceptions, the differential diagnosis can be separated into cardiogenic pulmonary oedema, non-cardiogenic pulmonary oedema, acute infectious processes, and non-infectious inflammatory diseases. This latter category is the most heterogeneous, and there is significant overlap among categories. 

Evaluation of uncommon diseases or unusual clinical presentations
While a clinical and empirical approach may be successful a majority of the time, the differential diagnosis of acute pulmonary infiltrates includes a large number of severe, life threatening, or unusual diagnoses. In the patient with severe illness or respiratory failure, unusual infiltrates, significant immunosuppression, an atypical history, or who does not respond appropriately to an empirical approach, a high index of suspicion for the less common diagnosis is necessary, and further extensive and invasive testing may be warranted. In this context, early consultation with a pulmonary sub-specialist is frequently helpful at making the diagnosis, as a much broader differential diagnosis needs to be considered, and even the most invasive or extensive evaluations can yield ambiguous information requiring expert clinical judgment and guidance.


AETIOLOGY
Acute pulmonary infiltrates are usually the result of an alveolar filling process, although an extensive extra-alveolar or interstitial process can be difficult to distinguish from an alveolar process on chest radiograph. The type of material filling the alveoli can be used to categorise these processes: oedema/water, pus, blood, or protein. Examples of these would include heart failure, pneumonia, alveolar haemorrhage, and pulmonary alveolar proteinosis, respectively. But it is perhaps most clinically useful to categorise acute pulmonary infiltrate aetiology into broad clinical categories representing the dominant pathophysiology of the disease.

Pulmonary oedema or vascular causes
These diseases are typically not associated with a high fever or productive cough, and there may be information in the patient's history to raise suspicion as to a cardiac or non-infectious cause.

• Cardiogenic pulmonary oedema: heart failure is the most common cause of pulmonary oedema, and is due to increased hydrostatic pressure in the pulmonary capillary bed from elevated left ventricular end-diastolic pressure

• Non-cardiogenic pulmonary oedema: includes acute respiratory distress syndrome (ARDS), drug and other toxic reactions, high altitude pulmonary oedema, transfusion associated acute lung injury, or a consequence of an acute infection. Transfusion associated acute lung injury usually occurs within one to two hours of transfusion. Even though a good PA and lateral chest x ray can reveal clues about cardiac dysfunction and volume status, it is often difficult to impossible to distinguish non-cardiogenic from cardiogenic oedema by radiography alone

• Pulmonary infarction: infarction rarely complicates pulmonary embolus, but can result in a peripheral, wedge shaped infiltrate. More commonly, in pulmonary embolus without infarction, the chest x ray is normal, or shows only atelectasis or a small pleural effusion

• Arteriovenous malformation: can present acutely as airspace disease as a result of acute haemorrhage. Typically a pulmonary nodule or mass is present, and the patient experiences dyspnoea and hypoxaemia due to shunt, but in a minority of cases the presentation is one of subacute haemorrhage or massive haemoptysis

Infectious causes
Common themes in the infectious category include an associated high fever and cough, which is more likely to be productive, as well as systemic symptoms of illness.

• Bacterial pneumonia: most common infectious cause. Certain radiographic features such as lobar consolidation or infiltrate location have been associated with specific organisms, but these signs are neither sensitive nor specific, and of limited clinical utility. Pleural effusions should be evaluated promptly, and can aid in diagnosis. In the normal host, community acquired bacterial pneumonia is divided into typical (eg Streptococcus pneumoniae, Haemophilus influenzae), atypical (eg Legionella pneumophila, Mycoplasma pneumoniae, Chlamydophila pneumoniae), and nosocomial pneumonia (eg meticillin-resistant Staphylococcus aureus (MRSA) and resistant Gram negative infections)

• Viral pneumonia: typically a diffuse process, with signs and symptoms of a viral syndrome. Common organisms include influenza A, respiratory syncytial virus, and parainfluenza viruses

• Fungal pneumonia: immunocompetent hosts can get acute infections from endemic soil mycoses such as histoplasmosis or coccidiomycosis, and present with acute symptoms of fever, cough, and dyspnoea. They tend to have mild symptoms and a self limited course

• Immunocompromised hosts may present with only fever or abnormal radiography, with a broader list of bacterial, fungal, viral, and mycobacterial organisms responsible. Aspergillosis is rarely invasive in the absence of a compromised immune system. Patients with diabetes are prone to disseminated and extrapulmonary fungal infections. Patients with HIV are susceptible to Pneumocystis jiroveci, cryptococcal pneumonia, tuberculosis, and many other opportunistic pathogens

• Septic emboli: haematogenous spread of (typically bacterial) infection to the lung, usually appearing as lower lobe-predominant irregular nodular opacities that can cavitate. Common organisms include streptococci and fusobacterium (as in Lemierre syndrome)

Non-infectious inflammatory causes
This is a broad category that includes pulmonary and extra-pulmonary diseases, and many auto-inflammatory conditions. This category presents a more difficult diagnostic dilemma than other categories, due to the uncommon nature of the diseases and the need for additional diagnostic evaluations. This category overlaps with some of the non-cardiogenic pulmonary oedemas, which have an inflammatory aetiology.

• Aspiration: while airway aspiration can lead to bacterial pneumonia, it more commonly leads to a chemical pneumonitis, with radiographic infiltrates in dependent lung zones (posterior upper lobes, superior and basilar segments of lower lobes) and non-specific pulmonary symptoms. Fever may or may not be present. Patients are commonly older or have neurologic disease

• Allergic bronchopulmonary aspergillosis: an inflammatory (not strictly infectious) condition associated with asthma and fleeting pulmonary infiltrates. CXR shows central bronchiectasis

• Drug toxicity: bleomycin, cyclophosphamide, melphalan, gold salts, penicillamine, non-steroidal anti-inflammatory agents, methotrexate, amiodarone, nitrofurantoin, and many others. Can present as diffuse alveolar damage, organising pneumonia, eosinophilic pneumonia, pulmonary fibrosis, or pulmonary haemorrhage. CXR shows scattered interstitial or mixed interstitial/alveolar infiltrates

• Radiation pneumonitis: diffuse ground glass may progress to alveolar consolidation or fibrosis. Changes are confined to the outline of the field of radiation, can appear non-anatomical or geometric on radiograph, and occur two to three months after radiation therapy

• Acute hypersensitivity pneumonitis: acute respiratory symptoms following exposure to known inciting antigen, with bilateral ground glass opacities and subcentimetre nodules. It can present as purely bronchiolitis without radiographic infiltrates

• Cryptogenic organising pneumonia: bilateral patchy alveolar infiltrates that are most commonly idiopathic, but can be secondary to another inflammatory process such as infection

• Acute eosinophilic pneumonia: acute onset mixed bilateral alveolar and interstitial pattern, commonly with bilateral exudative pleural effusions. Can be difficult to distinguish from acute bacterial pneumonia without further investigation

• Acute interstitial pneumonia (AIP or Hamman Rich syndrome): diffuse bilateral infiltrates in a previously healthy individual, or as an acute exacerbation of idiopathic interstitial lung disease

• Pulmonary vasculitis: difficult to diagnose without a lung biopsy. Can present as acute pulmonary infiltrates, alveolar haemorrhage, or non-specific signs and symptoms of an autoimmune disease. May follow or co-exist with infection or drug toxicity

• Wegener's granulomatosis: sinusitis, positive c-ANCA and bilateral localised nodular or patchy opacities

• Churg-Strauss syndrome: eosinophilia, severe asthma, and bilateral peripheral consolidation or nodular opacities

• Microscopic polyarteritis nodosa: positive p-ANCA, diffuse alveolar haemorrhage, rapidly progressive glomerulonephritis

• Meconium aspiration: late term or distressed infant with respiratory distress, low five minute APGAR score, meconium staining. CXR may show hyperinflation or patchy infiltrates

• Amniotic fluid embolism: cardiovascular collapse, DIC, and bilateral infiltrates suggestive of pulmonary oedema in a pregnant woman during labour or following rupture of the amniotic sac

• Fat emboli syndrome: Bilateral patchy upper and middle lobe infiltrates ("snow storm" appearance) and progressive respiratory failure 12-36 hours after long bone trauma or orthopaedic surgery

• Pulmonary contusion: Unilateral or bilateral patchy consolidation following blunt chest trauma, commonly associated with rib fractures, hypoxia, and respiratory compromise

Neoplastic causes

• Bronchioloalveolar cell carcinoma: commonly presents as solitary nodule or segmental consolidation. Known to spread rapidly along bronchial walls (lepidic growth), leading to cough, dyspnoea, and diffuse infiltrates
• Metastatic disease typically appears as multiple pulmonary nodules of varying sizes, but nodules can become confluent and appear as a consolidation or infiltrate
• Endobronchial lesions can cause post-obstructive pneumonia or atelectasis

Iatrogenic causes

• Atelectasis: more common in obesity, atelectasis can be a result of hypoventilation from medications, surgery, pain, diaphragm dysfunction, neuromuscular diseases, metabolic problems, or central nervous system depression. It can also suggest an airway obstruction, such as mucus or tumour. Radiographically difficult to distinguish from pneumonia, in the absence of additional clinical detail, but volume loss is common

• Retained bronchoalveolar lavage fluid: usually re-absorbed within hours, but can cause a more significant inflammatory reaction with persistent infiltrate and fever, difficult to clinically distinguish from bacterial pneumonia

• Haemorrhage: any procedure resulting in airway or alveolar trauma can result in blood filled airspaces and a new pulmonary infiltrate on chest x ray. Typical procedures would include bronchoscopy, transthoracic needle biopsy, and pulmonary artery catheterisation complicated by pulmonary artery infarction or rupture

Cardiogenic pulmonary oedema
This may be the presenting sign of an acute myocardial infarction or new arrhythmia. Urgent recognition and treatment may prevent respiratory failure. History is helpful. Testing should include ECG, cardiac enzymes, brain natriuretic peptide (BNP), and echocardiogram. Treatment includes diuretics, vasodilators, inotropes, ventilatory support if needed, and specific treatment for the underlying cause.

Pulmonary infarction
Most pulmonary emboli do not result in infarction. Presence of infarct on chest x ray could result in a misdiagnosis of pneumonia. High index of clinical suspicion needed. Leg ultrasound, CT angiography, and/or ventilation-perfusion scan are helpful. Immediate treatment is anticoagulation, similar to pulmonary embolism without infarct, but the development of necrotic lung may require subsequent surgical debridement or resection.

Acute non-infectious inflammatory pneumonias
The danger is in missing this group of diagnoses. Consider non-infectious, inflammatory pneumonias when the presentation is not typical for infection or the patient is not responding to antibiotics. Diagnosis requires a high index of clinical suspicion. Bronchoscopy and CT chest can be additionally helpful. Look for systemic and pulmonary eosinophilia, acute severe progressive respiratory failure, alveolar haemorrhage, or an appropriate environmental or past medical history that would prompt further investigation.

Acute haemorrhage
Presence of gross haemoptysis, particularly in the setting of an airway lesion or post-bronchoscopy, should raise concern. Respiratory compromise can result from relatively modest bleeding, particularly in the setting of chronic lung disease. Supportive care and observation indicated for mild cases. Patient should lie with bleeding side down, if known. Coagulopathy should be treated. More severe cases may require repeat bronchoscopy, tracheal intubation (consider double lumen tube to isolate the bleeding), angiography, or surgery. Diffuse alveolar haemorrhage is diagnosed by progressively bloody bronchoalveolar lavage, and is treated with high dose immunosuppression.

DIAGNOSTIC APPROACH

A chest x ray is one of the first and most common evaluations performed for a patient with acute thoracic complaints. It is inexpensive and easily available, but its lack of sensitivity and specificity requires the clinician to integrate radiographic findings with clinical signs and symptoms. Frequently, additional testing as indicated by the clinical situation will be necessary to confirm or exclude diagnoses. Empirical treatment approaches are often necessary, after excluding other items or groups of items from the differential. Close follow up is often necessary, and if the initial empirical treatment approach is not successful, a more thorough investigation, commonly with CT chest, laboratory testing, cardiac evaluations, and even biopsy will be indicated.

Start with simple, quick, inexpensive tests. Chest x ray, ECG, CBC, cardiac enzymes, and BNP are often ordered simultaneously, along with serum chemistries and liver function tests. If a cardiac aetiology is suspected, echocardiogram will be helpful. It is usually easy to identify or exclude cardiogenic pulmonary oedema based upon the x ray appearance and supplementary testing.

If a cardiac aetiology is not suspected on clinical grounds, and the chest x ray shows diffuse bilateral infiltrates, multilobar pneumonia and/or ARDS should be most commonly considered. The treatment approach is similar - supportive care with empirical antibiotics - but the clinical history is usually more helpful than additional testing.

When there is a pulmonary cause of acute infiltrates, and the history does not clearly suggest a specific diagnosis, a CT chest should often be the next test ordered. For non-infectious inflammatory pneumonias or unusual clinical presentations, or if the patient is not responding to initial empirical therapy, involvement of a pulmonary sub-specialist is highly recommended.


HISTORY

• Infectious symptoms: fever, night sweats, productive cough, change in cough, weight loss, flu-like symptoms, pleuritic chest pain, myalgias

• Cardiac symptoms: rapid unexplained weight gain, oedema, orthopnoea, paroxysmal nocturnal dyspnoea, exertional dyspnoea, syncope, palpitations, substernal chest pain, poor appetite, fatigue

• Type of cough: productive cough is more suggestive of typical bacterial pneumonia. A dry cough has a broad differential, to include non-infectious conditions. Blood-tinged phlegm can be seen in many types of pulmonary oedema, as well as bacterial, fungal, and viral pneumonias, but gross haemoptysis is likely to represent iatrogenic bleeding, endobronchial tumour, ruptured pulmonary arteriovenous malformation, pulmonary infarct, or diffuse alveolar haemorrhage

• Past medical history: a history of heart failure, arrhythmia, longstanding hypertension, or coronary artery disease should raise suspicion for a cardiac aetiology to diffuse bilateral infiltrates. The presence of chronic lung disease may increase the risk of pneumonia or acute lung injury, or may alter the radiographic appearance of an otherwise typical pneumonia

• Environmental history: immobility suggests pulmonary embolism/infarct or atelectasis, recent inhalational exposures suggest acute hypersensitivity pneumonitis, and exposure to specific agents (altitude, radiation, blood transfusions) should alert the provider to specific pulmonary diagnoses

• Medication list: cardiac medications may provide insight into cardiac aetiology. Recent chemotherapeutic agents or immunosuppressives are capable of causing pulmonary toxicity. If pulmonary drug toxicity is suspected, consider checking a serum eosinophil count, and going through the medication list in detail to evaluate for all possible toxicity. Diagnosis of drug reaction may require excluding other more common aetiologies like infection or cardiogenic pulmonary oedema, as several medications cause non-cardiogenic pulmonary oedema

• Chronic lung disease: an acute infiltrate on top of underlying emphysema or other chronic lung disease can alter the radiographic appearance and clinical presentation of that disease

• Endobronchial obstruction: the presence of an endobronchial lesion or obstruction can cause atelectasis, pneumonia, haemoptysis, or poor response to otherwise appropriate empirical therapy, and can confound the diagnosis. Bronchoscopy is very useful early on when obstruction is suspected or suggested by imaging

• Immunocompromised patients: patients with diabetes are more prone to disseminated fungal infections. Patients on chronic immunosuppressive medications may not present with fever or elevated WBC, and may have an atypical radiographic appearance when presenting with bacterial pneumonia. More severely immunocompromised individuals, such as those with advanced untreated HIV, solid organ transplant, haematological malignancy, or recent bone marrow transplantation can present with unusual infections, drug toxicity, or atypical versions of typical diseases. These patients require a much broader differential diagnosis, and a more aggressive approach to diagnosis, with early use of CT scan, bronchoscopy, and sub-specialty consultation

PHYSICAL EXAMINATION

• High fever strongly suggests infection, but fever can also be present with aspiration pneumonitis, acute eosinophilic pneumonia, non-infectious inflammatory disease, drug reaction, and pulmonary infarct

• Elevated jugular venous pressure, oedema, ascites, and cardiac gallup all suggest cardiac aetiology

• Diffuse crackles are non-specific, but signs of focal consolidation (ie egophony, dullness to percussion, localised crackles) are most common with bacterial pneumonia

• Tachycardia, hypotension, tachypnoea, hypoxia, and altered mental status are signs of severe illness and the need to intervene urgently, but do not necessarily help narrow the differential

• Unilateral lower extremity oedema or loud P2 could suggest pulmonary embolus

• Extra-pulmonary findings such as a rash or acute abdomen can help make the pulmonary diagnosis

LABORATORY STUDIES

• CBC is inexpensive and very useful. Leukocytosis is supportive of an infectious aetiology, such as pneumonia. Eosinophilia could suggest ABPA, drug reaction, or acute eosinophilic pneumonia

• BNP has been shown to be useful in differentiating acute dyspnoea due to cardiac or pulmonary causes. BNP <50 pg/ml is specific for excluding heart failure. BNP >100 pg/ml is highly sensitive for heart failure.

• Highly sensitive D-dimer test can exclude pulmonary embolus when there is a low pre-test suspicion

• Cardiac enzymes (troponin, creatinine phosphokinase, LDH) can suggest cardiac ischaemia due to acute coronary syndrome or heart failure

• Sputum Gram stain can evaluate for white blood cells or bacterial organisms, and sputum culture may identify a causative organism for bacterial pneumonia in a significant minority of cases. The routine use of either of these tests in non-hospitalised patients is unlikely to be cost effective, however

• Blood cultures may aid in the diagnosis of pneumonia or septic emboli for the complicated, hospitalised patient

• Autoimmune disease screening labs are of limited usefulness in the diagnosis of acute pulmonary infiltrates, but if vasculitis is suspected, anti-neutrophil cytoplasmic antibodies are helpful. Specific patients with suspected autoimmune disease may benefit from more comprehensive autoantibody screening labs

IMAGING STUDIES

• CT chest is very helpful in narrowing the differential of acute infiltrates when clinical details and laboratory testing are not helpful, and the history does not support empirical treatment. Order contrast (a CT angiogram) if there is suspicion for pulmonary embolus. Otherwise contrast is probably not necessary. Prone images can be helpful at differentiating dependent lung water from cardiac aetiology versus a peripheral and basilar predominant infectious or inflammatory process. CT also helps to assess for complications of pneumonia such as abscess or empyema

OTHER STUDIES

• ECG should be obtained immediately if there is any suspicion of cardiac aetiology

• Echocardiogram is particularly useful when there are bilateral alveolar opacities, and it is unclear whether they are due to infection or pulmonary oedema or both. If the study is technically limited or there remains concern about cardiac dysfunction, left and/or right heart catheterisation may be justified

• Bronchoscopy should be considered for a patient who is not responding to appropriate antibiotic therapy for suspected pneumonia, unexplained atelectasis, haemoptysis, immunosuppressed patient, or the CT chest suggests neoplasm or an atypical infectious or inflammatory aetiology that requires a definitive diagnosis

• Atelectasis: removal of mucus/foreign body/tumour, and assess airway patency

• Neoplasm: biopsies diagnostic, except in the case of small peripheral lesions

• Pneumonia: lavage and/or biopsy can support or make a more specific diagnosis, particularly for unusual infections or in the immunocompromised host

• Eosinophilic pneumonia: >20% eosinophils in bronchoalveolar lavage

• Alveolar haemorrhage: progressively bloodier lavage

• Diffuse inflammatory pneumonias: sensitivity of transbronchial biopsy is limited - may require surgical lung biopsy to make the diagnosis 

DIFFERENTIAL DIAGNOSES

Cardiogenic pulmonary oedema
Red flag

• Common

• History 
• History of cardiac disease, oedema, weight gain, PND, orthopnoea, chest pain, decreased appetite, fatigue, non-productive cough.
• Examination 
• Tachycardia, tachypnoea, presence of S3 or S4, increased jugular venous pressure, oedema, ascites, bilateral "wet" crackles and/or decreased breath sounds, tachypnoea, no fever. Hypoxaemia usually present.
• Specific tests to order
• ECG - Tachycardia, ST elevation, or other signs of ischaemia.
• BNP - >100 pg/ml.
• Echocardiogram - LV ejection fraction <50% or diastolic dysfunction. Sometimes an estimate of LV end-diastolic pressure will be provided.
• Right heart catheterisation - Pulmonary capillary wedge pressure >16 mm Hg. Cardiac index <1.8 l/min/m2.

Acute respiratory distress syndrome (ARDS)
Red flag

• Common

• History
• Presence of risk factor or the appropriate clinical setting: 
• pneumonia, pulmonary aspiration, infection/sepsis, severe trauma, pancreatitis, drug overdose, etc.
• Progressive shortness of breath, cough, and respiratory failure in the absence of cardiac dysfunction.
• Examination
• Bilateral crackles, tachypnoea, hypoxaemia, and respiratory failure. 
• Fevers and hypotension may be due to underlying sepsis. 
• Pulmonary compliance is reduced. 
• There may be other findings specific to the underlying cause, such as severe trauma or infection.
• Specific tests to order
• PAO2:FiO2 ratio (First test) - <200.
• ECG - Normal sinus rhythm or tachycardia, no ischaemia.
• Echocardiogram - Normal or hyperdynamic LV function.
• Right heart catheterisation - Pulmonary capillary wedge pressure <12 mm Hg.

Transfusion-associated acute lung injury (TRALI)

• History
• Acute dyspnoea, fevers, and chills within 1-2 hours of receiving whole blood, packed red blood cells, or fresh frozen plasma. 
• Essentially, a picture of non-cardiogenic pulmonary oedema difficult to distinguish from ARDS.
• Examination
• Tachypnoea, cyanosis, hypotension, fever, and bilateral crackles.
• Specific tests to order
• Anti-HLA Antibodies - Positive. Usually performed after the fact; this is a clinical diagnosis.

High altitude pulmonary oedema

• History
• Fatigue, weakness, dyspnoea, and non-productive cough 1-4 days after rapid ascent to high altitude (>2000 m). 
• Dyspnoea can progress to respiratory distress or death if untreated. 
• Improves with rapid descent. 
• Risk factors include previous episodes of high altitude pulmonary oedema, physical exertion, cold air.
• Examination
• Tachypnoea, tachycardia, cyanosis, bilateral crackles.

Hantavirus pulmonary syndrome

• History
• A zoonotic virus causing 3-5 day prodromal flu-like illness following rodent vector exposure (particularly deer mouse, or its urine or droppings) that progresses rapidly to ARDS (dry cough, dyspnoea, and circulatory collapse). 
• Respiratory failure is common. Most common during the autumn in southwest United States, but there are reports in Canada, eastern United States, and South America.
• Examination
• Bilateral crackles, hypoxaemia, tachypnoea, and respiratory failure.
• Specific tests to order
• IgG and IgM to Sin Nombre Virus Viral Nucleocapsid Protein - Positive. Performed at the CDC; delay in results reporting requires clinical diagnosis.
• CBC with differential - WBC >10 k/µl with left shift, PLT <100 k/µl.
• CT Chest - Interstitial oedema progressing to diffuse, severe airspace disease with dependent airspace flooding.

Post-transplant reperfusion injury

• History
• Persistent or progressive respiratory failure with complete opacification of the transplanted organ. 
• Occurs in the immediate 24-48 hours after lung transplantation. 
• Graft failure is common, although patients can improve and survive with aggressive supportive care.
• Examination
• Crackles, hypoxaemia, and respiratory failure in the absence of signs of volume overload or pneumonia.

Acute bacterial pneumonia, typical

• Common

• History
• Acute onset fever, chills, productive cough, dyspnoea, pleuritic chest pain. 
• Risk factors include cigarette smoking, chronic lung disease, and immunosuppression.
• Examination
• Fever, tachycardia, tachypnoea, localised crackles, egophony, dullness to percussion, decreased breath sounds.
• Specific tests to order
• CBC with differential - WBC >10 k/µl, left shift.
• Sputum Gram stain and culture - Identification of a single pathogenic organism.

Atypical bacterial pneumonia

• Common

• History
• Acute or subacute onset of fever, chills, minimally productive cough, dyspnoea, pleuritic chest pain. 
• Risk factors include cigarette smoking, chronic lung disease, and immunosuppression.
• Examination
• Fever, tachycardia, tachypnoea, localised crackles, dullness to percussion, decreased breath sounds.
• Specific tests to order
• CBC with differential - WBC >10 k/µl, left shift.
• Legionella urinary antigen - Positive. Detects only Legionella pneumophila serogroup, but this group is responsible for most clinical disease.

Acute viral pneumonia

• Common

• History
• Fever, headache, cough, dyspnoea, and myalgia. 
• Symptoms range from mild to very severe.
• Examination
• Fever, tachypnoea, tachycardia, crackles, wheezing, rhonchi.
• Specific tests to order
• Rapid antigen detection for influenza, RSV, and parainfluenza viruses (first test) - Positive.

Acute fungal pneumonia

• History
• Fever, non-productive cough, pleuritic chest pain, and dyspnoea in someone who has recently been exposed to an area with endemic mycoses. 
• Normal hosts often have fairly mild and self limited symptoms. 
• Immunocompromised hosts can develop severe, disseminated, or unusual fungal infections and may not have an exposure history.
• Examination
• Fever, tachycardia, tachypnoea, crackles, pulmonary friction rub.
• Specific tests to order
• CT Chest - Patchy consolidation, nodules, or cavities.
• Bronchoscopy - Transbronchial biopsies show fungal elements with tissue invasion. Bronchoalveolar lavage cultures grow fungal organism.

Septic emboli

• History
• Long standing extrapulmonary infection, infectious endocarditis, septic thrombophlebitis (Lemierre syndrome), indwelling catheters or artificial devices, and history of IV drug use are all risk factors. 
• May be confused with primary or metastatic malignancy. 
• Fevers, weight loss, productive cough, and dyspnoea common.
• Examination
• Fever, crackles, egophony, decreased breath sounds.
• Specific tests to order
• CT chest - Multiple irregular nodules or masses, commonly located peripherally and basally. Cavitary lesions typically thick walled.
• Typical CT scan appearance in the setting of a febrile illness strongly suggests the diagnosis.
• Blood cultures (first test) - Positive. Usually staphylococci or fusobacterium. Antibiotic therapy may decrease sensitivity.

Bronchioloalveolar cell carcinoma

• History
• Cough, dyspnoea, weight loss, and haemoptysis. 
• Many patients are asymptomatic. 
• Bronchorrhoea is uncommon, and a late manifestation of disease.
• Examination
• May be normal. 
• Tachypnoea, cough, and/or localised crackles or decreased breath sounds may be present.
• Specific tests to order
• CT chest 
• Peripheral nodule or localised ground glass lesion. 
• Can appear as segmental or lobar consolidation, multiple nodules, or more extensive ground glass.
• PET scan for solitary bronchioloalveolar cell carcinoma nodule lacks sensitivity.
• Lung biopsy 
•  Spreads locally along the bronchus (lepidic growth), with preservation of lung architecture. 
• A type of adenocarcinoma.

Metastatic neoplasm to the lung

• Common

• History
• Older patient with history of prior advanced or metastatic malignant neoplasm. 
• Not uncommonly metastasis to the lung is the presenting manifestation of a new (previously unknown) extrapulmonary neoplasm. 
• Commonly occurs with adenocarcinomas (breast, lung, colon), and head and neck cancer, less commonly with sarcomas, melanoma, others. 
• Presents as progressive dyspnoea, often with systemic symptoms of weight loss and poor appetite.
• Examination
• Lymph node enlargement, abnormal examination at primary site (breast, prostate, skin, etc), decreased breath sounds if tumour burden extensive or there is a pleural effusion.
• Specific tests to order
• CT chest 
• Multiple nodules of varying size. 
• Most metastases spread haematogenously, and tend to distribute in lung bases. 
• May have lymph node enlargement or pleural effusion.
• Lung biopsy 
• Metastatic neoplasm.
• Sometimes difficult to determine primary tumour type from biopsy of metastasis.
• PET scan - Increased metabolic activity in nodules/infiltrates.

Aspiration pneumonitis

• Common

• History
• Acute onset increased cough and dyspnoea. 
• May have fever or pleuritic chest pain. 
• May have dysphagia or severe nocturnal oesophageal reflux. 
• More common in patients who are older, have neurologic deficits, have been intoxicated, are taking sedative medications, or have some other cause of depressed consciousness.
• Examination
• Fever, tachypnoea, and crackles at the lung base. 
• Decreased pharyngeal sensation or decreased gag reflex should raise suspicion.
• Specific tests to order
• Tailored barium swallow (first test)
• Demonstration of aspiration, or at risk of aspiration.
• Bronchoalveolar lavage - oil-red-O stain - Lipid-laden macrophage index >100. 
• Reasonable sensitivity and poor specificity, but bronchoscopy useful at ruling out other processes or removing foreign body.
• CT chest 
• Consolidation in dependent lung zones (posterior upper lobes, superior segment lower lobes, basilar segments lower lobes). 
• May demonstrate basilar bronchiectasis, bronchial wall thickening, or fine lobular nodularity.

Allergic bronchopulmonary aspergillosis (ABPA)

• History
• Typically presents as symptoms of poorly controlled asthma (dyspnoea, wheeze, cough, chest tightness), but cough is very productive, often of brownish mucus plugs or casts. 
• Responds to oral steroids but not as well to inhaled pharmacotherapy.
• Specific tests to order
• Spirometry - Obstructive pattern, showing complete or incomplete reversibility.
• Serum total IgE (first test) - >1000 IU/ml.
• High resolution CT chest - 
• Central bronchiectasis and bronchial wall thickening. 
• Mucus plugs. 
• Areas of consolidation possible distal to plugs. 
• Areas of airspace disease may wax and wane over time on chest x ray or CT.
• Precipitating antibodies to Aspergillus sp - Positive.
• Aspergillus-specific IgE RAST - Positive.
• Skin prick testing - Positive to aspergillus.
• Sputum fungal culture - Aspergillus isolated.

Acute pulmonary drug toxicity

• History
• Many chemotherapeutic agents can cause early onset (immediate-weeks) or late onset (>2 months) disease. 
• Symptoms include low grade fevers, non-productive cough, and progressive dyspnoea. 
• Other drugs can cause non-cardiogenic pulmonary oedema (eg, heroin, morphine, hydrochlorothiazide).
• Examination
• Temp <38° C, tachypnoea, hypoxia, and scattered crackles.
• Specific tests to order
• CBC (first test) - Eosinophils > 10%.
• High resolution CT chest 
• Diffuse interstitial or mixed interstitial and alveolar opacities. 
• Late onset disease may appear with significant fibrosis.
• Transbronchial or surgical lung biopsy
• Interstitial plasma cells, lymphocytes, and eosinophils. 
• Organising pneumonia common. 
• Some reactions present as diffuse alveolar damage or non-cardiogenic pulmonary oedema. 
• Late onset disease can be fibrotic. 
• Biopsy not often necessary. 
• Diagnosis based on history, imaging, and PFT.
• PFT - Restrictive pattern with low diffusion capacity.

Radiation pneumonitis

• History
• Risk of radiation pulmonary toxicity increases with total dose, fractionation, and quality of radiation. 
• Requires radiation to >10% of the lung. 
• Uncommon with total radiation dose <20 Gy, but likely with a total dose >60 Gy. 
• Affects 5-15% of lung cancer patients. 
• Increased risk with concomitant chemotherapy, previous radiation, or withdrawal of steroids. 
• Occurs 2-3 months after irradiation.
• Dyspnoea and non-productive cough are common.
• Examination
• May have normal examination. 
• Tachypnoea, hypoxaemia, and crackles common. 
• Pleural rub uncommon.
• Specific tests to order
• High-resolution CT chest 
• Diffuse ground glass may progress to alveolar consolidation or fibrosis. 
• Changes are confined to the outline of the field of radiation.
• PFT - Decreased lung volumes and impaired diffusion capacity.
• Lung biopsy - Non-specific findings, but biopsy may be helpful to rule out other pathology, such as chemotherapy induced lung disease.

Acute hypersensitivity pneumonitis

• History
• Acute flu-like illness <24 hours after exposure, including non-productive cough, dyspnoea, fevers, chills, and malaise.
• Can recur with increasing intensity on repeated exposure. 
• Multiple animal and bioaerosol exposures are known to cause acute HP, and presence of known inciting antigen is predictive, but many times a cause is not found. 
• 95% of cases occur in non-smokers.
• Examination
• Tachypnoea and bilateral rales.
• Specific tests to order
• High resolution CT chest (first test)
• Bilateral scattered ground glass opacities and subcentimetre nodules.
• Serum precipitating antibodies - Positive. 
• May lack sensitivity. 
• Offending antigen may not be known.
• Transbronchial or surgical lung biopsy
• Lymphocytic inflammatory interstitial infiltrate and non-caseating, peribronchiolar granulomas. 
• Lung biopsy not necessary in the appropriate clinical setting with typical imaging findings on HRCT.

Cryptogenic organising pneumonia (COP)

• History
• Consider COP for any patient with airspace disease not responding to antibiotics. 
• Presentation is 2-10 weeks of cough and shortness of breath, although it can present more rapidly.
• Examination
• Tachypnoea, localised crackles.
• Specific tests to order
• High resolution CT chest (first test) - Bilateral, asymmetric, peripheral, patchy ground glass and consolidation.
• Video-assisted thoracoscopic lung biopsy - Bronchiolar and alveolar fibrous plugging.

Acute interstitial pneumonia (AIP or Hamman Rich Syndrome)
Red flag

• History
• Fever, cough, and dyspnoea with severe progression over 7-14 days, commonly in a previously healthy, middle aged individual. 
• Can also occur as an acute exacerbation of a pre-existing chronic idiopathic interstitial lung disease.
• Clinically AIP presents as idiopathic ARDS in an otherwise healthy individual.
• Examination
• Severe hypoxaemia and tachypnoea without signs of volume overload. 
• May present in respiratory failure.
• Specific tests to order
• High resolution CT chest (first test) - Bilateral patchy ground glass, possibly with some consolidation. Distribution is peripheral and subpleural.
• Echocardiogram - Normal LV function.
• Surgical lung biopsy - Diffuse alveolar damage.

Acute eosinophilic pneumonia

Red flag

• History
• Rapidly progressive dyspnoea and non-productive cough, often with respiratory failure within 24 hours of symptom onset.
• Pleuritic chest pain and fever are common.
• Examination
• Fever, tachycardia, tachypnoea, crackles.
• Specific tests to order
• CBC (first test) - WBC >20 k/µl. Most do not have systemic eosinophilia.
• Bronchoscopy - Bronchoalveolar lavage eosinophils >20%8 and no evidence of bacterial, fungal, or parasitic infection.

Pulmonary vasculitis
Red flag

• History
• Progressive dyspnoea, haemoptysis, cough, pleuritic pain, decrease in urine output.
• Sinusitis common in Wegener's.
• Examination
• Tachypnoea, hypoxaemia, crackles, rash.
• Specific tests to order
• CBC with differential - HGB <12 g/dl in capillaritis. Eosinophilia >12% in Churg-Strauss syndrome.
• ANCA - Positive.
• Urinalysis - Presence of blood, protein, casts.
• CT chest - Diffuse alveolar pattern, nodules with or without cavitation.
• CT sinus - Sinusitis present in Wegener's.
• Comprehensive metabolic panel - Looking for abnormal renal or liver function.

Meconium aspiration

• Common

• History
• More common in the setting of fetal distress or advanced gestation.
• Examination
• Early onset respiratory distress, meconium stained skin, hypoxaemia in the appropriate clinical setting. 
• Five minute APGARs are commonly low.

Fat emboli syndrome

• History
• Sometimes rapid but more often gradual onset of dyspnoea, hypoxaema, fever, neurologic symptoms, rash, respiratory failure, or cardiovascular collapse, 12-36 hrs after severe long bone trauma or orthopaedic surgery. 
• This is a clinical diagnosis of exclusion.
• Examination
• Tachypnoea, tachycardia, bilateral crackles, decreased urine output, fever, altered mentation, coma, jaundice, petechial rash.

Amniotic fluid embolism
Red flag

• History
• Intrapartum or immediate post-partum sudden onset dyspnoea, pulmonary oedema, hypotension, cardiac arrest, and/or coagulopathy/DIC. 
• This is a clinical diagnosis of exclusion.
• Examination
• Hypotension, cyanosis, bilateral crackles, neurologic impairment.

Pulmonary infarction
Red flag

• Common

• History
• History of deep vein thrombosis or pulmonary embolus. 
• Infarction is rare in the absence of underlying chronic cardiac or pulmonary disease. 
• Pleuritic chest pain, dyspnoea, cough. 
• Haemoptysis can occur.
• Examination
• Unilateral decreased breath sounds, hypoxaemia.
• Specific tests to order
• Contrast-enhanced CT chest (first test) - Presence of pulmonary embolus, and ipsilateral peripheral consolidation with central lucency.

Arteriovenous malformation (AVM)

• History
• Fatigue, dyspnoea. 
• 90% have hereditary haemorrhagic telangiectasia (HHT), and 8% present with massive haemoptysis.
• May have history of TIA, stroke, cerebral abscesses, severe epistaxis, or gastrointestinal bleeding.
• Examination
• Severe hypoxaemia, possibly with clubbing or cyanosis. 
• Superficial telangiectasias are common.
• Specific tests to order
• Contrast-enhanced echocardiogram (first test) - Presence of extracardiac right to left shunt.
• Contrast-enhanced CT chest - Identification of pulmonary AVM.
• 100% oxygen shunt study - Shunt fraction >5%

Atelectasis

• Common

• History
• Non-productive cough, dyspnoea, and hypoxaemia. 
• Patient may be asymptomatic. 
• No fevers or systemic symptoms. 
• Patient may report history of immobility, bed rest, or chest or abdominal pain. 
• Common in postoperative state.
• Examination
• Decreased breath sounds, hypoxaemia. 
• Obesity is common. 
• Usually afebrile, but low grade fever possible.
• Specific tests to order
• CBC (first test) WBC <10 k/µl.
• Repeat chest x ray - Improves with deep breaths, increased activity level, or improved pain control.

Acute haemorrhage

• History
• Recent bronchoscopy, needle biopsy, or other pulmonary procedure. 
• Acute cough productive of bright red blood.
• Examination
• Bright red blood in sputum. 
• Examination may be normal, or crackles may be present in dependent lung zones.
• Specific tests to order
• Bronchoscopy (first test) - Identification of site of active bleeding. Observation only for mild cases.

Retained bronchoalveolar lavage fluid

• Common

• History
• Bronchoalveolar lavage performed <24 hours prior. 
• Patient may be asymptomatic, or present with cough, dyspnoea, and low grade fever
• Examination
• Focal crackles over the lavaged segment. Tachypnoea or hypoxaemia may be present.
• Specific tests to order
• Repeat chest x ray (first test) - Infiltrate should resolve within 24 hours.
• CBC - WBC <10 k/µl.

FURTHER READINGS

• Ware LB, Matthay MA. The Acute Respiratory Distress Syndrome. N Engl J Med 2000;342(18):1334-49.
• Duchin JS, Koster FT, Peters CJ, et al. Hantavirus Pulmonary Syndrome: A Clinical Description of 17 Patients With a Newly Recognized Disease. N Engl J Med 1994;330:949-55.
• Simpson SQ. Hantavirus Pulmonary Syndrome. Heart Lung 1998;27(1):51-7.
• Abid SH, Malhotra V, Perry MC. Radiation-Induced and Chemotherapy-Induced Pulmonary Injury. Curr Opin Oncol 2001;13:242-8.
• Cornier Y, Gagnon L, Berube-Genest F, et al. Extrinsic Allergic Alveolitis: the Influence of Cigarette Smoking. Am Rev Respir Dis 1988;137:1104-9.
• Schlesinger C, Koss MN. The Organizing Pneumonias: An Update and Review. Curr Opin Pulm Med 2005;11:422-30.
• Collard HR, Moore BB, Flaherty KR. Acute Exacerbations of Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med 2007;176:636-43.
• Pope-Harman A, Davis W, Allen E, et al. Acute Eosinophilic Pneumonia: A Summary of 15 Cases and Review of the Literature. Medicine 1996;75(6):334-42.
• Frankel SK, Cosgrove GP, Fischer A, et al. Update in the Diagnosis and Management of Pulmonary Vasculitis. Chest 2006;129:452-65.
• Mellor A, Soni N. Fat Embolism. Anaesthesia 2001;56:145-54.
• Revel MP, Triki R, Chatellier G, et al. Is It Possible to Recognize Pulmonary Infarction on Multisection CT Images? Radiology 2007;244:875-82.
• Ference BA, Shannon TM, White RI, et al. Life-Threatening Pulmonary Hemorrhage with Pulmonary Arteriovenous Malformations and Hereditary Hemorrhagic Telangiectasia. Chest 1994;106(5):1387-90.