Hypersensitivity pneumonitis (HP), also known as extrinsic allergic alveolitis, is a syndrome that results from repeated inhalation and subsequent sensitization to a wide variety of airborne organic particles. The presentation and clinical course are highly variable and depend from intensity and duration of exposure to the antigen and the nature of the antigen and specific factors of the host, such as an individual predisposition probably genetically determined (Spagnolo et al. 2015). According to data from registries of interstitial lung diseases (ILDs) in three European countries, HP accounts for 4–15 % of all ILD cases (Thomeer et al. 2001). However, the incidence and prevalence of HP are difficult to estimate with precision, mainly because of the number of cases that are misdiagnosed or not recognized and a lack of uniform diagnostic criteria.

The disease is diagnosed on the basis of a history of exposure to an offending antigen with onset of compatible clinical, HRCT, or physiological findings within 4–12 h. Other diagnostic criteria include clinical improvement after removal from exposure and recurrence on reexposure. In cases where the inciting antigen cannot be identified or in the presence of conflicting clinical, radiological, and functional findings, fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial lung biopsy are indicated. Surgical lung biopsy is only required if these prove inconclusive (Elicker et al. 2016).

HP comes from an immune-mediated inflammatory process involving the lung parenchyma (terminal bronchioles, alveoli, and interstitium), based on mechanisms likely independent from single causative agent, mediated by immune complexes in the acute phases of the disease and an altered response of T lymphocytes in the early stages subacute and chronic (Vogelmeier et al. 1993; Barrera et al. 2008). HP seems that cigarette smoking can play a protective effect by reducing the intensity of hyperimmune response. The immune pathogenesis, not yet fully clarified, is linked to hyperactivity of T cells and the action of immune complexes.

In every living environment, antigens potentially causative of the disease may be present. The reported culprits have included microbes, animal and plant proteins, and low-molecular-weight chemicals that combine with host proteins to form haptens. HP-inducing antigens may be classified in broad categories represented by disease prototypes (Table 2) (Hanak et al. 2007; Spagnolo et al. 2015; Selman 2011). In the table is a selected list of the possible innumerable agents and disease.

HP has been conventionally classified as acute, subacute, and chronic (Richerson et al. 1989), although a significant overlap exists and there are no widely accepted criteria to distinguish the various forms. In this regard, (Selman et al. 2012) proposed an alternative classification scheme based primarily on disease behavior, distinguishing between acute nonprogressive and intermittent disease, acute progressive/subacute disease, chronic nonprogressive disease, and chronic progressive disease. Which pattern of illness occurs presumably depends upon the intensity and duration of contact, the nature of the antigen, and host factors.

Acute HP is characterized by an influenza-like syndrome occurring a few hours after a substantial exposure. Symptoms gradually decrease over hours/days but often recur with reexposure. Acute episodes can be indistinguishable from an acute respiratory infection caused by viral or mycoplasmal agents. Attacks often follow exposure to the allergen within enclosed spaces with poor ventilation. Patients typically have a restrictive ventilatory defect with reduced DLCO or, in rare cases, an obstructive pattern. Mild hypoxemia at rest is common. In general, the acute form is nonprogressive and intermittent, with spontaneous improvement after antigen avoidance (Selman et al. 2012).

The differential diagnosis with other disorders manifesting with acute/subacute diffuse GGO e.g., opportunistic infections, pulmonary edema, and cellular nonspecific interstitial pneumonia (NSIP) may be difficult. However in HP the frequent association of lobular air trapping and centrilobular snowflake nodules is crucial for the diagnosis.

The so-called head-cheese pattern may also be observed in respiratory bronchiolitis-associated ILD (RB-ILD). Integrating nicotine poisoning and laboratory findings may indicate the most likely diagnosis (Chong et al. 2014).

GGO combined with cysts resemble those seen in lymphocytic interstitial pneumonia (LIP). However, LIP is often associated with other conditions, such as connective tissue diseases or lymphatic disorders (e.g., human immunodeficiency virus infection, lymphoma) (Ichikawa et al. 1994).

Patients with acute/subacute HP, if correctly and timely diagnosed and treated, generally have an excellent prognosis. The most important recommended therapy is inhibiting exposure to the causal agent by eliminating it from the environment, avoiding settings where it is present, or using a respirator in those settings. Systemic corticosteroids for a few days to weeks may improve symptoms. Indications for the use of such drugs include acute, severe, or progressive disease (Kokkarinen et al. 1992).

Acute respiratory distress syndrome (ARDS) is a condition characterized by sudden onset of severe hypoxemia and diffuse pulmonary infiltrates.

The syndrome was firstly introduced by Ashbaugh and colleagues in 1967 (Ashbaugh et al. 1967), while the criteria for the diagnosis of ARDS were first established in 1994 by the American-European Consensus Conference (AECC) (Bernard et al. 1994).

In 2012 the “Berlin definition,” the new updated consensus definition of ARDS, has been published in a high-impact journal. ARDS is defined as: “[…] type of acute diffuse, inflammatory lung injury, leading to increased pulmonary vascular permeability, increased lung weight, and loss of aerated lung tissue. The clinical hallmarks are hypoxemia and bilateral radiographic opacities […]” (ARDS Definition Task Force 2012).

ARDS may follow several different types of lung injury that ultimately determine the same monomorphic pulmonary response, characterized histopathologically by the presence of diffuse alveolar damage (DAD).

There are many triggering events that have been classically classified as pulmonary or extrapulmonary. Pulmonary or direct injuries are processes determining direct injury to lungs, like infection, gastric aspiration, or toxic inhalation. Extrapulmonary or indirect injuries may be systemic processes like polytrauma, drug toxicity, sepsis, transfusions, or extra-thoracic diseases like acute pancreatitis.

From a histopathologic point of view, “diffuse” refers to the involvement of the whole alveolar structure: endothelium, basal membrane, and epithelium. The process is widespread throughout the lungs, but not always in a homogeneous manner: frequently there is presence of spared areas (Kligerman et al. 2013).

The process is characterized by a sequence of phases. Not necessarily the process develops through all the phases: it can stop and reverse anytime (Castro 2006).

The early or exudative phase lasts up to 7 days and is characterized by the presence of hyaline membranes. The alveolar epithelium is damaged and the basal membrane is exposed.

The next stage is the organizing, or proliferative, phase, characterized by the presence of organizing tissue and fibrosis. If this phase does not resolve favorably, there is progression to the last phase, the fibrotic phase.

The pattern of fibrosis is atypical and usually with predilection of the anterior segments (anti-gravitational distribution). Some patients may show areas of “honeycombing,” more frequently encountered following acute interstitial pneumonia (AIP), which is the “idiopathic” form ARDS (Tomiyama et al. 2001).

The term ARDS should not be confused with the term permeability edema and it is not interchangeable with the term noncardiogenic edema. ARDS is the most severe form of permeability edema, but there are other forms of permeability edema without DAD (Ketai and Godwin 1998). Classification of pulmonary edema is discussed in the “Acute pulmonary edema” section.

ARDS, which is a life-threatening condition, is associated histopathologically to DAD.

In the AECC definition, ARDS was defined as an acute onset of hypoxemia, without specifying a timeframe to define acute; the PaO₂/FiO₂ (ratio of partial pressure of arterial oxygen to fraction of inspired oxygen) must be under <200 mmHg, with presence of bilateral infiltrates on frontal chest X-ray. Presence of left atrial hypertension must be ruled out. PaO₂/FiO₂ between 200 and 300 is termed acute lung injury (ALI).

When idiopathic, the process is termed acute interstitial pneumonia (AIP), also known as Hamman-Rich syndrome (Kliegerman et al. 2013). AIP may sometimes present with a more subacute course, and as a result, it does not always fulfill the criteria of ARDS (Janz et al. 2000).

The new definition of Berlin introduces several important changes to the old criteria (ARDS Definition Task Force 2012). The timeframe for define acute onset is specified within a week from a determinate event. A minimum level of positive end-expiratory pressure (PEEP) is established to evaluate the severity of the respiratory failure. The need to measure pulmonary wedge pressure is removed and the term ALI is suppressed. ARDS is now classified in three grades: mild (200< PaO₂/FiO₂ <300 with PEEP or C-PAP >5 cm H₂O), moderate (100< PaO₂/FiO₂ <200 with PEEP >5 cm H₂O), and severe (PaO₂/FiO₂ <100 with PEEP >5 cmH₂O). Finally, it is stated that the pathologic correlate of ARDS is DAD.

A set of training radiograph is attached to improve interobserver reliability (Ferguson et al. 2012). Opacities seen on CT scan may substitute chest X-ray evaluation for the diagnosis of diffuse pulmonary infiltrates (Table 3).

Historically, the radiographic differentiation of hydrostatic and permeability edema has always been a big radiological challenge (Milne et al. 1985; Aberle et al. 1988).

Criteria for the radiographic differentiation of permeability edema from hydrostatic pulmonary edema (HPE) have been discussed in the acute pulmonary edema paragraph. Although there are several signs that can help the diagnosis, the distinction is frequently impossible. Moreover, chest radiograph interpretation shows poor interobserver reliability (Rubenfeld et al. 1999; Meade et al. 2000).

Likely HRCT may improve the diagnostic accuracy, but at present there is a scarcity of literature in regard. HRCT findings that suggest presence of HPE are perihilar and upper lobar distribution of GGOs, central predominant distribution of consolidations, dilatation of the pulmonary veins and of the superior cava vein, thickening of the bronchial walls (peribronchovascular thickening), and right pleural effusion. Even distribution of the GGOs and of the consolidations is found more often in ARDS. Gravity-dependent opacities, septal pattern, air bronchograms, and traction bronchiectasis did not show significant difference in prevalence between HPE and ARDS (Komiya et al. 2013).

This difficulty in the differential diagnosis of the nature of the edema is implicitly recognized by the definition of Berlin. In the Berlin definition, a differential diagnosis between cardiogenic and noncardiogenic edema on chest radiograph is not required, nor it is considered relevant: it is now recognized that hydrostatic edema and ARDS may coexist. The diagnosis of ARDS requires that the respiratory failure is not fully explained by cardiac failure, or fluid overload, using all available data (Ferguson et al. 2012). Therefore, radiologically, the focus is on the generic diagnosis of bilateral edema that must not be confused with pleural effusions, lobar/lung collapse, or nodules/masses. In fact, HPE is not the only condition with which the ARDS goes in differential diagnosis: bioptic and autoptic studies have demonstrated only moderate agreement between the clinical diagnosis of ARDS and presence of DAD. Specificity of the various criteria for presence of DAD is variable in literature, but always quite poor (Lorente et al. 2015).

There is no pathognomonic laboratory test or radiological sign to establish the diagnosis of ARDS, which is generally clinical. Apart from HPE, the most common conditions that share a similar clinical presentation are atelectasis, pneumonia, and pulmonary embolism (Murray 1975). In reality there are many more and encountered less frequently: miliary tuberculosis, CMV pneumonia, invasive aspergillosis, hantavirus pneumonia, herpes simplex pneumonia, bronchoalveolar cell carcinoma, drug toxicity, lymphangitis, acute leukemia, lymphoma, veno-occlusive disease, sickle lung, acute eosinophilic pneumonia, acute cryptogenic organizing pneumonia (COP), acute fibrinous organizing pneumonia (AFOP), diffuse alveolar hemorrhage, and acute hypersensitivity pneumonia (Dakin and Griffiths 2002; Schwarz and Albert 2004).

Some of the abovementioned conditions may show peculiar HRCT findings (many are discussed elsewhere in this book). For example, presence of subpleural peripheral distribution of the consolidations is suggestive of acute eosinophilic pneumonia, while peribronchial distribution is suggestive of COP or AFOP (Obadina et al. 2013).

Most of those mimickers (or imitators) of ARDS require a different and specific therapy. Therefore, when performing a HRCT examination in patients with clinical diagnosis of ARDS, maximum attention is required to highlight any sign, or pattern, that may suggest an alternative diagnosis to the complex ARDS/DAD.

No pharmacologic therapy has proved effective in the prevention or management of ARDS.

The only specific therapy for ARDS is ventilation (noninvasive or mechanical) using low tidal volumes (lung-protective strategy), to improve blood oxygen levels, and providing supportive care.

Great deal of attention must be placed to not miss a treatable cause of ARDS and to early diagnose the complications (barotrauma, ventilator-associated pneumonia, and fluid overload, among others).

Diffuse alveolar hemorrhage (DAH) is not a specific disorder, but a syndrome that suggests a differential diagnosis and a specific sequence of testing. DAH may be a life-threatening condition characterized clinically by the presence of hemoptysis, falling hematocrit, diffuse pulmonary infiltrates, and hypoxemic respiratory failure, which can be severe. However, chest radiographic and CT findings may be nonspecific (the alveolar infiltrates can even sometimes be unilateral), and hemoptysis may be lacking. DAH should be considered a medical emergency due to the morbidity and mortality associated with failure to treat the disorder promptly (Collard and Schwarz 2004; Lara and Schwarz 2010).

The diagnosis of diffuse alveolar hemorrhage is made on the basis of the clinical and radiological pattern and may be confirmed by bronchoalveolar lavage (BAL). In acute and severe forms, the BAL findings include bright red blood from multiple sites in different bronchi and, microscopically, hemosiderin-laden macrophages. BAL is also useful for excluding other differential diagnoses, such as infections or other endobronchial sources of bleeding (Park 2013). Once the diagnosis is established, the underlying cause must be established in order to initiate treatment.

DAH is a life-threatening condition which refers to hemorrhage originating in the pulmonary microvasculature, rather than from the bronchial circulation or parenchymal abnormalities. All causes of DAH have the common denominator of an injury to the alveolar microcirculation. Pulmonary small vessel vasculitides, connective tissue disorders, and drugs make up the majority of the cases of DAH (Table 4).

DAH includes diseases associated with pulmonary capillaritis (cellular infiltrate of neutrophils in the capillaries and venules) and those associated with normal vessels (Colby et al. 2001). A pulmonary capillaritis is considered the most common underlying lesion associated with diffuse alveolar hemorrhage.

The cardinal sign of DAH, hemoptysis, may be a dramatic event or evolve over days to weeks; however, it may be initially absent in up to 33 % of DAH cases. The other symptoms of DAH are nonspecific and include fever, cough, and dyspnea. Nonpulmonary signs and symptoms are those that accompany the underlying systemic disease. A possible association of hematuria and renal failure due to concomitant glomerulonephritis may be present (Dalpiaz et al. 2003).

The causes of diffuse alveolar hemorrhage are many, but the association with primary renal involvement (pulmonary-renal syndrome) reduces the range of diagnostic possibilities to a handful of diseases: Goodpasture’s syndrome, systemic lupus erythematosus (SLE), ANCA-associated vasculitis (antineutrophil cytoplasmic antibodies), particularly micropolyangiitis (MPA), granulomatosis with polyangiitis (Wegener granulomatosis), and, more rarely, eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (Jennette 2013; Chung et al. 2010; Marten et al. 2005; Mayberry et al. 2000). Knowledge of the patient’s clinical data and laboratory tests may be sufficient to guide toward the possible cause of this group of patients (Table 5).