35  Organizing Pneumonias and Acute Interstitial Pneumonia	617
a	b

Fig. 35.6  Acute brinous and organizing pneumonia in a 68-old woman with symptoms of several months duration and lack of response to empirical antibiotic therapy. (a) Multifocal alveolar opacities with air

Table 35.7  Histopathological features of acute brinous and organizing pneumoniaa

Major features

Organizing intra-alveolar brin “balls” as dominant nding

Organizing pneumonia pattern, less prominent than brin balls

Patchy distribution of lesions

Minor features

Mild to moderate acute and/or chronic interstitial infammation

Alveolar septal expansion by myxoid connective tissue

Type 2 pneumocyte hyperplasia

Interstitial changes co-localized with patchy intra-alveolar brin lesions, with only minimal changes in the intervening parenchyma

Absence of:

hyaline membranes

prominent eosinophilic infammation

prominent neutrophilic infammation or abscesses

granulomatous infammation

a Adapted from reference [56]

and outcome [56]. However, more than half of the patients did not receive corticosteroids, or received them late in the disease course. It therefore cannot be concluded that steroids are not effective in AFOP. Furthermore, signi cant and even dramatic improvement with corticosteroids has been reported by some authors [144]. The usefulness of cyclophosphamide and mycophenolate mofetil in addition to corticosteroids has been occasionally reported [145, 146]. Similarly to classical COP, relapses have been reported in AFOP [144].

Until the clinical signi cance of the AFOP pattern is further clari ed, this histopathological nding should lead the clinician to consider the disease course as potentially more severe and life-threatening than classical OP. Similarly to OP, a cause or associated condition should be looked for in AFOP, and removed whenever possible. Corticosteroids

bronchogram predominant at the lung bases. (b) Surgical lung biopsy showing prominent brin clusters lling alveolar spaces, with a lesser component of broblasts and infammatory cells

seem effective in a number of cases and a steroid trial should be attempted after having ruled out or treated an infectious process.

Granulomatous Organizing Pneumonia

A granulomatous variant of OP has been reported in a retrospective series of histopathological specimens obtained by surgical lung biopsy in patients investigated for thoracic malignancies, and termed “granulomatous OP” (GOP) [147]. It is characterized histologically by non-necrotizing poorly formed granulomas intimately associated with the plugs of granulation tissue of OP, in the absence of any microorganism, which could explain this nding. The clinical picture and chest imaging did not differ signi cantly from other patients presenting with either OP or AFOP at histopathology, except for being less likely to have had cancer and to have received prior chemotherapy, and more frequently presenting as a nodule or mass [147]. The clinical signi cance of GOP remains to be further characterized in other studies.

Acute Interstitial Pneumonia

De nition and Terminology

Acute interstitial pneumonia, formerly known as Hamman– Rich syndrome, de nes an idiopathic form of acute lung injury characterized clinically by acute or subacute respiratory failure, bilateral lung in ltrates at imaging, and DAD at histopathology. By de nition, no cause is identi ed despite comprehensive investigations. This combination of features was rst described in 1935 by Hamman and Rich in four

618	R. Lazor and M.-E. Müller

cases [148] and named consequently Hamman–Rich syndrome. However, this term was later used incorrectly to describe more broadly other forms of subacute and chronic lung brosis, including IPF. Therefore, Katzenstein et al. introduced the term “acute interstitial pneumonia” (AIP) in 1986 to describe the very single acute idiopathic clinico-­ pathological condition recognized by Hamman and Rich [149]. In 1990, Olson et al. con rmed that AIP is identical to Hamman–Rich syndrome [150]. In 2000 and 2002, American Thoracic Society/European Respiratory Society guidelines recognized AIP as a distinct form of idiopathic interstitial pneumonia (IIP) [3, 151]. In a revised version of the guidelines published in 2013, AIP was classi ed among the six major IIP in a subgroup of acute/subacute IIP, together with COP [4].

Epidemiology

Data on AIP are sparse and based on small case series. The disease is found at any age. Patients from 1 to 83 years old have been reported, with a median age between 50 and 60 years. AIP affects equally males and females. No risk factor was identi ed so far and in most cases AIP occurs in previously healthy individuals [149, 152–161].

Clinical Picture

AIP has an acute or subacute presentation, and usually begins as a fu-like syndrome with dry cough, sore throat, myalgia, fatigue, and headache in the rst week of the disease. Fever may sometimes be present. In most cases, severe dyspnea occurs rapidly after the rst symptoms, usually in the rst day to 3 weeks [149, 153], and evolves towards respiratory failure. However, slowly progressive forms over 2 or 3 months have also been reported [153, 159–162]. On physical examination, patients appear ill, with tachycardia, tachypnea, diffuse pulmonary crackles and sometimes wheeze on chest auscultation. Associated signs of extra-pulmonary disease are uncommon and should raise the suspicion of another diagnosis [148, 161]. Digital clubbing, which is not a feature of AIP, is more suggestive of acute exacerbation of a pre-­ existing ILD (AE-ILD) [158]. Virtually all patients develop respiratory failure requiring mechanical ventilation. Only a few patients do not require hospitalization.

Imaging

Chest radiograph usually shows bilateral patchy or diffuse in ltrates. Pleural effusion is uncommon. At HRCT, ground glass attenuation and diffuse airspace consolidation are the

main ndings through the early stages of the disease. Traction bronchiectasis and distortion of bronchovascular bundles appear in the proliferative phase of the disease, and the number of affected lung segments may correlate with disease duration [163]. Honeycombing may also be found at a later stage. However, it is unclear whether its presence is the consequence of DAD or indicates pre-existing ILD undergoing acute exacerbation [152, 163].

Histopathology

Histopathology showing a DAD pattern of unknown cause constitutes a mandatory criterion for a de nite AIP diagnosis. However, in clinical practice, the risks of performing a biopsy may outweigh the bene t in a patient with respiratory failure. After having carefully weighted the risk/bene t ratio, a (transbronchial or surgical) biopsy may be performed in a patient already on mechanical ventilation. In some cases, the histopathological diagnosis is obtained retrospectively at autopsy. If performed, surgical or transbronchial biopsy in AIP may show either one of two disease stages: an exudative stage in the rst week of the disease, followed by an organizing stage. The tissue damage is usually diffuse and has a uniform temporal appearance. The exudative stage is characterized by interstitial and intra-alveolar edema, formation of hyaline membranes (amorphous eosinophilic structures plastered along alveolar septa and composed of necrotic pneumocytes and serum proteins), hyperplasia of type II pneumocytes, intra-alveolar hemorrhage, and a sparse interstitial in ltrate of mononuclear infammatory cells. Alveolar collapse and thrombosis of smallto medium-sized pulmonary arterioles are common ndings. The organizing stage begins one or more weeks following injury and is most prominent after 2 weeks. It shows hyaline membranes resorption by alveolar macrophages, or incorporation in the alveolar septa resulting from type II pneumocytes proliferation on the luminal side of the hyaline membranes. Loose broblastic proliferation occurs in the interstitium, and focally in the alveolar spaces. In the late phase, broblasts proliferation in the interstitium gives an image of interstitial thickening. Infammatory cells, especially neutrophils, are usually scant. Recovery of lung architecture may be complete, or progression towards honeycomb brosis may be observed if the patient survives [3, 149]. Acute and organizing DAD frequently coexist on lung biopsies, as the process is a continuum. Temporally uniform lesions, presence of hyaline membranes, edematous stroma, an important number ofbroblasts and little collagen deposition are distinctive characteristics allowing to differentiate DAD from usual interstitial pneumonia, NSIP or OP pattern [3, 164]. Once DAD has been identi ed, a determined cause must be ruled out before accepting the diagnosis of AIP. To exclude an alternative

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35  Organizing Pneumonias and Acute Interstitial Pneumonia	619

diagnosis, the histology must not show granulomas, necrosis, abscess or infectious agents. Biopsy may allow to identify the cause of DAD, such as pathogens that are not or slowly growing on culture, especially Pneumocystis, cytomegalovirus, mycobacteria, Blastomyces, and Histoplasma [165]. Biopsy culture is also recommended. Infections, drug toxicities, aspiration, and connective tissue diseases are typical causes of DAD [150]. The pneumotox.com website provides a comprehensive and updated list of drugs which can induce DAD. Other causes of DAD are listed in Table 35.8.

Diagnosis

AIP is a diagnosis of exclusion based on the following criteria [3, 149, 165, 168]:

\1.\ rapid onset (<60 days) of respiratory symptoms leading to severe hypoxemia, and in most cases to acute respiratory failure

Table 35.8  Causes of diffuse alveolar damage. From references [12, 165–167]

Aspiration

Acute exacerbation of usual interstitial pneumonia

Connective tissues diseases

Rheumatoid arthritis, Polymyositis/dermatomyositis, Systemic lupus erythematosus, Systemic sclerosis, Mixed connective tissue disease, Sjögren syndrome, Anti-synthetase syndrome

Drugs

Amiodarone, Azathioprine, Bleomycin, Busulfan, Carmustine (BCNU), Cocaine, Cyclophosphamide, Cytosine-arabinoside (Ara-C), Gemcitabine, Gold, Heroin and opiates, Melphalan, Methotrexate, Mitomycin, Nitrofurantoin, Penicillamin, others (see www.pneumotox.com)

Infection

Bacteria

Legionella, Mycoplasma, Rickettsia

Viruses

 infuenza, herpes simplex virus type 1, cytomegalovirus, adenovirus, respiratory syncytial virus, hantavirus, SARS, SARS-CoV-2

Fungi

Histoplasma, Cryptococcus, Pneumocystis

Nontuberculous mycobacteria

Oxygen toxicity

Radiation

Sepsis

Shock

Traumatic, hemorrhagic, neurogenic, cardiogenic

Miscellaneous

Acute pancreatitis, burns, cardiopulmonary bypass, high altitude, intravenous contrast material, leukemic cell lysis, molar pregnancy, near-drowning, peritoneovenous shunt, lymphangiography, toxic shock syndrome, transfusion, uremia, venous air embolism

Unknown cause

Acute interstitial pneumonia (Hamman–Rich syndrome)

\2.\ bilateral lung in ltrates on chest imaging

\3.\ DAD on (anteor postmortem) histopathology

\4.\ absence of any etiology or predisposing factor after thorough investigations looking for infections, connective tissue disease, prior ILD, drugs, or toxic exposures.

Blood neutrophilia is present in many patients but laboratory ndings are not speci c.

A histological evidence of DAD is theoretically needed for the diagnosis of AIP, in contrast to the diagnosis of ARDS. If DAD is demonstrated without identi ed cause despite comprehensive work-up, the condition is diagnosed as AIP. In case of ARDS of undetermined origin without histologic examination, the condition will remain termed ARDS of unknown etiology [165]. Indeed, ARDS is de ned solely on clinical grounds, whereas a diagnosis of AIP requires both clinical and histopathological data. Thus, some cases meeting the clinical de nition of ARDS do not show DAD at histopathology but other features such as infection, OP, or alveolar hemorrhage. Additionally, the de nition of AIP requires that DAD has no identi ed cause, whereas the de - nition of ARDS remains valid regardless of the existence of an underlying cause [165]. AIP and ARDS are therefore not two distinct entities but two different (and overlapping) ways of de ning subsets of patients with acute lung injury. The relationships between AIP and ARDS de nitions are illustrated in Fig. 35.7. However, one could question whether the historical de nition of AIP strictly based on histopathology could be reconsidered, and incorporate a less rigid concept of “working diagnosis” based on a combination of criteria without histopathology, by analogy with other IIP.

Clinically, the differential diagnosis of AIP mainly includes congestive heart failure, infections such as viral or P. jiroveci pneumonia, diffuse alveolar hemorrhage, OP, acute eosinophilic pneumonia, acute hypersensitivity pneumonitis, drug-induced lung disease, toxic exposure, acute/ subacute connective tissue disease-associated ILD occurring in some idiopathic infammatory myopathies, and AE-ILD. A detailed clinical history and systems review is of high importance to identify systemic disease, predisposing drugs or toxic exposures [168]. A thorough clinical examination must also be performed to look for alternative diagnoses.

Lung function tests are rarely performed in AIP, as patients are too ill for such a procedure. If done, they show a restrictive ventilatory pattern with reduced carbon monoxide diffusion capacity.

BAL could be performed to exclude alternative diagnosis, if a spontaneously breathing patient could undergo the procedure without risk of subsequent intubation, or in an already intubated patient. BAL cytology ndings in AIP are not speci c, showing mainly increased neutrophils and sometimes red blood cells and/or hemosiderin. BAL allows the diagnosis of infection or alveolar hemorrhage, which should prompt

620

R. Lazor and M.-E. Müller

ARDS

acute onset

bilateral infiltrates

PaO2/FlO2 ratio ≤

200

CHF excluded

yes

no

DAD ?

lung histology

cause identified ?

available?

yes

no

yes

no

diagnosis:

diagnosis:

diagnosis:

infection, organizing

ARDS due to sepsis,

cause identified ?

ARDS of unknown

pneumonia,

trauma, aspiration,

cause

capillaritis, etc.

etc.

yes

no

diagnosis:

DAD due to infection,

diagnosis:

connective tissue

AIP

disease, drug toxicity,

etc.

Fig. 35.7  Diagnostic relationships between acute respiratory distress syndrome (ARDS), diffuse alveolar damage (DAD), and acute interstitial pneumonia (AIP). Adapted from reference [165]

to look for systemic vasculitis or connective tissue disease. Blood, sputum and BAL fuid should be sent for culture, and serology performed for autoimmune diseases [3, 168].

In the absence of diagnosis after BAL, open lung biopsy is sometimes considered. However, in most cases, the patient’s condition does not allow this invasive procedure. Transbronchial lung biopsy may be an acceptable alternative, as even small tissue specimens can allow con rmation of DAD pattern or give clue to alternative diagnosis [153]. In patients considered too ill for biopsy, empirical management is acceptable (see below).

Since AIP is an idiopathic condition, time between onset of symptoms and diagnosis is usually long because alternative diagnoses must be excluded.

Patients affected with ILD and especially IPF sometimes develop an acute form of their disease resembling AIP but which must be considered as a separate entity named “acute exacerbation of ILD” (AE-ILD), representing an acute-on-­ chronic process, whereas AIP is a purely acute event. In patients known for pre-existing ILD, the diagnosis of AE-ILD is easier than in those in whom the acute episode is the rst manifestation of an underlying but previously unknown ILD, which is discovered only when the superimposed lung injury brings the patient to clinical attention. Clinically, it may be dif cult to differentiate AIP from AE-ILD [165]. HRCT features are also similar, with ground

glass opacities, consolidation, traction bronchiectasis and honeycombing in both cases [163]. Hence, the pathologic specimen is of foremost importance. In chronic interstitialbrosis it demonstrates both acute and chronic lesions, in contrast to AIP which shows a homogeneous temporal injury [158]. As the concept of AE-ILD is more recent than AIP, it is likely that some older reports of AIP with traction bronchiectasis at imaging and UIP associated with DAD at histopathology are more consistent with AE-ILD than AIP [165].

Treatment

Given the rarity of the disorder, no controlled trial is available to guide the management of AIP. Therapeutic measures remain primarily supportive. Most patients require invasive mechanical ventilation with lung-protective settings. Extracorporeal membrane oxygenation (ECMO) may have a rescue role in patients with refractory respiratory failure. ECMO may also allow to minimize ventilator-induced lung injury, and carry out diagnostic procedures [155].

Many patients receive high-dose corticosteroids based on studies showing a lower mortality in ARDS patients receiving such a therapy, but conficting data exist and the role of immunosuppressive treatment in AIP remains debated. The bene t of corticosteroids could depend on the disease stage.

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