Pathology of Acute Interstitial Pneumonia

Acute interstitial pneumonia (AIP) is an idiopathic interstitial lung disease that is clinically characterized by sudden onset of dyspnea and rapid development of respiratory failure. ^{[1, 2]}  AIP is histologically characterized by diffuse alveolar damage with subsequent fibrosis. ^{[2, 3, 4]}  The definition of AIP excludes patients with acute respiratory distress syndrome (ARDS) attributable to an identifiable cause, as well as patients with underlying fibrotic lung disease or systemic disorders known to be associated with lung involvement such as connective tissue disease. ^{[1, 2]}

Most affected patients are adults, but AIP has been reported in a wide age range of patients, including children as young as 7 and in patients over 80 years old, with a mean age at diagnosis of 54 years old. ^[5] No gender preference exists.

In comparison, the overall US incidence of idiopathic pulmonary fibrosis (IPF)  is an estimated 6.8-16.3 per 100,000 person-years, with an increased incidence with advancing age. ^[1]

By definition, the diagnosis of AIP assumes the absence of a specific etiologic agent or inciting event.

Acute interstitial pneumonia involves the alveolated lung parenchyma in a bilateral, generally symmetric and diffuse fashion. ^[1]

Most patients describe a upper respiratory infection/viral-like prodrome and a nonproductive cough. A bimodal distribution appears to exist, with about 50% of patients presenting with symptoms of dyspnea within the first week of symptoms and others presenting after at least a month and up to 60 days from the onset of symptoms. ^[5] With rare exception, patients progress rapidly from shortness of breath to hypoxemic respiratory failure that requires prolonged mechanical ventilation.

Physical examination and laboratory findings are nonspecific. In the early course of the disease, attention is focused on excluding known causes of acute lung injury by history, physical examination, and ancillary studies. The radiographic findings associated with AIP, both in the early and late phase of the disease, overlap with those of ARDS. As in ARDS, the earliest phase begins with a subtle increase in interstitial markings with rapid development of a diffuse alveolar pattern. HRCT scans show bilateral and symmetric, diffuse ground glass and alveolar consolidation opacities. Traction bronchiectasis and bronchiolectasis appear as the disease progresses.

Honeycomb fibrosis may be seen in the later phase of the disease. It has been reported that patients with AIP tend to have a more symmetrical and lower zone distribution of abnormalities as well as more honeycombing than patients with ARDS. ^[6] Differences in AIP survivors and nonsurvivors have also been reported, with the former group having more ground-glass opacification and less traction deformity of the airways. ^[7] Honeycomb change is not present early in the course of AIP, and its identification on HRCT should prompt consideration of pre-existing fibrotic lung disease.

The gross appearance is identical to other patients who die with ARDS and the gross findings correlate with the stage of diffuse alveolar damage. In the early phase, the lungs are firm, heavy, and have a homogeneous dark red (“beefy”) appearance. In later phases, the lungs are extremely heavy with irregular areas of dense consolidation and fibrosis. Cobblestoning of the pleural surface, associated with progressive fibrosis, may exist. Extensive peripheral cyst formation consistent with honeycombing should suggest the possibility of underlying chronic fibrotic lung disease.

Transbronchial biopsy may be attempted in the early course of the disease, primarily to exclude other etiologies such as infection. Surgical lung biopsy is performed for similar reasons when the patient is stable enough. The time at which the biopsy is obtained is quite variable but typically occurs after at least 1-2 weeks following the onset of respiratory failure and often after other etiologies have been considered. ^[2]  

Biopsy findings from patients with idiopathic interstitial pneumonia may vary on the basis of when the biopsies are performed relative to the onset of acute injury. ^{[1, 2]} The initial stages show diffuse alveolar damage, usually in the proliferative or organizing phase, although hyaline membrane remnants can be seen. ^{[8, 9]}  The interstitial fibrosis is diffuse, temporally uniform and characterized by extensive fibroblastic and myofibroblastic proliferation with relatively little collagen deposition. The prominence and the uniformity of the fibroblastic/myofibroblastic proliferation distinguishes AIP from the other types of idiopathic interstitial pneumonia.

In addition to the spindle cell proliferation that thickens and distorts the alveolar septa, intraluminal polypoid plugs indistinguishable from organizing pneumonia may also be present. ^[9] As in other cases of diffuse alveolar damage, regardless of etiology, prominent type II pneumocyte hyperplasia with cytologic atypia and bronchiolar squamous metaplasia is present.

Organizing thrombi involving small and medium-sized arteries are often present and help to support the diagnosis of acute lung injury. Biopsies that are taken later in the course of the disease show enlarged and remodeled airspaces that resemble the honeycomb change of UIP, but fibroblastic proliferation, along with collagen deposition, should still be conspicuous within the walls of the air spaces. As with other interstitial lung diseases, the diagnosis of AIP should be rendered within the specific context of a detailed clinical evaluation and with radiographic correlation.

In the intervening years since AIP’s formal description in 1986, little progress has been made in the understanding of the disease. Currently, no specific or proven effective treatments for AIP exist, management is largely supportive, and multidisciplinary team involvement is best for optimal therapy. ^[1] Broad-spectrum antibiotics, antiviral agents, and high-dose steroids are often administered on an empiric basis. Specific clinical features that would predict survival have not been clearly identified. Similarly, histologic features predictive of survival have not been identified. ^[10]

Although relative differences in the radiographic features of patients with AIP and ARDS and AIP survivors versus nonsurvivors have been reported, these findings are difficult to extrapolate to prognosis for an individual patient. Survival data are limited and likely subject to some study bias, but the acute case fatality ratio is estimated to be 50% or more. ^{[5, 11]} Most deaths occur within 1-3 months of diagnosis; whereas median survival for IPF patients is about 2-5 years from the time of diagnosis. ^[1] Of those patients who survive, some return to their baseline respiratory function, but a significant proportion will exhibit some degree of functional respiratory impairment. Recurrent episodes of AIP have also been described.

In a retrospective study (2000-2012) with 203 of 1625 patients (12.5%) who underwent resection of primary lung cancer and were found to idiopathic interstitial pneumonia, multivariate analyses revealed the following as significant radiologic predictors of 90-day mortality ^[12] :

• Preoperative pO ₂ below 70 mm Hg
• Diffuse distribution and central extension of interstitial pneumonia on CT scan
• Operative blood loss

The differential diagnosis of AIP is broad and includes all of the known causes of acute lung injury. In addition, the presentation of a patient with AIP may overlap with the clinical presentation of patients with underlying fibrotic disease who present with an acute exacerbation. Other than manifest clues in the clinical history and appropriate ancillary studies to exclude such etiologies as infection, acute hypersensitivity pneumonitis, connective tissue disease, drug toxicity, aspiration, inhalants/toxins, and nonpulmonary disorders such as pancreatitis, no specific way exists to distinguish AIP from known causes of acute lung injury.

Radiographic review may be helpful in identifying underlying fibrotic lung disease, but, otherwise, the radiographic findings are not robust enough to exclude other etiologies of acute lung injury. The pathologic evaluation of open biopsies is similarly challenging and may be limited by sampling error or difficulties in histologic interpretation. In some instances, the findings of diffuse alveolar damage obscure the underlying pattern of fibrotic lung disease and only honeycomb change is recognizable. ^{[3, 13]} In this situation, the possibility of accelerated injury in a patient with unrecognized UIP or another type of fibrotic lung disease should be suggested in addition to AIP. As previously mentioned in the gross appearance section, autopsy specimens of patients with purported AIP should be carefully evaluated and sectioned to exclude underlying chronic fibrotic interstitial lung disease.