Abbreviations

Acute Interstitial Pneumonia (AIP)

Case

A 34-year-old woman with a history of hypothyroidism presents to her primary care doctor with a 1-week history of dry cough and myalgias. She reports a fever with a temperature of 38.4 °C 1 day prior to presentation. On exam she is mildly tachycardic, but she is not tachypneic. Her oxygen saturation is 97% on room air. Her lungs are clear to auscultation bilaterally, and she has no rashes or skin lesions. She is diagnosed with a viral upper respiratory tract infection and sent home with return precautions.

Over the next 3 days her cough persists, and she develops dyspnea with exertion causing her to present to the emergency department. She is more tachycardic and oxygen saturation is now 87% on room air. She has soft, diffuse crackles on exam. A chest radiograph demonstrates hazy opaci cations bilaterally, without focal consolidation (Fig. 34.1). A

P. Ntiamoah · R. Purpura · S. Vehar · C. J. Coley II · J. Hasvold L. A. Schmidt · K. R. Flaherty · L. B. Tolle (*)

Cleveland Clinic Respiratory Institute, Cleveland, OH, USA e-mail: tollel@ccf.org

Fig. 34.1  Chest radiograph from a patient with acute interstitial pneumonia demonstrating diffuse bilateral in ltrates without focal consolidation

pulmonary embolus protocol CT is negative for pulmonary embolus but shows diffuse patchy ground glass opaci cations (GGO) without effusions (Fig. 34.2). She is admitted to the hospital and develops progressive respiratory failure requiring intubation for hypoxic respiratory failure on hospital day 2.

Her labs demonstrate a leukocytosis with a white blood cell count of 14,000 with a differential of 82% neutrophils. Urinalysis shows no evidence of infection, and blood cultures are negative. A transthoracic echocardiogram shows no evidence of increased pulmonary arterial or right ventricular pressure, and no left ventricular dysfunction. She is started on empiric broad spectrum antibiotics, but does not improve by hospital day 4 and subsequently 1 g of methylprednisolone daily is added to her regimen. A lung biopsy is performed on hospital day 6 and reveals diffuse alveolar damage. The nal suspected diagnosis is acute interstitial pneumonia (AIP).

a

b

Fig. 34.2  High-resolution computed tomography images from the upper (panel a) and mid (panel b) lung elds demonstrating diffuse bilateral ground glass opaci cations without consolidation or effusions

History and Defnition

Acute interstitial pneumonia (AIP), also known as Hamman-­ Rich syndrome and rst described in 1935, is an acute and fulminant form of diffuse parenchymal lung disease of unknown etiology [1, 2]. Characteristically it inevitably results in severe hypoxemic respiratory failure requiring mechanical ventilation with an estimated mortality rate greater than 50%. The presentation, both clinically and radiographically, is identical to acute respiratory distress syndrome (ARDS) and may represent a subset of idiopathic ARDS. AIP is one of six categories within the American Thoracic Society (ATS)/European Respiratory Society (ERS) of Idiopathic Interstitial Pneumonias (IIP) major classi cation with the latest update in 2013 [3].

By de nition, AIP is an idiopathic respiratory disease with bilateral in ltrates and histological nding of diffuse alveolar damage (DAD). AIP is a diagnosis of exclusion and must have the proper work up, which is further discussed below [2].

Epidemiology

AIP is a rare lung disease that is likely underdiagnosed or misclassi ed as ARDS. The de nition, which requires a lung biopsy, most likely precludes the diagnosis in most cases. Review of the literature suggests that an individual academic institution may diagnose only a few cases a year [4–6].

AIP generally affects previously healthy male and female patients equally. Most individuals are over the age of 40, but both pediatric and the elderly can be affected [6]. No clear risk factors have been convincingly identi ed in the literature, including tobacco exposure.

Presentation

Patients present within a week of developing a dry cough, dyspnea, and fever. Many mistake the symptoms for a viral upper respiratory tract infection. As the disease progresses, shortness of breath becomes the hallmark feature with room air hypoxemia [2, 5, 6]. Most patients will need non-invasive ventilation or mechanical ventilation (MV) with one case series from Vourlekis et al. noting mean duration of MV of 20 days [6]. Given the relatively nonspeci c historical features, this condition is commonly misdiagnosed early on as pulmonary embolism, infection or congestive heart failure [2, 7].

Physical exam ndings are relatively nonspeci c, including tachypnea and diffuse crackles. Individuals with clubbing of ngers would suggest another chronic process and

unlikely to be AIP [8, 9]. All patients should be examined for joint, muscle or cutaneous abnormalities that might suggest the presence of connective tissue disease.

Virtually all patients with fulminant AIP are too ill to perform pulmonary function testing, which would likely refect a restrictive pattern with reduced DLCO [10]. Unlike ARDS, patients with AIP will not be in profound shock requiring vasopressors, or showing signs of multi-organ failure.

Diagnostic Evaluation

Infectious and cardiac etiologies of respiratory failure must be excluded. Thorough evaluation with microbiological and serological testing evaluating for respiratory viruses, blood cultures, and sputum cultures. Frequently bronchoalveolar lavage (BAL) or mini-BAL is required to exclude atypical infections such as pneumocystis pneumonia (PJP), legionella, mycoplasma, and fungal pneumonias. Typical thoracic imaging studies including chest X-ray and high-resolution computed tomography (HRCT) are appropriate. A transthoracic echocardiogram to evaluate for left ventricular dysfunction and valvular disease, along with troponin and brain natriuretic peptide are crucial. Basic labs like comprehensive metabolic panel and complete blood count with differential to evaluate for another organ damage can help trajectory of clinical course. Most patients will have a leukocytosis at time of presentation [6, 10].

Patients or surrogates require a thorough medical history focused on medications (e.g. chemotherapy, over-the-­counter medications, supplements, and herbals), radiation exposure, social history (e.g. recreational drugs, toxic inhalants or occupational exposures), and any history of connective tissue diseases. A positive rheumatological antibody with the appropriate phenotype might be worrisome for an underlying connective tissue associated-ILD. A positive dsDNA or anti-smith antibody would be consistent with SLE. Positive anti-Scl-70 arises suspicion for systemic sclerosis, whereas a rheumatoid factor or cyclic citrullinated peptide suggests rheumatoid arthritis. Positive anti-Jo antibodies in conjunction with elevated CPK, aldolase and ALT would be consistent with an anti-synthetase syndrome [11].

BAL ndings are indistinguishable from ARDS and typically include increased total cells, red blood cells, hemosiderin, and neutrophils [12]. These ndings while supportive are not diagnostic, and the chief utility of a BAL is to exclude other etiologies of respiratory failure, like diffuse alveolar hemorrhage syndromes or acute eosinophilic pneumonia. A clinical decision to obtain diagnostic tissue via transbronchial, video-assisted thoracoscopic surgery (VATS), and/or open lung biopsy must be weighed carefully. Surgical lung biopsy specimen can aid in diagnosis like granulomatous diseases (sarcoidosis), certain infections or malignancy.

However, these procedures can come with higher risk for mortality with varying degree of alterations in therapeutic plans [13–15].

Radiology

Common ndings on HRCT are similar to ARDS, including diffuse GGO, air-space consolidation, interlobular septal thickening, and traction bronchiectasis. Patients with AIP are more likely to have a distribution of disease that is largely symmetric with a predilection for lower lung elds compared to ARDS [16]. Most patients have involvement that is quite diffuse, involving 45–95% of lung parenchyma [7]. There is some evidence that the presence of traction bronchiectasis may refect brosis and portend a worse outcome [17]. However, this nding could also unveil an acute exacerbation of another interstitial pneumonias like IPF, nonspeci c interstitial pneumonia or connective tissue disease [3, 9].

Histopathology

As mentioned earlier, the histopathologic hallmark of AIP is acute and organized diffuse alveolar damage (DAD). DAD has been described in three different phases: acute exudative, early organizing proliferative, and late proliferative (orbrotic) stage. Organizing proliferative stage is the most common and characterized by thickening of alveolar septa secondary to edema, infammatory cells, and collapse of alveolar septa. Other key features on biopsy include interstitial brosis and the presence of type II pneumocyte hyperplasia [5, 9, 10] (Fig. 34.3).

A key feature that distinguishes AIP from more chronic processes is the presence of extensive broblast proliferation and relative absence or paucity of collagen deposition. The relative uniformity of disease, as referred to “temporally uniform lesion,” suggest a single insult in time compared to a chronic interstitial pneumonia that refects multiple insults with varying degrees of infammation and brosis [5, 9, 10].

Given the diffuse nature of the disease, however, AIP is one of the few interstitial pneumonias in which transbronchial biopsy can be helpful as even small transbronchial specimens may be suf cient to capture the pathologic characteristics [10]. Many diagnoses are made on autopsy [17].

Clinical Course

Onset of symptoms prior to rapid deterioration is somewhat variable, but patients typically have vague symptoms for 1–2 weeks before progressing to a critically ill state requir-

Fig. 34.3  At low power (panel a), acute interstitial pneumonia is characterized by diffuse interstitial thickening with associated alveolar septal collapse. At higher magni cation (panel b), subepithelial proliferations of broblasts and myo broblasts in a myxoid collagen

background are common (arrowhead) and residual hyaline membranes are usually not prominent. Squamous metaplasia (arrow), although a nonspeci c nding, is common in acute interstitial pneumonia

ing hospitalization in an intensive care unit. Many become ventilator dependent secondary to refractory hypoxemia. The mortality rate is greater than 50%, and average time to death is approximately 2 weeks [2, 4–8]. The minority of patients who survive AIP generally do well in the absence of other comorbidities. In addition, there have been some reports of recurrent AIP, but most patients go on to develop variable degrees of interstitial brosis or airway scarring [6, 7].

Treatment

Initial treatment is both empiric and supportive with supplemental oxygen and prevention of other complications like ventilator associated pneumonia or venous thromboembolism. All patients should receive lung-protective ventilation, as this is appropriate for most diagnoses on the differential. Broad spectrum antimicrobial coverage is appropriate until infection is satisfyingly excluded.

Once the diagnosis is established, however, there is unfortunately insuf cient data for any evidence-based therapy. In addition to lung-protective ventilation strategies, many clinicians trial a course of corticosteroids. Some experts have suggested methylprednisolone 1 g/day IV for 3 days followed by 1 mg/kg/day IV or oral prednisolone for 4 weeks with subsequent tapering. Most observational trials had less than 30 patients total and with varying amounts of corticosteroids [2, 5–7]. There is limited evidence that patients who receive steroid therapy during the acute, exudative phase of their disease fare better than those whose lung biopsies already demonstrated proliferation and architectural distortion [7]. Alternative immunosuppressive treatments have

been reported in case reports with limited success [18]. Lung transplantation has also been reported in only a few case reports to date [6, 19].

Smoking-Related Idiopathic Interstitial

Pneumonias: Respiratory Bronchiolitis

Interstitial Lung Disease (RB-ILD)/

Desquamative Interstitial Pneumonia (DIP)

Case

A 38-year-old man presents to his primary care clinic complaining of a persistent dry cough for approximately 1 year. He complains of mild dyspnea on exertion that does not limit any of his activities. In addition, he denies any fevers or chills and has not been exposed to any sick contacts. The patient is a current smoker of 1.5 packs per day and has been doing so for 21 years. On exam, his vital signs are normal, and he is not hypoxic. He has diffuse bilateral dry crackles but the rest of his physical exam is entirely normal. His primary care physician orders a chest X-ray that shows upper lung predominant reticulonodular opacities. At this point the patient is referred to a pulmonologist who performs pulmonary function testing. A mild obstructive defect is seen with normal lung volumes and a decreased DLCO. A HRCT is performed and shows patchy GGO and centrilobular nodularity. Due to his persistent symptoms and abnormal imaging the patient undergoes a bronchoscopy with BAL and transbronchial biopsies. BAL cultures are unremarkable and cell count shows a normal differential. Biopsies reveal clusters of pigmented macrophages with associated brous scarring extending into the alveolar wall. A diagnosis of RB-ILD is made.