Fig. 34.8  Chest radiograph from a patient with nonspeci c interstitial pneumonia showing bilateral interstitial in ltrates

ences in prognosis and treatment options between NSIP and UIP, a surgical lung biopsy should be performed to when HRCT suggests NSIP. In fact, this is the only way a de nitive diagnosis of NSIP can be made [53].

Histopathology

Bronchoscopy, while useful to rule out infection or other interstitial lung diseases, cannot make a speci c diagnosis of NSIP. When evaluated, broncho-alveolar lavage (BAL) ndings in NSIP often demonstrate increased lymphocyte counts and a reduced CD4:CD8 ratio (cellular NSIP), although some patients present with increased neutrophils and eosinophils ( brosing NSIP) [59, 60].

A surgical lung biopsy via VATS or thoracotomy is required to make a de nitive diagnosis of NSIP. The role of transbronchial cryobiopsy is not well de ned. Traditional transbronchial forceps lung biopsies have been reported to have a low diagnostic yield. Ideally, biopsy samples should be obtained from more than one lobe. The histopathology of NSIP is characterized by varied degrees of alveolar wall infammation andbrosis in a pattern that suggests temporal homogeneity, nottting the patterns of other IIPs [1, 61] (Fig. 34.10).

Temporal homogeneity is the major feature which distinguishes NSIP from UIP, the histologic pattern for IPF. There are three subgroups into which patients with NSIP are further classi ed. Group I has interstitial infammation as the primary nding (cellular NSIP). Group II has both infammation and brosis. Group III has brosis as the primary

a

b

Fig. 34.9  High-resolution computed tomography from the mid (panel a) and lower (panel b) lung elds of patient with nonspeci c interstitial pneumonia. The images demonstrate patchy areas of ground glass opaci cation, reticular thickening, and traction bronchiectasis. Some subpleural sparing of disease can be appreciated. Honeycombing is absent

nding ( brotic NSIP). This third group is differentiated from UIP by the absence of broblast foci and the presence of temporal homogeneity [47]. In clinical practice most pathologists simplify the division into two groups (cellular or brotic NSIP). Even expert pathologists have dif culty distinguishing between NSIP and UIP on a particular biopsy specimen [62, 63]. Further complicating this process, both

a

b

Fig. 34.10  At low power (panel a), brosing nonspeci c interstitial pneumonia demonstrates prominent, uniform septal thickening by mature collagen. At higher power (panel b), the septal thickening is due mainly to thick collagen with minimal infammation

NSIP and UIP patterns can be found in the same individual when biopsies are taken from multiple locations in 13%– 26% of patients [64, 65]. Those with discordant biopsy results have a prognosis similar to UIP, and should be considered to have UIP in all lobes (Fig. 34.9).

Clinical Course

Patients with NSIP tend to have a better prognosis and response to treatment compared to those with UIP/IPF [59, 61, 66]. This difference persists after adjusting for age, gender, smoking history, and physiologic variables. 5- and 10-year survival has been estimated as 43% and 15%, respectively, among patients with UIP, compared to approximately 90% 5-year survival and 30% 10-year survival rates among patients with NSIP with the brotic component [49]. Survival is the better in patients with a purely cellular pat-

tern, indicating that prognosis is determined by the degree of brosis [30, 31] That said, not all patients respond to therapy and progressive disease clearly occurs in some patients. The prognosis also depends on the presence of associated diseases and exposures and the ability to treat and mitigate these factors.

Treatment

Generally, the treatment and prognosis of NSIP vary signi - cantly and rely on the identi cation and management of associated conditions or environment/occupational, and drug exposures [67–69].

For SSc-ILD, which is commonly associated with NSIP pattern, studies have favored the use of mycophenolate mofetil over the use of cyclophosphamide due to similar ef - cacy with a more tolerable side effect pro le [70]. Other CTDs that may manifest ILD features include Sjogren’s syndrome, rheumatoid arthritis, systemic lupus erythematosus, mixed connective tissue disease, and infammatory myositis. There are no guidelines or consensus on the treatment of ILD associated with those CTDs due to lack of controlled trials. However, corticosteroid is often the rst-line medication, while immunosuppressants such as azathioprine, cyclophosphamide, mycophenolate mofetil, or calcineurin inhibitors are considered as adjunctive, in steroid refractory cases, or in cases where corticosteroid is intolerable due to complications [71–73].

With regard to idiopathic NSIP, asymptomatic patients with mild disease may be followed without treatment [74]. However, for those with progressive disease or moderate to severe disease, corticosteroid treatment seems to be bene - cial in stabilizing pulmonary function [75, 76]. The optimal dose and duration of glucocorticoid therapy is not known, however, a starting dose of 1 mg/kg ideal body weight per day (maximum 60 mg/day) for 1 month followed by 40 mg/ day for an additional 2 months is recommended based on a compilation of studies [47, 54, 59, 61, 76].

Prednisone should be tapered to a goal of 5–10 mg daily to every other day in responders. After 12 months of treatment, practitioners can attempt to discontinue prednisone therapy. As prednisone is tapered or discontinued, some patients can experience clinical deterioration [66]; consideration of a longer prednisone course or steroid-sparing agents such as cyclophosphamide, azathioprine, or mycophenolate is appropriate in these cases. Combination therapy has also been shown by Kondoh et al. [65] to be effective in improving vital capacity percent predicted (VC % pred) in patients with idiopathic NSIP compared to IPF. Subjects in this study received methylprednisolone 1000 mg per day for 3 days weekly for 4 weeks, followed by combination therapy for 1 year with cyclophosphamide (1–2 mg/kg/day) plus low

dose prednisolone 20 mg every other day [65]. After pulse therapy, 33% of patients with NSIP had improved VC % pred versus 15% with IPF [65]. After 1 year of combination therapy, 66% of patients with NSIP had improved versus 15% of the IPF group [65].

Cyclophosphamide has also been used as a sole agent with either known or suspected NSIP. Despite having severe, progressive disease, patients receiving IV cyclophosphamide had stable lung function at 6 months. The generally accepted dose of cyclophosphamide is 1–2 mg/kg/day orally, with a maximum dose of 200 mg or 750 mg/m2 body surface area.

When azathioprine is utilized, dosing is usually started at 50 mg daily, increased in 25–50 mg increments every 14 days to a dosage of 1–2 mg/kg/day (maximum dose of 150 mg daily) as long as blood counts and hepatic function are not impacted. Prior to initiation of this therapy, it is possible to evaluate patients for abnormal thiopurine methyltransferase (TPMT) enzymatic levels. If the TPMT level is low, a lower dose of azathioprine or an alternative immunosuppressive agent could be utilized.

For subset of patients with either idiopathic or secondary NSIP who suffer from progression regardless of aforementioned treatment, anti brotic agents may be an option. Nintedanib and pirfenidone are the two anti brotic agents available in the market which have successfully delayed the progression and suppressed acute exacerbation of idiopathic pulmonary brosis [77, 78]. Studies continue to explore the ef cacy and safety of anti brotic treatment in brotic NSIP due to multiple etiologies. Unfortunately, the trials have been limited or discontinued due to slow recruitment although some limited data suggested adding pirfenidone may slow the decline in FVC and thus disease progression [79].

In patients with severe, progressive NSIP or disease that is refractory to immunosuppressive therapy, lung transplantation can be considered [80]. Usually, patients should be referred for transplantation when the life-expectancy of the patient is between 24 and 36 months, however, poor quality of life can also be taken into consideration.

Unclassifable Interstitial Pneumonia

Even with multidisciplinary discussions at top institutions there are cases that remain unclassi able and now fall into its own category of IIP since the 2013 ATS/ERS update [3]. The ATS/ERS statement on the diagnosis and classi cation of idiopathic interstitial pneumonias lists the following areas that commonly lead to this situation including.

\1.\ Inadequate clinical, radiographic, or pathologic data.

\2.\ Major discordance between clinical, radiologic, and pathologic ndings in the following situations.

\(a)\ Previous therapy resulting in substantial alteration of radiologic of histologic ndings.

\(b)\ New entity, or unusual variant of recognized entity, not adequately characterized by the current classi cation.

\(c)\ Multiple HRCT and/or pathologic patterns that may be encountered in patients with IIP (2).

When these situations arise, the recommendation is to decide on treatment based on the most probable diagnosis. A 2012 retrospective series suggested that this situation may occur in approximately 10% of cases [69]. The main reasons for unclassi able ILD diagnosis were too old or frail for lung biopsy (52%), conficting data (18%), or mild/stable disease (9%). Patients with unclassi able disease had a better prognosis compared to IPF (HR 0.62, p = 0.04), but a similar survival to other non-IPF controls (HR 1.54, p = 0.12) [69].

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