Fig. 22.1
Diffuse ground glass opacities in diffuse alveolar hemorrhage, confirmed by BAL. BAL bronchoalveolar lavage
b.
Pulmonary function tests (PFTs) show increased DLCO; however, often these patients cannot participate in such testing.
c.
Bronchoscopy with BAL is the confirmatory diagnostic method. BAL shows progressive bloody return. Cytology with Prussian blue staining should show > 20 % hemosiderin-laden macrophages. This test is limited if alveolar hemorrhage occurred < 48–72 h before the procedure, as duration of time may be too short for red blood cells (RBC) phagocytosis by pulmonary macrophages.
4.
Pathogenesis of DAH
There is no clear etiology for DAH post-HSCT. The development of DAH around the engraftment period suggests an inflammatory cascade involving the alveoli. Pre-HSCT conditioning regimens (including total body irradiation (TBI)) may initiate the inflammatory process.
5.
Management
Patients with suspected DAH should be transferred to the medical intensive care unit, given that respiratory failure may develop rapidly. Some patients require high-flow oxygen and subsequent mechanical ventilation for acute respiratory distress syndrome (ARDS). Supportive management and high-dose systemic steroids are the key elements of DAH treatment.
a.
Mechanical ventilation should be tailored to each individual, reflecting the ARDS mechanical ventilation protocol/low tidal volume for management of acute lung injury. This practice has not been validated in DAH, but the pathological pattern of DAH is similar to acute lung injury/ARDS. Similarly, prone positioning may be of benefit in refractory cases.
b.
Immunosuppressive therapy with high-dose corticosteroids is the mainstay of therapy based on case reports and retrospective series. Doses of up to 1 g of methylprednisolone daily divided into 2–4 doses should be given daily for 3–5 days, followed by a slow taper over 1–3 months. Alternate dosing schedules have been suggested, beginning at 2 mg/kg daily in divided doses, tapering over a 2-month period.
c.
Correction of underlying coagulopathy by maintaining platelet count > 50,000/mm3 and INR < 2.
d.
BAL to rule out a concomitant infectious pathogen.
e.
Recombinant factor VIIa (NovoSeven®) has been used; however, no benefit has been demonstrated.
f.
Aminocaproic acid (Amicar®) has been used less frequently with limited supporting data.
22.4 Idiopathic Pneumonia Syndrome
IPS is severe lung injury that develops after allogeneic HSCT with no evidence of an infectious process. The incidence ranges between 2 and 35 % with mortality rates ranging from 60 to 80 %. More recent studies report a lower incidence likely reflecting improved diagnosis of viral infections with newer PCR tests. If mechanical ventilation becomes necessary, mortality approaches 95 %. IPS typically occurs within the first 2 months post-HSCT. However, delayed onset has been reported.
Delayed pulmonary toxicity syndrome (DPTS) is considered distinct from IPS per the American Thoracic Society official statement due to its relationship with a specific conditioning regimen. DPTS occurs in up to 64 % in patients who receive a conditioning regimen containing bis-chloroethylnitrosourea (BCNU), cyclophosphamide, and cisplatin.
1.
Risk factors
a.
Grade 3–4 aGVHD
b.
Donor cytomegalovirus (CMV) positivity
c.
Conditioning regimens containing TBI
d.
Older age
e.
Certain malignancies (acute leukemia, myelodysplastic syndrome)
f.
Drug toxicity has been implicated; however, there is no method to discriminate between drug-induced lung damage and IPS.
2.
Clinical findings
Findings are indistinguishable from pneumonia which include fever, cough usually productive of scant or no phlegm, shortness of breath, and hypoxia.
3.
Diagnostic tests
All patients with suspected IPS should undergo chest imaging and bronchoscopy with BAL to rule out infection. Occasionally, chest X-ray does not show obvious infiltrates and CT scan of the chest is warranted. The criteria for diagnosis of IPS proposed by the National Heart Lung and Blood Institute in 1993 include:
a.
Radiologic imaging evidence of multilobar diffuse alveolar infiltrates.
b.
Hypoxia or elevated alveolar–arterial gradient.
c.
Negative BAL for blood and cultures for bacterial, fungal, and viral pathogens.
d.
Negative infectious studies from the blood, specifically for CMV.
4.
Pathogenesis of IPS
Evaluation of BAL fluid from IPS patients shows elevated inflammatory cytokine markers compared to negative or healthy controls. IPS is likely a complex cytotoxic and immune-mediated attack of the lung.
5.
Management
a.
Corticosteroids should be started early in the disease course. Historically, patients who developed IPS around engraftment responded better to steroids. A reasonable starting dose is 2 mg/kg daily of methylprednisolone (or equivalent) for the first week followed by a slow taper over the course of 2–3 months.
b.
PCP and fungal prophylaxis are recommended.
c.
Etanercept (Enbrel®) 25 mg SQ twice weekly for 8 weeks has been used in conjunction with corticosteroids; however in small case series, no additional benefit was seen when compared with placebo.
22.5 Bronchiolitis Obliterans Syndrome
The most common late pulmonary complication following allogeneic HSCT is BOS . The reported incidence varies from 2 to 6 % with estimate as high as 20 %. However, recent studies suggest the incidence is more prevalent than previously reported. The median time to onset is 1 year post-HSCT. However, the onset varies from 3 months to > 10 years post-HSCT. BOS is rarely reported after autologous HSCT or umbilical cord blood HSCT. Most investigators consider BOS to be GVHD of the lung. It is also important to recognize BOS as a separate clinical entity from cryptogenic organizing pneumonia (COP) .
1.
Risk factors reported by the Center for International Blood and Marrow Transplant Research (CIBMTR) include:
a.
Blood-derived stem cells
b.
Busulfan-based conditioning regimen
c.
Degree of human leukocyte antigen (HLA) mismatch
d.
Presence of gastroesophageal reflux
e.
Prior interstitial pneumonitis
f.
An episode of grade 3–4 aGVHD
Additional risk factors include:
a.
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