Idiopathic pneumonia syndrome (IPS)
Diffuse alveolar hemorrhage, peri-engraftment respiratory distress syndrome (PERDS)
1. Description of the problem
Interstitial Pneumonitis (IP) is a relatively common (5-15%) complication occurring early after allogeneic hematopoietic cell transplant (HCT) and is characterized by widespread alveolar injury in the absence of lower respiratory tract infection or fluid overload. Symptomatic IP is associated with a very high mortality rate.
Patients present non-specifically with dyspnea, cough, fever and hypoxemia. Chest radiographs or CT usually show patchy or diffuse mixed interstitial / alveolar infiltrates. There is a wide clinical spectrum ranging from asymptomatic radiographic changes to acute respiratory failure.
The median time of onset is 15-65 days after transplant.
The diagnostic criteria are outlined below, but in brief, patients with IP present with signs and symptoms consistent with pneumonia, but have no evidence of infection upon intensive investigation, and are not fluid overloaded.
Appropriate management mandates prompt diagnostic evaluation as soon as adequate ventilatory support has been provided. The chief aim of aggressive investigation is the timely exclusion of infective and other causes of this presentation, as IP is treated with immunosuppression. In practice, patients with suspected IP are initially treated with both immunosuppression and antimicrobial therapy.
2. Emergency Management
1. Supportive care – IP can rapidly progress to respiratory failure
careful fluid balance including continuous veno-venous hemofiltration if required
empiric and prophylactic (while on high-dose steroids) antimicrobials
High-dose intravenous methylprednisolone
The dose of corticosteroids is not well defined. One approach is to use 1-2 mg/kg/day. Another approach is higher doses at 1 gm/d of methylprednisolone for 3 days followed by a rapid taper to 1 mg/kg. Steroids can then be tapered over a 2- to 3-month period.
3. TNFα blockade
Etanercept (Enbrel) 0.4 mg/kg (max 25mg) subcutaneously twice weekly for a maximum of 8 doses has shown some success.
The 1993 National Heart Lung and Blood Institute consensus workshop defined IP syndrome as progressive respiratory failure with multi-lobar pulmonary infiltrates on chest radiography or computed tomography which are determined to be non-infectious and non-cardiogenic in nature. IP syndrome typically occurs within 100 days of HSCT and is associated with high mortality rates ranging between 50-80%.
Therefore, IP is essentially a diagnosis of exclusion and as such, the following tests are useful:
1. Radiology – multilobar infiltrates
2. Blood tests – exclusion of bacterial, fungal or viral causes of pneumonia
3. Broncho-alveolar lavage (BAL) – BAL is often useful to exclude other causes of pneumonia. BAL does not provide information about interstitial fungi, vascular damage or histopathological structure. BAL specimens should be submitted for staining, culture or special tests to exclude bacterial, fungal and viral infection. Increasingly bloody sequential BAL returns are consistent with diffuse alveolar hemorrhage rather than IP. The minority (13%) of BAL specimens collected from patients within the first 30 days after HCT show microbiological positivity, rising to 30% from days 30-100. Hence, patients requiring BAL for the investigation of respiratory complications early after HCT are most likely to have a non-infectious etiology. It should be noted that many patients are too unstable to undergo BAL without subsequent intubation, and thus IP syndrome is often treated without BAL confirmation/exclusion.
4. Transbronchial lung biopsy should be performed if the patient’s condition permits, and should demonstrate the absence of infective agents but is otherwise non-specific, showing diffuse alveolar damage, pneumonic changes and an interstitial lymphocytic infiltrate.
The current diagnostic approaches for IP are:
1. Widespread alveolar injury
symptoms and signs consistent with pneumonia
multilobar infiltrates on chest radiograph or CT
abnormal pulmonary physiology (e.g., restrictive defects on lung function tests; increased A-a gradient)
2. Absence of lower respiratory tract infection
infection excluded after aggressive investigation (broncho-alveolar lavage; transbronchial lung biopsy may be performed if safe)
investigations to exclude infection should be repeated within two weeks
3. Absence of renal dysfunction, cardiac dysfunction , or iatrogenic fluid overload.
How do I know this is what the patient has?
The patient has widespread alveolar injury with hypoxia, multi-lobar infiltrates and no evidence for other causes of lung damage such as infection, heart failure, pulmonary embolus, etc.
IP is a diagnosis of exclusion but is suggested by the presence of contributory factors in the proper clinical setting:
1. Patient characteristics: older patients with poor pre-transplant respiratory function are at increased risk.
2. Transplant characteristics: allogeneic, rather than autologous HCT; patients undergoing myeloablative HCT (especially where conditioning includes TBI)
3. Post-transplant course: Presentation within 25-65 days of HCT, and often (but not always) in association with acute GVHD
1. Lung injury secondary to the conditioning chemo- or radiation regimen (prior radiation, chemo especially carmustine) tends to occur within the first 3 months post-HCT, is associated with restrictive pulmonary function tests and rapidly progressive bilateral interstitial infiltrates.
2. Infection – Any infection after allogeneic SCT can present with hypoxia and multi-lobar infiltrates. Bacterial and fungal infections should be ruled out and treated empircally. Viral pneumonia is often more difficult to diagnose. CMV, HHV6, parainfluenza, RSV, adenovirus are the most common causes; these should be excluded with appropriate microbiological investigation, although this may not be available at presentation.
3. Pulmonary edema (cardiogenic vs. noncardiogenic)
4. Diffuse alveolar hemorrhage; high-resolution CT scan may show bilateral ground-glass opacities but is non-specific; hemoptysis is uncommon. This diagnosis is often confirmed on BAL.
5. Peri-engraftment respiratory distress syndrome (PERDS) – IP is often diagnosed at around the same time or within a few days of engraftment; PERDS has a better prognosis than IP.
6. Bronchiolitis obliterans organizing pneumonia (BOOP) – tends to occur later than IP, from 2-12 months post transplant.
7. Obliterative bronchiolitis (OB) tends to occur later (after day 100), is characterized by the absence of fever, and the presence of mostly obstructive signs and lung function tests. CT scan shows bronchiectasis, centrilobular nodules, septal lines, and ground-glass opacities.
8. Transfusion-associated lung injury (TRALI) – occurs rapidly (within 6-8 hours) of the infusion of plasma-containing products and has an acute onset.
There are no specific confirmatory tests. There are a number of exclusionary tests as noted above. They include blood and sputum cultures, viral PCR testing, echocardiogram or other testing to rule out heart failure, testing to rule out pulmonary embolus if suspected.
4. Specific Treatment
Standard first-line therapy is intravenous high-dose methylprednisone and aggressive supportive care..
Due to the high mortality associated with IP / IP syndrome, some limited data support the use of the TNFα inhibitor etanercept with first-line therapy.
There are no routine second-line approaches.
Drugs and dosages
1. Methylprednisone: Between 1mg/kg IV daily for 7 days and 1 gm daily for 3 days (followed by a rapid taper to 1 mg/kg; a suggested schedule is to taper 50% every 3 days until dose is 1 mg/kg. Thereafter taper as possible over 1-3 months. Doses higher than 2 mg/kg/day have not necessarly been shown to be more effiacious.
2. When used, etanercept is given 0.4 mg/kg sq twice a week (max 25 mg/dose, for up to 8 injections). This recommendation is based on small case series; the results of randomized trials are awaited.
Most patients who respond to steroids +/- etanercept do so within 7 days. There is no standard therapy for the treatment of patients failing to respond to first-line steroids and TNFα blockade.
5. Disease monitoring, follow-up and disposition
Expected response to treatment
Based on case series of patients treated with steroids in conjunction with TNFα blockade, there appears to be a high early response rate, with a substantial percentage of patients managing to wean off respiratory support. However, long-term survival in patients diagnosed with IP / IP syndrome is still poor even after successful early therapy of IP.
Clinical follow-up and periodic radiographs are necessary. Eventually monitoring with PFTs for long-term follow-up may be useful.
Repeat evaluations for infectious causes of respiratory failure may turn positive during treatment. These need to be managed on their merits, as it is difficult to differentiate a supervening infection occurring during the course of appropriate therapy for IP from the late diagnosis of an underlying infection that was responsible for this presentation.
Patients recovering from IP continue to have a high risk of mortality, with the causes of death including respiratory complications as well as GVHD, infection, and relapse of the underlying malignancy. Patients will be followed up by their treating physician according to standard guidelines for HCT.
IP likely results from a variety of lung insults, which include the effects of high-dose chemotherapy or radiation (employed prior to HCT as well as those used in the conditioning regimen), inflammatory cytokines, donor cell-mediated immunity (although IP is not typically thought of as pulmonary GVHD), and possibly undiagnosed viral infection.
Using mouse models of IP, it has been shown that there are at least two mechanisms of lung injury in IP. Both donor antigen-specific T cells and soluble cytokines (including but not limited to TNF-alpha, which is derived from the donor and in particular donor T cells) contribute to inflammation, the upregulation of chemokine and chemokine receptors, and further recruitment of immune cells. Experimental IP syndrome is also associated with pulmonary vascular endothelial cell apoptosis.
Factors contributing to the development of IP include use of high-dose chemotherapy (especially high doses of cyclophosphamide or busulfan) or total body irradiation (TBI). Myeloablative conditioning regimens containing TBI lead to an increased risk (up to 10-fold, especially for those patients older than 40). Other risk factors include severe GVHD, donor CMV positivity, and possibly underlying disease of AML or MDS.
Historically, patients diagnosed with IP / IP syndrome have a 75% mortality within 30 days, or higher (95%) if they require mechanical ventilation. The main cause of death in these patients is progressive respiratory failure. Additional prognostic indicators include the need for mechanical ventilation, renal insufficiency, and early (within 3 days of the diagnosis of IP) requirement for vasopressor therapy.
It is important to note that these relatively large studies of the natural history were performed before the routine use of TNF inhibitors. 30-day mortality seems to be improved in limited single-institution phase II studies using steroids plus etanercept, but long-term survival still remains poor.
Special considerations for nursing and allied health professionals.
What's the evidence?
Description of the problem:
Clark, JG, Hansen, JA, Hertz, MI. “NHLBI workshop summary: idiopathic pneumonia syndrome after bone marrow transplantation”. Am Rev Respir Dis.. vol. 147. 1993. pp. 1601-1606. The diagnostic criteria are based on this workshop summary
Panoskaltsis-Mortari, A, Griese, M, Madtes, DK. “An official American Thoracic Society research statement: Noninfectious lung injury after hematopoietic stem cell transplantation: Idiopathic pneumonia syndrome”. Am J Respir Crit Care Med. vol. 183. 2011. pp. 1262Revised diagnostic criteria and a summary review of preclinical and clinical research.
Yanik, GA, Ho, VT, Levine, JE. “The impact of soluble tumor necrosis factor receptor etanercept on the treatment of idiopathic pneumonia syndrome after allogeneic hematopoietic stem cell transplantation”. Blood. vol. 112. 2008. pp. 3073-3081. Pivotal if small-scale study showing that TNF blockade can lead to rapid responses in patients requiring ventilatory support.
Tizon, R, Frey, N, Heitjan, DF, See-Tan, K, Goldstein, SC. “High-dose corticosteroids with or without etanercept for the treatment of idiopathic pneumonia syndrome after allogeneic stem cell transplantation”. A retrospective comparison from a single institution of high-dose corticosteroids vs. corticosteroids plus etanercept showing significant improvement in response rates, ICU and hospital discharges, and overall survival.
Fukuda, T, Hackman, RC, Guthrie, KA. “Risks and outcomes of idiopathic pneumonia syndrome after nonmyeloablative and conventional conditioning for allogeneic hematopoietic stem cell transplantation”. Blood. vol. 102. 2003. pp. 2777-2785.
Afessa, B, Litzow, MR, Tefferi, A. “Bronchiolitis obliterans and other late onset non-infectious pulmonary complications in hematopoietic stem cell transplantation”. Bone Marrow Transplant. vol. 28. 2001. pp. 425-434. Review summarizing 12 studies comprising 4496 HCT patients.
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- 1. Description of the problem
- 2. Emergency Management
- 3. Diagnosis
- 4. Specific Treatment
- 5. Disease monitoring, follow-up and disposition
- Special considerations for nursing and allied health professionals.
- What's the evidence?