Non-infectious complications after bone marrow transplant: pulmonary complications
What every physician needs to know about non-infectious complications after bone marrow transplant: pulmonary complications:
Non-infectious pulmonary complications after allogeneic hematopoietic cell transplantation are common but their differential diagnoses are difficult. The purpose of this chapter is to enable the right diagnosis to be made, by providing timings and other specific characteristics of these complications. It also discusses how to manage these complications.
Non-infectious pulmonary complications can occur early or late after hematopoietic stem cell transplantation (HCT) (Table I).
Pulmonary complications after bone marrow transplant (BMT) may include:
- Idiopathic pneumonia syndrome (IPS)
- Diffuse alveolar hemorrhage (DAH)
- Bronchiolitis obliterans (BO)
- Bronchiolitis obliterans with organizing pneumonia also known as cryptogeneic organising pneumonia (BOOP)
- Less commonly, periengraftment syndrome (PES),veno-occlusive disease (VOD) of the lung, pulmonary cytolytic thrombi (PCT) etcetera
Differential diagnosis might be difficult and require lung biopsy (Table II).
Respiratory symptoms or hypoxemia
Definitions and incidence
IPS is a clinical syndrome of different etiologies, defined as presence of widespread alveolar injury with increases A-a gradient in the absence of active lower respiratory tract infection or heart failure. Its pathogenesis is not very clear. The incidence of IPS in the first 4 months is around 10%, ranging from 3 to 35% post-alloHCT and around 6% post-autoHCT. Its response to treatment is poor.
- Non-infectious DAH
Non-infectious DAH is a clinical syndrome of acute onset of progressive dyspnea, cough, hypoxemia, without hemoptysis and fever associated with pulmonary infiltrates and progressively bloodier aliquots of bronchoalveolar lavage (BAL) fluid. The incidence of DAH is approximately 5 to 10% and 2 to 5% in alloHCT and autoHCT, respectively.
BO is a nonspecific inflammatory injury affecting small airways and can be considered a pulmonary manifestation of chronic graft-versus-host disease (GVHD). The incidence of BO varies between 6 to 20%, but the lack of definitive diagnostic criteria confound precise iestimates.
BOOP is characterized by intra-alveolar fibrosis, resulting from organization of inflammatory exudates and favorable response to steroid therapy. Its incidence has been reported as 1 to 10% post alloHCT.
PES is a clinical proposed syndrome characterized by erythrodermatous skin rash, noninfectious, and noncardiogenetic pulmonary infiltrates, fever, diarrhea at the time neutrophil engraftment.
PCT is an exclusive complication of alloHCT, which occurs in the setting of GVHD. PCT characterized by occlusive vascular lesions and hemorrhagic infarcts due to thrombi that consist of intensely basophilic, amorphous material. The onset of PCT is at a median of 72 days (ranging 8 to 343 days) post alloHCT. Symptoms include cough, chest pain, and fever.
VOD of the lung is a rare complication and is characterized by increased pulmonary vascular resistance (that is, elevated capillary and arterial pressures), which may lead to right ventricular failure. Increased pulmonary vascular pressure occurs, caused by the intimal proliferation and fibrosis of the pulmonary venules and small veins.
Older age, pretransplant chemotherapy, methotrexate for GVHD prophylaxis, lower performance status at transplantation, transplantation for a malignant disease, high-intensity conditioning regimens (for example, bis-chloroethylnitrosourea or higher total body irradiation [TBI] dose rate greater than 6cGy/min), severe acute GVHD, Cytomegalovirus [CMV] seropositivity). Reduced intensity conditioning (RIC) may be associated with less IPS.
Age greater than 40 years, TBI, transplantation for solid tumors, use of allogeneic donor source, GVHD and the presence of high fevers, severe mucositis, leukocyte recovery, and renal insufficiency. Using RIC does not decrease the risk for DAH.
Myeloablative condtioning, peripheral blood stem cells grafts, older recipients (greater than 20 years), FEV1 (forced expiratory volume in 1 second):FVC (forced vital capacity) ratio less than 0.7 before transplantation, respiratory viral infection in first 100 days posttransplant, busulfan based conditioning, acute GVHD, chronic GVHD (cGVHD) (particularly progressive onset cGVHD), low surfactant protein D levels, and genetic factors (such as nulceotide-binding oligomerization domain-containing protein [2NOD2]/caspase recruitment domain-containing protein [15CARD15] polymorphism.
HLA-B35 is suggested as a risk factor for the development of BOOP. T-cell depletion may have protective effect.
What features of the presentation will guide me toward possible causes and next treatment steps:
Dyspnea, cough, hemopthysis, wheezing, hypoxemia, fever, and syncope are more common symtoms and signs, which would be useful in differential diagnosis (Table I).
What laboratory studies should you order to help make the diagnosis and how should you interpret the results?
Radiology: Chest X-ray, computed tomography (CT) scan of the lung with inspiratory/expiratory views if obstructive syndromes and air trapping are possible), plus bronchoscopy and bronchoalveolar lavage are the most important tools in the differential diagnosis (Table I, Table II).
Pulmonary function tests, catheterization for pulmonary vascular pressure, and transbronchial or video-assisted thoracic (VAT) lung biopsy may be needed (Table I, Table II).
Radiologic studies reveal bilateral interstitial infiltrates.
The most common CT findings are bilateral areas of ground-glass attenuation or consolidation involving middle and lower lung zones. Lung infiltrates usually start centrally.
Radiologic exams are normal or notable for hyperinflation. Pneumothorax, pneumomediastinum, and pneumopericardium may be detected in advanced patients. High resolution CT of the chest is most sensitive imaging (demonstrating air trapping or small airway thickening or bronchiectasis in inspiratory and expiratory phases).
- VOD of the lung
High resolution CT is important and reveals septal lines, ground-glass opacities and lymph node enlargement.
Chest radiographic findings mimic (for example, multiple nodules, mostly peripheral) invasive fungal infections. Interstitial prominence and atelectasis can be detected as well.
Associated blood tests
CBC, prothrombin time (PT)/partial thromboplastin time (PTT), fibrinogen, D-dimer might be useful to diagnose coagulopathy, infection, and pulmonary embolism. Serum immunoglobulin G (IgG) level can be obtained to find out if intravenous immunoglobulin (IVIG) replacement is needed.
What conditions can underlie non-infectious complications after bone marrow transplant: pulmonary complications:
Thrombocytopenia may increase risks for DAH
Rule out infections through respiratory cultures as well as blood CMV PCR (Cytomegaloviruspolymerase chain reaction), blood cultures, serum or BAL galactomannan ELISA (enzyme-linked immunosorbent assay) Enzyme-linked immunosorbent assay .
Table I and Table II show how to interpret BAL results.
– Not specific, mainly to rule out infections.
– Although BAL is diagnostic with bloody return, if it is performed a few days later, it may be misleading with non-bloody return. In cases with delayed BAL beyond 48 to 72 hours, the presence of greater than 20% hemosiderin-laden macrophages in BAL fluid can be useful, but non-diagnostic.
BAL may show neutrophilic inflammation.
- VOD of the lung
Occult alveolar hemorrhage.
Non specific, mainly to rule out infections.
Viruses such as CMV, respiratory syncytial virus (RSV), parainfluenza virus, fungi including aspergillosis (order galactomannan in BAL as it may be more sensitive than blood), and bacterial infections.
When do you need to get more aggressive tests:
The most invasive test for differential diagnosis in non-infectious complication of lung is video-assisted thoracoscopic surgery (VATS) or open lung biopsy. Its indication and interpretation are shown in Table I and Table II.
Two main patterns are diffuse alveolar damage with hyaline membranes and interstitial pneumonitis.
Lung biopsy shows diffuse alveolar damage with alveolar hemorrhage and pulmonary capillaritis with interstitial neutrophilic predominance. To diagnose DAH, more than 30% of the alveolar surface of the examined lung tissue covered by blood is required, but this syndrome is better diagnosed by BAL than by biopsy.
Lung infiltrates are usually not seen with BO so lung biopsy is not required for diagnosis; however, in a patient with cGVHD and pulmonary infiltrates, a lung biopsy is sometimes helpful in order to exclude BOOP. However VATS surgical biopsy may be more informative than transbronscopic biopsy because of its patchy involvement. Histological exam reveals intraluminal dense fibrosis and thus narrowing or obliteration. No mononuclear cell infiltration in interstitial or alveolar tissue is seen.
Lung injury is predominant in small conducting airways. The injury is repaired by proliferation of granulation tissue. Intra-alveolar inflammation and organisation (intra-alveolar buds with prominent capillarisation) may also be present. Fibrinoid inflammatory cell clusters at beginning of the process will be followed by formation of fibroinflammatory buds, and lastly by mature fibrotic buds (inflammatory cells will disappear).
- VOD of the lung
Lung biopsies are informative (intimal proliferation and fibrosis of the pulmonary venules and small veins) but not recommended because of serious complications.
Transbronchial biopsies are often nondiagnostic, but surgical biopsies reveal occlusive vascular lesions and hemorrhagic infarcts due to thrombi that consist of intensely basophilic, amorphous material.
Other useful tests
Pulmonary Function Testing
Obstructive pattern is common (for example, decreased forced expiratory volume in one second [FEV1] less than 75% of predicted normal, and FVC ratio less than 0.7. Residual volume is increased (greater than 120% of predicted).
Pulmonary function tests show reduced diffusion capacity and reduced lung volume while expiratory flow is normal in majority of patients.
Right-sided cardiac catheterization
- VOD of the lung
VOD of the lung confirms pulmonary hypertension (a mean PAP [pulmonary artery pressure] greater than 25mmHg at rest) with normal pulmonary capillary wedge pressure (PCWP) (that is, PCWP is less than 15mmHg). Although the anatomic obstruction affects mainly the postcapillary system, right heart catheterization gives a pattern of precapillary pulmonary arterial hypertension.
What imaging studies (if any) will be helpful?
CT of the chest should be used in differential diagnosis as mentioned above (Table I and Table II).
What therapies should you initiate immediately and under what circumstances – even if root cause is unidentified?
There is no established treatment and the effect of steroids is controversial. However, most patients are treated with steroid 2mg/kg daily. Early initiation of etanercept may be of added value.
Treatment is mainly composed of ventilatory support and correction of coagulopathy. Although high dose corticosteroids (500 to 1000mg per day of methylprednisolone for 3 to 4 days, followed by taper over 2 to 4 weeks) have been used widely, the clinical evidence is from case series, rather than from large prospective studies. Recombinant factor VIIa, aminocaproic acid, cytokine antagonists, and extracorporeal membrane oxygenation (ECMO) support have been studied, without any consensus as to their value.
Treatment is generally unsuccessful because of irreversible fibrosis. However, systemic corticosteroids and other immunosuppressive drugs are administered in a similar way to aggressive cGVHD treatment. In case series, extracorporeal photodynamic (ECP) therapy have been associated with clinical improvements. High dose inhaled steroids can be useful.
Macrolide antibiotics can be used for the prevention of opportunistic infections. Antimicrobial (macrolide antibiotics) and other standard antimicrobials, vaccinations, and correction of macroglobulinemia are important for prevention of opportunistic infections. Lung transplantation has been tried in a few patients. A case report showed imatinib used for chronic myeloid leukemia coincidentally showed improvement in BO.
Discontinuation of G-CSF, plus steroids are effective in most patients.
- VOD of the lung
Treatment includes general measures for management of pulmonary arterial hypertension such as oxygen, diuretics, calcium channel blockers, warfarin and specific agents like prostanoids, endothelin antagonists, phosphodiesterase type-5 (for example, sildenafil).
Systemic steroids (1mg/kg/day for 1 to 3 months, and then tapered off 6 to 9 months) are standard therapy for BOOP. Most patients (up to 80%) can respond to steroids.
What other therapies are helpful for reducing complications?
General measurements to prevent infectious complications, including vaccinations against Influenza, Streptococcus pneumonia, might be critical to prevent further lung damage in these patients.
What should you tell the patient and the family about prognosis?
Prognosis is poor in untreated patients (approximately 75% of patients will die in a short-term and 15% will have 1 year survival. Etanercept, a soluble tumor necrosis factor (TNF) receptor inhibitor, with or without steroids, has resulted in encouraging results.
Mortality rate can be as high as 70%, although some studies shows better survival (40 to 60%).
Patients with BO have significantly shorter survival. In almost 1,800 alloHCT patients, 5 year survival was only 10%, versus 40% in the patients with no BO.
- VOD of the lung
Without treatment, most patients die in 2 years.
Treatment consists of increasing immunosuppressive therapy. It does not increase mortality, but may be associated with lower relapse rates.
Up to 80% of patients respond to steroids.
“What if” scenarios.
Radiation (TBI) induced lung damage, cytokines like TNF-alpha, and T cell mediated lung injury appear to be important in pathogenesis
It is not well known, but DAH most likely results from a complex interaction of a variety of factors, including diffuse alveolar damage caused by radiation/chemotherapy or occult infection. Inflammatory damage due to neutrophils and cytokines regarding DAH occurs during the peri-engraftment period.
The key mechanism seems to be donor T-lymphocytes that target the epithelial cells of the bronchioles, thus lead to the inflammatory reaction and peribronchiolar fibrosis.
Proinflammatory cytokines, granulocyte colony-stimulating factor (G-CSF) administration, neutrophil influx, and capillary leakage may play a role in the pathogenesis of PES.
Patients with a diagnosis of leukemia and receiving radiation therapy in conditioning regimen have higher risk of developing BOOP. Moreover, acute and chronic GVHD association with BOOP and increased lymphocyte content (in particular CD8+ cells) in BAL, suggest T-cell mediated immune mediated reactions in the pathogenesis of BOOP.
What other clinical manifestations may help me to diagnose non-infectious complications after bone marrow transplant: pulmonary complications?
In differential diagnosis, consider the following factors as well:
- Timing of complication (for example, around engraftment consider DAH or PES) (Table I)
- The presence of other complications such as acute or chronic GVHD can support diagnosis (for example BO and cGVHD)
- Whether patients are on active antimicrobial prevention or not
- Whether there is coexistence infection such as CMV
- Type of transplantation (allo HCT versus autoHCT)
- Conditioning regimens (RIC or myeloblative, TBI-based or not)
What other additional laboratory studies may be ordered?
What’s the evidence?
Clark, JG, Hansen, JA, Hertz, MI, Parkman, R, Jensen, L, Peavy, HH. “NHLBI workshop summary. Idiopathic pneumonia syndrome after bone marrow transplantation”. Am Rev Respir Dis. vol. 147. 1993. pp. 1601-1606. [A work-shop defines IP.]
Cordier, JF. “Cryptogenic organising pneumonia”. Eur Respir J. vol. 28. 2006. pp. 422-446. [A good review on BOOP.]
Castellano-Sanchez, AA, Poppiti, RJ. “Pulmonary cytolytic thrombi (PCT). A previously unrecognized complication of bone marrow transplantation (BMT)”. Am J Surg Pathol. vol. 25. 2001. pp. 829-831. [Describes PCT.]
Spitzer, TR. “Engraftment syndrome following hematopoietic stem cell transplantation”. Bone Marrow Transplant. vol. 27. 2001. pp. 893-898. [Describes PES.]
Capizzi, SA, Kumar, S, Huneke, NE. “Peri-engraftment respiratory distress syndrome during autologous hematopoietic stem cell transplantation”. Bone Marrow Transplantation. vol. 27. 2001. pp. 1299-1303. [Describes PES.]
Montani, D, Achouh, L, Sitbon, O, Simonneau, G, Humbert, M. “Pulmonary venoocclusive disease and failure of specific therapy”. Chest. vol. 136. 2009. pp. 1181-1182. [Describes VOD of the lung.]
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. [Reviews posttransplant lung complications.]
Marasco, WJ, Fishman, EK, Kuhlman, JE, Hruban, RH. “Acute pulmonary hemorrhage. CT evaluation”. Clin Imaging. vol. 17. 1993. pp. 77-80. [Describes CT findings of DAH.]
Yousem, SA. “The histological spectrum of pulmonary graft-versus-host disease in bone marrow transplant recipients”. Hum Pathol. vol. 26. 1995. pp. 668-675. [Describes histologic changes in lung of GVHD.]
Colby, TV, Roychowdhury, M, Pambuccian, SE, Aslan, DL. “Pulmonary complications after bone marrow transplantation: an autopsy study from a large transplantation center”. Arch Pathol Lab Med. vol. 129. 2005. pp. 366-371 . [Describes histopathologic findings of lung complications after transplantation.]
Afessa, B, Tefferi, A, Litzow, MR, Peters, SG. “Outcome of diffuse alveolar hemorrhage in hematopoietic stem cell transplant recipients”. Am J Respir Crit Care Med. vol. 166. 2002. pp. 1364-1368. [Describes relatively good outcome in DAH.]
Sohl, M, Arat, M, Cao, Q, Majhail, NS, Weisdorf, D. “Late-onset noninfectious pulmonary complications in adult allogeneic hematopoietic cell transplant recipients”. Transplantation. vol. 91. 2011. pp. 798-803. [Describes late-onset complications of alloHCT in the pulmonary system.]
Clark, JG, Crawford, SW, Madtes, DK, Sullivan, KM. “Obstructive lung disease after allogeneic marrow transplantation. Clinical presentation and course”. Ann Intern Med. vol. 111. 1989. pp. 368-376. [Describes posttransplant lung complications in particular IPS.]
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- Non-infectious complications after bone marrow transplant: pulmonary complications
- What every physician needs to know about non-infectious complications after bone marrow transplant: pulmonary complications:
- What features of the presentation will guide me toward possible causes and next treatment steps:
- What laboratory studies should you order to help make the diagnosis and how should you interpret the results?
- What conditions can underlie non-infectious complications after bone marrow transplant: pulmonary complications:
- When do you need to get more aggressive tests:
- What imaging studies (if any) will be helpful?
- What therapies should you initiate immediately and under what circumstances – even if root cause is unidentified?
- What other therapies are helpful for reducing complications?
- What should you tell the patient and the family about prognosis?
- “What if” scenarios.
- What other clinical manifestations may help me to diagnose non-infectious complications after bone marrow transplant: pulmonary complications?
- What other additional laboratory studies may be ordered?