Oncology

Non-infectious complications after bone marrow transplant: pulmonary complications

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:

Summary

Non-infectious pulmonary complications after allogeneic hematopoietic cell transplantation are common but their differential diagnoses can be difficult. The purpose of this chapter is to enable the right diagnosis to be made by providing specifics on clinical presentation radiologic findings, diagnostic work-up, and other specific characteristics of these complications. Discussion on the management of these complications is also included.

Non-infectious pulmonary complications can occur early or late after hematopoietic stem cell transplantation (HCT) (Table I).

Table I

Differences between pulmonary complications of hematopoietic stem cell transplantation

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 (BOOP) also known as cryptogeneic organising pneumonia (COP)

  • Serositis (pleural or pericardial effusion)

  • Pleuroparenchymal fibroelastosis (PPFE)

  • Less common: periengraftment syndrome (PES), veno-occlusive disease (VOD) of the lung, pulmonary cytolytic thrombi (PCT) etcetera

Differential diagnosis might be difficult and a lung biopsy may be required for a definitive diagnosis (Table II).

Table II

Pulmonary algorithms

Respiratory symptoms include cough (productive or non-productive), chest pain, or shortness of breath. Fever may also be present. Patients may present with hypoxemia.

Definitions and incidence

  • IPS

IPS is a clinical syndrome of different etiologies, defined as the 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 (with or without hemoptysis), hypoxemia, 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

BO is a nonspecific inflammatory injury affecting small airways and is 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 estimates.

  • BOOP

BOOP is characterized by intra-alveolar fibrosis, resulting from organization of inflammatory exudates. It has a favorable response to steroid therapy. Incidence has been reported as 1 to 10% post alloHCT. It can commonly occur after respiratory infections.

  • PES

PES is a clinically proposed syndrome characterized by erythrodermatous skin rash, noninfectious, and noncardiogenetic pulmonary infiltrates, fever, and diarrhea at the time neutrophil engraftment.

  • PCT

PCT is an exclusive complication of alloHCT, which occurs in the setting of GVHD. PCT is 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

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.

Serositis

Serositis is characterized by new onset pleural or pericardial effusions that are typically large. This is a rare complication after HSCT occurring in 4-5% of patients with cGVHD. Presentation is cough, SOB, tachycardia, and possibly dizziness.

PPFE (Pleuroparenchymal fibroelastosis)

Is a recently described rare complication that appears to be separate from cGVHD. Presentation is of chronic progressive shortness of breath and cough. Diagnosis is made by CT imaging and confirmation by VATS mediated lung biopsy.

Risk factors

  • IPS

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.

  • DAH

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.

  • BO

Myeloablative conditioning, 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 the 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 [NOD2]/caspase recruitment domain-containing protein [CARD15] polymorphism.

  • BOOP

HLA-B35 is suggested as a risk factor for the development of BOOP. T-cell depletion may have protective effect.

Serositis

No risk factors for serositis after HSCT have been identified. Recent viral infection has been suggested to be associated with its onset but this is not conclusive.

PPFE

This is a recently described post-HSCT complication and no risk factors have been identified at present.

What features of the presentation will guide me toward possible causes and next treatment steps:

Dyspnea, cough, hemoptysis, wheezing, hypoxemia, fever, and syncope are common symptoms and signs that are useful in the differential diagnosis. Symptom duration can also assist in reaching a diagnosis (Table I).

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

Studies required

Laboratory: CBC, comprehensive metabolic panel, INR

Radiology: Chest X-ray, computed tomography (CT) scan of the lung with inspiratory/expiratory views if obstructive syndromes and air trapping are possible, (Table I, Table II).

Other ancillary tests:

Pulmonary function tests- to identify alteration in airflow or diffusion capacity

Echocardiogram- Evaluate left ventricular function and valvular disease

Right and left heart catheterization- for pulmonary vascular pressure and evaluate for ischemic cardiac disease

Bronchoscopy with bronchoalveolar lavage- evaluate for bleeding or respiratory infection. If BAL is not diagnostic then transbronchial (or cryobiopsy) or video-assisted thoracic (VAT) lung biopsy may be needed (Table I, Table II).

Radiological findings

  • IPS

Radiologic studies reveal bilateral interstitial infiltrates.

  • DAH

The most common CT findings are bilateral areas of ground-glass attenuation or consolidation involving the middle and lower lung zones. Lung infiltrates usually start centrally.

  • BO

Radiologic exams are normal or notable for hyperinflation. High resolution CT of the chest is the most sensitive imaging modality demonstrating air trapping or small airway thickening. Pneumothorax, pneumomediastinum, and pneumopericardium may be detected in advanced patients.

  • VOD of the lung

High resolution CT is important and reveals septal lines, ground-glass opacities and lymph node enlargement.

  • PCT

Chest radiographic findings mimic (for example, multiple nodules, mostly peripheral) invasive fungal infections. Interstitial prominence and atelectasis can be detected as well.

  • Serositis

Chest radiographs and CT imaging shows pleural and pericardial effusions without associated lung parenchymal changes.

  • PPFE

CT imaging shows pleural thickening with parenchymal bands of fibrosis extending from the pleura toward the hilum. There is usually an upper lobe predominance but all lobes can be affected in later stages of the disease.

Associated blood tests

CBC, prothrombin time (PT)/partial thromboplastin time (PTT), fibrinogen, D-dimer are useful to diagnose coagulopathy, infection, and pulmonary embolism. Serum immunoglobulin G (IgG) level is useful in the setting of infection. If levels are less than 400 gm/ml intravenous immunoglobulin (IVIG) replacement is needed.

What conditions can underlie non-infectious complications after bone marrow transplant: pulmonary complications:

Thrombocytopenia or coagulopathy may increase risks for DAH

Rule out infection through blood cultures, bacterial and fungal respiratory cultures, and testing for respiratory viruses by nasopharyngeal PCR (polymerase chain reaction) as well as blood CMV PCR. If a fungal infection is suspected, testing for fungal cell wall proteins by serum or BAL galactomannan or serum 1,3 β D-glucan (Fungitell) ELISA (enzyme-linked immunosorbent assay) may be useful

BAL findings

Table I and Table II shows how to interpret BAL results.

  • IPS

- Not specific; used mainly to rule out infections.

  • DAH

- Although BAL is diagnostic with progressively bloody returns on serial lavages. If it is performed a few days later, it may be misleading with a 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.

  • PES

BAL may show neutrophilic inflammation.

  • VOD of the lung

Occult alveolar hemorrhage.

  • PCT

Not specific, used mainly to rule out infections.

  • Infections

Includes bacteria; viruses such as CMV, respiratory syncytial virus (RSV), influenza, parainfluenza, metapneumovirus; fungi including aspergillosis (order galactomannan in BAL as it may be more sensitive than blood), Nocardia, Actinomyces, and Mycobacteria.

When is further invasive testing necessary:

Inconclusive laboratory tests, CT imaging, or negative results from bronchoscopy with BAL. The most invasive test to assist in the diagnosis of non-infectious complication of the lung is video-assisted thoracoscopic surgery (VATS) or open lung biopsy. Its indication and interpretation are shown in Table I and Table II.

Histopathological findings

  • IPS

Two main patterns are diffuse alveolar damage with hyaline membranes and interstitial pneumonitis.

  • DAH

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.

  • BO

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. A VATS surgical biopsy may be more informative than transbronscopic biopsy because of its patchy involvement and size of tissue obtained. Recently, a cryobiopsy via the bronchoscope may obviate the need for VATS. Histological examination in BO reveals intraluminal dense fibrosis and thus narrowing or obliteration. No mononuclear cell infiltration in interstitial or alveolar tissue is seen.

  • BOOP

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 capillarization) may also be present. Fibrinoid inflammatory cell clusters at the 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.

  • PPFE

Pleural thickening with broad bands of fibrous tissue. Fibroelastic stain is positive.

  • CT

Transbronchial biopsies are often nondiagnostic. 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

  • BO

An obstructive pattern on spirometry (FEV_1/FVC ratio < 70%) is diagnostic. There is no reversibility after bronchodilator administration. Commonly FEV-1 levels decrease by 30-40% from baseline. Lung volume testing may show hyperinflated lungs (Total lung capacity (TLC) > 120% predicted) with air trapping (Residual volume (RV) > 150%) Diffusion capacity is usually normal.

  • BOOP

Pulmonary function tests show reduced lung volumes and decreased diffusion capacity. Expiratory flow is normal.

Right-sided cardiac catheterization

  • VOD of the lung

VOD of the lung is confirmed by finding pulmonary hypertension (a mean PAP [pulmonary artery pressure] greater than 25 mmHg at rest) with normal pulmonary capillary wedge pressure (PCWP) (that is, PCWP is less than 15 mmHg). 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?

Treatment

  • IPS

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.

  • DAH

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.

  • BO

Treatment is generally unsuccessful because of irreversible fibrosis and airway narrowing. However, systemic corticosteroids and other immunosuppressive drugs are administered in a similar way to aggressive cGVHD treatment. In a case series, extracorporeal photodynamic (ECP) therapy has been associated with clinical improvements. High dose inhaled steroids, macrolide antibiotics (azithromycin), and leukotriene antagonists (montelukast) have been shown to be useful individually. Currently studies are underway testing the usefulness of combined therapy using all three agents (FAM; fluticasone, azithromycin, montelukast).

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 successful in a few patients. A case report showed imatinib used for chronic myeloid leukemia coincidentally showed improvement in BO.

  • PES

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).

  • BOOP

Systemic steroids (1mg/kg/day) for 1 to 2 months, then tapering ot off over the next 4 to 6 months is standard therapy for BOOP. Most patients (up to 80%) respond to steroids.

  • Serositis

Evaluation to exclude other etiologies, particularly heart failure or infection. Increase in the level of immunosuppression may be helpful. A steroid burst trial may decrease effusion size. Commonly, however, pharmacologic treatment is not successful. Large volume thoracentesis has been shown to be effective and prevents recurrence. If hemodynamic compromise is present, urgent pericardiocentesis is necessary.

  • PPFE

Currently there is no therapy for PPFE except for supportive care.

What other therapies are helpful for reducing complications?

General measurements to prevent infectious complications, including vaccinations against Influenza, Streptococcus pneumonia, are critical to prevent further lung damage in these patients.

What should you tell the patient and the family about prognosis?

Outcome

  • IPS

Prognosis is poor in untreated patients. Approximately 75% of patients will die in the short-term and there is a 15% 1 year survival. Etanercept, a soluble tumor necrosis factor (TNF) receptor inhibitor, with or without steroids, has resulted in encouraging results.

  • DAH

Mortality rate can be as high as 70%, although some studies shows better survival (40 to 60%).

  • BO

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. Lung function generally declines slowly over several years unless a secondary respiratory insult (infection) occurs.

  • VOD of the lung

Without treatment, most patients die in 2 years.

  • PCT

Treatment consists of increasing immunosuppressive therapy. It does not increase mortality, but may be associated with lower relapse rates.

  • BOOP

Up to 80% of patients respond to steroids.

  • Serositis

Generally a chronic condition that does not respond well to treatment. Persistent SOB and DOE.

  • PPFE

A chronic, slowly progressive disease. Progressive SOB and DOE. Long term outcomes are not currently known.

“What if” scenarios.

N/A

Pathophysiology

Pathogenesis

  • IPS

Radiation (TBI) induced lung damage, cytokines like TNF-alpha, and T cell mediated lung injury appear to be important in pathogenesis

  • DAH

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.

  • BO

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.

  • PES

Proinflammatory cytokines, granulocyte colony-stimulating factor (G-CSF) administration, neutrophil influx, and capillary leakage may play a role in the pathogenesis of PES.

  • BOOP

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 or serositis)

  • Level of immunusuppression

  • 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?

N/A

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.]

Leonard, JT, Newell, LF, Meyers. "Chronic GvHD-associated serositis and pericarditis". Bone Marrow Transplantation. vol. 50. 2015. pp. 1098-1104.

[Describes serositis after HSCT]

Sullivan, KM, Shulman, HM, Storb, B. "Chronic graft versus host disease in 52 patients: adverse natural course and successful treatment with combination immunosuppression". Blood. vol. 57. 1981. pp. 267-276.

[Describes serositis after HSCT]

von der Thusen, JH, Hansell, DM, Tominaga, M, Veys, P, Ashworth, MT, Owens, C, Nicholson, AG.. "Pleruooparenchymal fibroelastosis in patients with pulmonary disease secondary to bone marrow transplantation". Mod Pathol. vol. 24. 2011. pp. 1633-1639.

[Overview of PPFE in post-HSCT and Oncology patients]

Rosenbaum, JN, Butt, YM, Johnson, KA, Meyer, K, Batra, K, Kanne, JP.. "Pleuroparenchymal fibroelastosis: a pattern of chronic of lung injury". Hum Pathol. vol. 46. 2015. pp. 137-146.

[Overview of PPFE in post-HSCT and Oncology patients]
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