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Pulmonary complications after autologous hematopoietic cell transplantation

Pulmonary complications after autologous hematopoietic cell transplantation
Literature review current through: Jan 2024.
This topic last updated: Oct 08, 2021.

INTRODUCTION — Autologous hematopoietic cell transplantation is performed with increasing frequency, particularly as salvage therapy after high dose chemotherapy for recurrent lymphoma, leukemia, multiple myeloma, germ cell tumors, and neuroblastoma. A variety of pulmonary complications have been described with these procedures, occurring either early (within the first 30 days or pre-engraftment) or late (more than one month or post-engraftment) after transplantation. This distinction can guide the differential diagnosis and clinical evaluation of these disorders.

The term "hematopoietic cell transplantation" (HCT) will be used throughout this review as a general term to cover transplantation of progenitor cells from any source (eg, bone marrow, peripheral blood, umbilical cord blood). Otherwise, the source of such cells will be specified (eg, autologous peripheral blood progenitor cell transplantation). (See "Hematopoietic cell transplantation (HCT): Sources of hematopoietic stem/progenitor cells".)

Significant pulmonary complications are a leading cause of morbidity and mortality following HCT [1]. The pulmonary complications of autologous HCT will be reviewed here. The pulmonary complications of allogeneic HCT are discussed separately. (See "Pulmonary complications after allogeneic hematopoietic cell transplantation: Causes".)

OVERVIEW

Technique of autologous HCT — Autologous HCT refers to collection of hematopoietic progenitor cells from the patient prior to the administration of high dose chemotherapy designed to target an underlying malignancy, followed by reinfusion of these cells. In the past, autologous bone marrow was obtained from the patient by multiple iliac crest aspirations under general anesthesia. However, most transplant centers now exclusively utilize peripheral blood progenitor cells (PBPCs) mobilized by hematopoietic growth factor administration for autologous transplantation. The cells are collected by leukapheresis, avoiding the need for general anesthesia. (See "Hematopoietic cell transplantation (HCT): Sources of hematopoietic stem/progenitor cells".)

Comparison with allogeneic HCT — The pulmonary complications of autologous HCT share many of the features associated with allogeneic HCT, but there are also important differences. (See "Pulmonary complications after allogeneic hematopoietic cell transplantation: Causes".)

Cellular interactions between graft and host cells are largely eliminated with autologous transplantation. Thus, graft rejection and graft-versus-host disease are insignificant and do not require prevention or treatment. The net effect is reduced need for pharmacologic immunosuppression after the transplant.

Posttransplant pneumonitis associated with cytomegalovirus (CMV) infection is rarely a problem after autologous transplantation, in contrast to its high incidence after allogeneic transplantation.

Certain other opportunistic infections, such as Toxoplasma gondii, are very rare after autologous transplantation [2,3].

The infectious complications during the first four to six weeks after both allogeneic and autologous transplants are primarily caused by bacterial and fungal infections secondary to neutropenia (figure 1).

In both types of HCT, intensive treatment of the underlying malignancy with chemotherapy and radiotherapy (particularly to the chest) predisposes to serious noninfectious posttransplant pulmonary complications, including diffuse alveolar hemorrhage, idiopathic pneumonia syndrome, and drug or radiation toxicity.

Risk factors for pulmonary complications — Older patients and those with pre-existing abnormal lung function appear to have increased risk for pulmonary complications following HCT. While older age, reduced forced expiratory volume in one second (FEV1; ≤80 percent of predicted), and a reduced diffusing capacity for carbon monoxide (DLCO; <50 percent of predicted) are associated with increased risk, the optimal method for predicting an individual patient’s risk is not known [4-6]. In general, a DLCO ≤50 percent of predicted (corrected for anemia) is considered a criterion for ineligibility. The pretransplant assessment of patients for autologous HCT is described separately. (See "Determining eligibility for autologous hematopoietic cell transplantation".)

APPROACH TO THE PATIENT WITH RESPIRATORY SYMPTOMS OR SIGNS

Initial evaluation

Clinical history – The approach to evaluating pulmonary complications developing after autologous HCT begins with considering the clinical features of the patient’s presentation:

Timing of onset of the pulmonary disease – The likelihood of the potential complications following autologous HCT varies with the amount of time that has elapsed since HCT. Certain complications are much more likely to occur before or during engraftment (in the first month after HCT), while others are more likely to occur later (>1 month after HCT). (See 'Early complications (first month)' below and 'Late complications (after first month)' below.)

Risk for specific infections – Bacterial infections account for approximately 20 percent of pulmonary complications of autologous HCT, while fungal infections account for 4 percent [1]. Respiratory infections following HCT are discussed separately. (See "Overview of infections following hematopoietic cell transplantation" and "Approach to the immunocompromised patient with fever and pulmonary infiltrates".)

Of note, the risk of certain infections varies based on:

-Pretransplant serostatus (eg, cytomegalovirus, herpes simplex virus, HIV, varicella-zoster virus, Epstein-Barr virus, toxoplasmosis)

-Prior exposures (eg, cats, birds, mycobacteria, endemic fungi)

-Current and previous immunosuppressive agents (eg, methotrexate, cyclophosphamide, busulfan, glucocorticoids)

-Pre-HCT prophylaxis for infectious agents

-Duration of time since HCT (figure 1)

History of radiation therapy – The timing, dose, and field of any radiation therapy delivered to the chest to treat the underlying malignancy or as part of the conditioning regimen helps to determine whether radiation pneumonitis is a potential cause of respiratory symptoms and signs. (See "Radiation-induced lung injury".)

Drug-induced pulmonary toxicity – Drugs used during the pretransplant treatment of the primary disease or during the preparative conditioning regimen should be reviewed for their potential to cause pulmonary toxicity. (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment" and "Pulmonary toxicity associated with antineoplastic therapy: Cytotoxic agents".)

Laboratory testing and imaging – The clinical impression is further refined by laboratory testing (eg, complete blood counts, brain natriuretic protein [BNP], blood cultures, peripheral blood and urine tests for viral, fungal, and Legionella infection) and a chest radiograph; often chest computed tomography is performed as well.

Subsequent testing — The results of the initial evaluation, acuity of illness (eg, fever, tachypnea, hypoxemia, leukocyte counts), and pattern/extent of radiographic involvement help to guide the subsequent evaluation:

Dyspnea and normal chest radiograph – Patients with gradual onset of dyspnea and normal chest radiographs should undergo full pulmonary function testing with assessment of gas transfer by oximetry or arterial blood gas analysis. Abnormalities on pulmonary function testing should be followed by a chest high resolution computed tomography (HRCT) scan to look for subtle parenchymal changes that are not apparent on the chest radiograph and might suggest early interstitial disease.

Diffuse pulmonary opacities – For patients with diffuse pulmonary opacities on imaging, further evaluation is typically needed to identify the cause (eg, infection, aspiration, heart failure, fluid overload, diffuse alveolar damage, engraftment syndrome, diffuse alveolar hemorrhage); idiopathic pneumonia syndrome is a diagnosis of exclusion. Typical testing includes microbiologic studies, a plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration, and possibly an echocardiogram.

Almost all febrile HCT recipients with diffuse pulmonary opacities are treated empirically with broad-spectrum antibiotics, until a causative organism is identified, or an alternate diagnosis is confirmed. The choice of empiric therapy should depend upon the risk for specific infections and the susceptibility patterns at that institution (figure 1). (See "Overview of infections following hematopoietic cell transplantation" and "Approach to the immunocompromised patient with fever and pulmonary infiltrates", section on 'Selection of initial therapy'.)

Bronchoscopy with bronchoalveolar lavage (BAL) should be performed in patients without a clear diagnosis, particularly if the process is rapidly progressive [7,8]. The additional diagnostic value of transbronchial biopsy in conjunction with BAL is controversial [7,9].

A surgical lung biopsy, usually via video-assisted thoracoscopic surgery (VATS), should be strongly considered if a diagnosis is not made bronchoscopically and the patient has not responded to empiric antibiotics. Diagnoses made by VATS may alter management, although it is controversial whether outcome improves [10].

Focal or nodular pulmonary opacities – Patients with focal or nodular opacities are more likely to have bacterial or fungal infection. Blood cultures and serologic assays for galactomannan and beta-D-glucan should be obtained. Patients can often be given a trial of empiric antibiotics (based on local susceptibility patterns) with or without antifungal agents; bronchoscopy or other diagnostic procedures can be performed in the next few days, if there is no response and no causative agent has been identified. (See "Overview of infections following hematopoietic cell transplantation", section on 'Pneumonia'.)

EARLY COMPLICATIONS (FIRST MONTH) — In the first several weeks after autologous HCT, the incidence of pulmonary disease due to noninfectious and infectious causes is about equal [1,11]. Acute respiratory failure necessitating mechanical ventilation is usually due to diffuse alveolar hemorrhage, bacterial or fungal infection, pulmonary edema (cardiogenic or noncardiogenic), or idiopathic pneumonia syndrome (IPS). Viral infection causes acute respiratory failure in children more often than in adults [12]. While IPS can cause respiratory failure in the first few weeks after HCT, it is more common later in the course. (See 'Idiopathic pneumonia syndrome' below.)

The mortality of acute respiratory failure after HCT is high in both adults and children. However, an aggressive diagnostic approach and a trial of mechanical ventilation are indicated; in one study, 12 percent of patients with acute hypoxemic respiratory failure after HCT survived [13]. (See "Prognosis of cancer patients in the intensive care unit", section on 'Predictors of prognosis'.)

Pre-engraftment respiratory infections — Respiratory infections during the first few weeks after autologous HCT are primarily due to bacteria or fungi and are usually associated with neutropenia; viral pneumonia is less common [1]. Bacterial infections in the first month are frequently due to Gram negative bacteria or to Staphylococcus or Streptococcus species. Vancomycin-resistant Gram positive organisms, including Staphylococcus aureus, have been reported in immunocompromised hosts. Empiric antibiotic therapy for lung infection should incorporate susceptibility patterns at a given institution to cover these and other resistant organisms. (See "Overview of infections following hematopoietic cell transplantation".)

Fungal disease (eg, Aspergillus, Candida), although less common following autologous than allogeneic HCT, should be suspected in patients with prolonged neutropenia or previous glucocorticoid therapy, particularly if nodular opacities are present on the chest radiograph. Chest CT scanning adds to the sensitivity of the plain radiograph for detecting fungal infection, since nodules may be seen on CT scan before they are visible on chest radiographs. A nodule with surrounding ground glass opacity (halo sign) strongly suggests the presence of fungus. (See "Epidemiology and clinical manifestations of invasive aspergillosis", section on 'Imaging' and "Overview of infections following hematopoietic cell transplantation", section on 'Pneumonia' and "Clinical manifestations and diagnosis of candidemia and invasive candidiasis in adults" and "Diagnosis of invasive aspergillosis".)

Endemic fungi are less common pathogens, and mucormycosis is rare, following autologous HCT. (See "Overview of infections following hematopoietic cell transplantation", section on 'Pneumonia' and "Mucormycosis (zygomycosis)".)

Pneumocystis jirovecii (P. carinii) pneumonia and Herpes simplex viral infections can occur in the pre-engraftment phase, although generally less commonly than after allogeneic HCT. Most studies of pulmonary infections after bone marrow transplantation have focused on patients who received allogeneic transplants, so the literature regarding infection following autologous transplants is less well-developed. (See "Prevention of infections in hematopoietic cell transplant recipients", section on 'Pneumocystis prophylaxis' and "Pulmonary complications after allogeneic hematopoietic cell transplantation: Causes", section on 'Pulmonary infections' and "Overview of infections following hematopoietic cell transplantation", section on 'Pneumonia'.)

Aspiration — The risk of aspiration pneumonitis may be increased by mucositis, a frequent complication of HCT, and treatment of the associated pain with opiates. Aspiration can progress to noninfectious acute respiratory distress syndrome or pneumonia. (See "Early complications of hematopoietic cell transplantation", section on 'Oral mucositis'.)

Pulmonary edema — Pulmonary edema following autologous HCT, both cardiogenic and noncardiogenic, may be multifactorial in etiology. Acute pulmonary edema complicates approximately 5 percent of autologous HCT [1], although fatal heart failure occurs in less than 1 percent [14]. Risk factors for heart failure include:

Acute cardiac toxicity can occur after treatment with high dose cyclophosphamide, used in many conditioning regimens. This is particularly problematic in patients with preexisting cardiac dysfunction, but patients with normal cardiac function pretransplant may also develop subclinical cardiac dysfunction after autologous HCT.

Chronic cardiac toxicity due to previous anthracycline administration may only become clinically apparent after the patient is exposed to large volumes of intravenous fluid in the immediate posttransplant period.

Total body irradiation may be contributory in patients with preexisting heart disease. In addition, intercurrent infections and anemia can add to the stress on a previously well-compensated but dysfunctional heart.

Pleuropericarditis, possibly secondary to prior radiation therapy, occurs rarely and may be accompanied by pericardial tamponade.

Noncardiogenic pulmonary edema can be caused by infection, aspiration, diffuse alveolar hemorrhage, engraftment syndrome, or blood transfusions. Cardiac arrest secondary to noncardiogenic pulmonary edema has rarely been reported immediately following the infusion of autologous marrow [14-16]. (See "Acute respiratory distress syndrome: Epidemiology, pathophysiology, pathology, and etiology in adults", section on 'Etiologies and predisposing factors' and 'Aspiration' above and 'Diffuse alveolar hemorrhage' below and 'Engraftment syndrome and PERDS' below and "Transfusion-related acute lung injury (TRALI)".)

Engraftment syndrome and PERDS — The pulmonary component of the engraftment syndrome, known as the peri-engraftment respiratory distress syndrome (PERDS), is reported in 3 to 5 percent of autologous HCT [1,17]. The engraftment syndrome is generally suspected when a patient develops fever and a rash approximately 9 to 16 days following autologous HCT. The incidence of the engraftment syndrome varies with the criteria used, the underlying disease that necessitated HCT, and the chemotherapeutic agents used prior to HCT; reported numbers range from 12 to 60 percent; however, the frequency of patients with symptoms severe enough to consider treatment is probably much lower [18-20].

Definition and pathogenesis – PERDS is generally defined as the combination of fever, hypoxemia (pulse oxygen saturation <90 percent on room air), pulmonary opacities, absence of infection, fluid overload, or cardiac dysfunction, and presentation within five days of neutrophil engraftment [1,17]. However, the exact criteria for the syndrome are not well-established: some sets of criteria require a close temporal relationship with neutrophil recovery (eg, onset within one to five days of recovery of neutrophils in the peripheral blood) [18,21], while others uncouple the onset of the syndrome and neutrophil recovery [20].

PERDS is associated with increased capillary permeability that occurs during the neutrophil recovery phase following HCT [18,19,22,23]. It is attributed to release of proinflammatory cytokines, such as interleukin (IL)-2, tumor necrosis factor-α, interferon-γ, IL-8 and IL-6, macrophage colony-stimulating factor (M-CSF), and erythropoietin, that precedes neutrophil engraftment [20].

Clinical manifestations – Clinical manifestations include noninfectious fever (>38.3°C), maculo-papular rash mimicking acute graft-versus-host disease, diffuse radiographic pulmonary opacities, and diarrhea [18]. The median time to onset is 11 days after transplant. Weight gain, edema, ascites, and hypoalbuminemia are common accompanying features. Diffuse opacities are visible on initial chest radiograph in 11 to 37 percent [19,24]. Approximately one third of patients with PERDS also have DAH [17,25].

Evaluation – Bronchoalveolar lavage is typically performed to rule out infection and assess for DAH. A predominance of neutrophils may be noted even in the absence of infection [17]. Transbronchial biopsy is typically contraindicated due to thrombocytopenia.

Management – Appropriate cultures should be obtained, and empiric antibiotics are frequently administered. For patients with engraftment syndrome who do not have severe respiratory impairment (see above criteria for PERDS), systemic glucocorticoids are rarely needed [18-20]. However, for patients who meet these criteria for PERDS, systemic glucocorticoids are typically initiated. The optimal dose and duration of glucocorticoid therapy is not known; reported doses range from prednisone 0.5 to 10 mg/kg per day to methylprednisolone 1 mg/kg per 12 hours [1,19,21]. After a clinical response, the glucocorticoids are tapered, usually over 7 to 10 days. Prompt defervescence usually follows the administration of glucocorticoids (within 1 to 2 days).

The reported mortality of PERDS is about 26 percent [17,25].

Diffuse alveolar hemorrhage — Diffuse alveolar hemorrhage (DAH), which complicates approximately 1 to 2 percent of autologous HCT, may occur early or late after HCT, and can be associated with infectious or noninfectious causes (eg, peri-engraftment syndrome, idiopathic pneumonia syndrome) [1,26,27]. It is associated with a high mortality. Prompt diagnosis is important, since retrospective studies suggest that glucocorticoid treatment may favorably alter the outcome (see below). A general approach to the diagnosis and management of DAH is provided separately. (See "The diffuse alveolar hemorrhage syndromes".)

Pathophysiology and risk factors – The pathophysiology of DAH in autologous HCT is incompletely understood but appears to co-associate with risk factors for lung injury [28]. Thrombocytopenia or the presence of a bleeding disorder is not directly related to its development, although current practice is to correct these abnormalities when present. Although the pathogenesis of pulmonary hemorrhage remains obscure, possible risk factors have been identified:

The incidence of posttransplant hemorrhage is increased in patients with lymphoma who received pretransplant external beam radiotherapy to the chest for the treatment of bulky disease [29]. However, this should not prevent lymphoma patients with disease in the chest from undergoing autologous HCT, since their overall relapse-free survival is not reduced compared with patients with lymphoma in the absence of pulmonary involvement [30].

In a mixed series of autologous and allogeneic HCT, risk factors that increased the likelihood for DAH in multivariate analysis included renal dysfunction (blood urea nitrogen >40 mg/dL or creatinine >1.5 mg/dL), thrombocytopenia (platelet count <60x109/L), and preconditioning with the combinations of busulfan/fludarabine or melphalan/fludarabine [31].

Clinical features – Affected patients usually present with tachypnea, dyspnea, and/or hypoxemia developing during the first two weeks after autologous HCT [32]. Gross hemoptysis is uncommon and was noted in only 15 percent of patients in one series and 13 percent in another [25,27]. The progression of signs and symptoms can be rapid, and often occurs over less than 48 hours.

Imaging – Chest radiographs typically reveal a single or multiple patchy ground glass or consolidative opacities, which then become more widespread (image 1). The central portions of the lung are initially involved, particularly the mid- and lower-lung zones [33]. The radiographic findings may precede the development of symptoms by several days [27]. Chest CT is more sensitive than chest radiographs for the detection of alveolar hemorrhage and typically reveals diffuse ground glass or consolidative opacities, mainly in the middle lung fields [34].

Bronchoalveolar lavage – Bronchoalveolar lavage, with the classic diagnostic finding of progressively bloodier aliquots of lavage fluid and/or stains showing ≥20 percent iron-laden macrophages, is usually necessary for a presumptive diagnosis after fungal and other infections have been excluded [1]. (See "The diffuse alveolar hemorrhage syndromes", section on 'Bronchoalveolar lavage'.)

Treatment – The treatment of DAH in the setting of autologous HCT is largely supportive, but anecdotal and retrospective reports suggest improved survival in patients treated with systemic glucocorticoids when the cause is noninfectious [31,35,36]. Given the high mortality associated with DAH, we suggest giving systemic glucocorticoids after infection has been adequately excluded. Treatment regimens vary among institutions, ranging from 0.25 to 1 g of intravenous (pulse) methylprednisolone daily for several days (eg, three days), followed by a transition to oral prednisone (eg, 40 to 60 mg daily) with a rapid taper over approximately one to two weeks [27,31,37].

The evidence in favor of glucocorticoid therapy for DAH in this setting comes from retrospective studies [27,31,36,37]. One study of 63 patients with DAH after HCT found a higher survival rate among patients treated with high-dose methylprednisolone compared with those receiving low-dose or no glucocorticoids (33 versus 9 percent, respectively) [36]. In contrast, a subsequent study of 99 patients (40 percent autologous and 60 percent allogeneic HCT) found that survival was greater among those who received modest doses of glucocorticoids (<250 mg methylprednisolone equivalent/day) rather than high doses (≥250 mg methylprednisolone equivalent/day), odds ratio (OR) 0.21; 95% CI 0.07-0.72 [27]. These data may be skewed by selection of higher doses of glucocorticoids for patients presenting with greater acuity of illness.

Investigational therapies – Intravenous and endobronchial use of recombinant human factor VIIa (rFVIIa) have been reported in the management of DAH, but experience is limited. Off-label treatment with rFVIIa after DAH cannot be recommended, except as part of a clinical trial. rFVIIa is associated with an increased risk of thromboembolic events. The use of rFVIIa is discussed separately. (See "Recombinant factor VIIa: Administration and adverse effects", section on 'Pulmonary hemorrhage'.)

Adjunctive treatment with aminocaproic acid has yielded mixed results [37,38]. Treatment with nebulized or intrabronchial tranexamic acid in children with DAH of diverse causes has shown some benefit in small case series [39-41].

Overall, survival after pulmonary hemorrhage has been poor, particularly in patients who develop respiratory failure requiring mechanical ventilation and those with associated infection [27,31,37].

LATE COMPLICATIONS (AFTER FIRST MONTH) — The category of late pulmonary complications refers to those disorders developing more than one month after autologous HCT.

Respiratory infections — Respiratory infections occurring in this period are often due to bacterial and fungal organisms, even after initial neutropenia has resolved. These infections may be related to inadequate specific antibody production and to other more subtle immunologic abnormalities. Persistent mass-like lesions that do not respond to empiric antibiotics should be evaluated for focal fungal or mycobacterial disease, although recurrent and new primary malignancies are in the differential. (See "Overview of infections following hematopoietic cell transplantation", section on 'Pneumonia'.)

Tuberculous and atypical mycobacterial infections can also occur during this period. While rare in settings with low background prevalence (<1 percent), the frequency of mycobacterial infection can reach 5 percent in patients from populations with a high background prevalence [42]. Treatment with antimycobacterial drugs is highly effective in this setting.

Viral infections of the lung can occur following autologous HCT, but with lower morbidity and mortality (due to a lesser degree of immunosuppression) than seen after allogeneic transplantation. Cytomegalovirus, for example, can be the cause of interstitial pneumonitis [43]. (See "Pulmonary complications after allogeneic hematopoietic cell transplantation: Causes", section on 'Pulmonary infections'.)

Other respiratory viral infections can develop as a late complication following autologous HCT, including Herpes simplex virus, Varicella zoster (after acyclovir prophylaxis is discontinued), and influenza. Adenovirus and respiratory syncytial virus pulmonary infections are rare after autologous transplant, in contrast to patients treated with allogeneic HCT.

Abnormal pulmonary function tests — Studies of pulmonary function tests in patients receiving autologous transplants show that diffusing capacity and total lung capacity are typically decreased from pretransplant values; however, many patients with lung function abnormalities are not symptomatic [44-47]. Observed decrements in lung function are usually due to high-dose chemotherapy given prior to the transplant (particularly if carmustine is used) [48,49], but also can be associated with relapse of the underlying malignancy. (See 'Toxicity from chemotherapy and/or radiotherapy' below and "Nitrosourea-induced pulmonary injury" and "Cyclophosphamide pulmonary toxicity".)

Idiopathic pneumonia syndrome — The idiopathic pneumonia syndrome (IPS; a syndrome characterized by the signs and symptoms of pneumonia associated with widespread alveolar injury in the absence of lower respiratory tract infection) complicates approximately 1 to 5 percent of autologous HCT, which is substantially less frequent than after allogeneic HCT [1,50-52]. The median time to onset is 63 days; range 7 to 336 [50,53-55]. (See "Pulmonary complications after allogeneic hematopoietic cell transplantation: Causes", section on 'Idiopathic pneumonia syndrome'.)

Among patients who develop IPS following autologous HCT, the prognosis is generally better than for IPS following allogeneic HCT. Improvement can occur spontaneously, although most patients receive empiric oral glucocorticoid therapy after exclusion of infection. The treatment of IPS is discussed in greater detail separately. (See "Pulmonary complications after allogeneic hematopoietic cell transplantation: Causes", section on 'Idiopathic pneumonia syndrome'.)

Toxicity from chemotherapy and/or radiotherapy — Pulmonary toxicity from the combination of previous chemotherapy, radiotherapy, and/or the pretransplant conditioning regimen may become clinically apparent in the immediate posttransplant period [56]. Pneumonitis is a well-known complication of high-dose chemotherapy regimens containing carmustine (BCNU). Among 222 patients who received a preparative regimen of cyclophosphamide, BCNU, and etoposide (VP-16), pneumonitis developed in 22 percent [55]. Risk factors associated with pneumonitis included prior mediastinal irradiation, a total BCNU dose >1000 mg, and age less than 54.

In a series of breast cancer patients treated with high dose cyclophosphamide/cisplatin/BCNU followed by autologous HCT, a >30 percent decrease in diffusing capacity (DLCO) was noted on average by week 18 posttransplant [48]. Symptomatic patients treated with glucocorticoids (prednisone 60 mg/day for two weeks, followed by a six week taper) had a 17 percent improvement in DLCO.

Patients typically present with fever, dyspnea, cough, and hypoxemia. Chest radiographs can show patchy or diffuse mixed reticular and ground glass opacities. Biopsy findings are nonspecific and include diffuse alveolar damage, type II alveolar epithelial cell atypia and hyperplasia, interstitial pneumonitis, and thickening of the interstitium with early fibrosis. There is usually minimal acute inflammation.

After infection has been adequately excluded, glucocorticoids (eg, 1 to 2 mg/kg per day of prednisone) are usually employed for the treatment of antineoplastic agent or radiation-induced lung toxicity. There are, however, no prospective studies to document the efficacy of glucocorticoid therapy in this setting [52]. (See "Radiation-induced lung injury" and "Cyclophosphamide pulmonary toxicity" and "Busulfan-induced pulmonary injury" and "Nitrosourea-induced pulmonary injury".)

Patients who develop end-stage pulmonary fibrosis may be candidates for lung transplantation if there has been no evidence of recurrent malignancy within two to five years prior to listing. (See "Lung transplantation: General guidelines for recipient selection", section on 'Malignancy'.)

Bronchiolitis obliterans — While obstructive airways disease is rare after autologous HCT, fatal bronchiolitis obliterans (also referred to as obliterative bronchiolitis) has been reported [57,58]. (See "Pulmonary complications after allogeneic hematopoietic cell transplantation: Causes", section on 'Airflow obstruction and bronchiolitis obliterans'.)

Cardiac and pulmonary vascular — Heart failure, pericarditis, and thromboembolic disease are in the differential of late pulmonary complications following autologous HCT.

Heart failure can be due to co-morbid cardiac disease or be a consequence of prior chemotherapy or cardiac irradiation. (See 'Pulmonary edema' above.)

Pericarditis due to prior irradiation or sirolimus immunosuppression can present with dyspnea and hypoxemia and may be life-threatening if tamponade is not recognized [59]. (See "Acute pericarditis: Clinical presentation and diagnosis" and "Cardiac tamponade".)

Thromboembolic disease is seen most often in patients with catheter-related thrombosis [60]. Visualization of the thrombus via Doppler ultrasound or computed tomography pulmonary angiography is needed to confirm the diagnosis. (See "Catheter-related upper extremity venous thrombosis in adults".)

Malignancy — The risk of recurrence of the primary malignancy following autologous HCT varies with the primary indication for HCT [61]. Second primary malignancies can also contribute to late pulmonary complications [61].

SUMMARY AND RECOMMENDATIONS

Overview – Autologous hematopoietic cell transplantation (HCT) refers to procurement of hematopoietic progenitor cells from the patient prior to the administration of high-dose chemotherapy designed to target an underlying malignancy, followed by reinfusion of these cells. A variety of infectious and noninfectious pulmonary complications have been described with autologous HCT, occurring either early (within the first few weeks) or late (more than one month) post-transplant. With autologous HCT, cellular interactions between graft and host cells are largely eliminated. Thus, prevention and treatment of graft rejection and graft-versus-host disease are not needed, and pharmacologic immunosuppression is less than with allogeneic HCT. (See 'Overview' above.)

Infections – Aerobic Gram positive and Gram negative bacteria account for most documented infections during the early granulocytopenic period after autologous HCT; fungal and viral infections are uncommon (<5 percent) both early and late; and mycobacterial infections may occur in the late post-transplant phase (figure 1). (See 'Pre-engraftment respiratory infections' above and 'Respiratory infections' above and "Overview of infections following hematopoietic cell transplantation".)

Timing of noninfectious pulmonary complications – Early noninfectious pulmonary complications of autologous HCT include aspiration, acute pulmonary edema, engraftment syndrome, diffuse alveolar hemorrhage, and toxicity from chemotherapy or radiation therapy. Late pulmonary complications include restrictive abnormalities on pulmonary function testing, idiopathic pneumonia syndrome, chronic lung toxicity from antineoplastic agents, bronchiolitis obliterans (rarely), and recurrence of the primary malignancy or development of a second primary malignancy. (See 'Early complications (first month)' above and 'Late complications (after first month)' above.)

Evaluation – The initial evaluation of pulmonary complications of autologous HCT typically includes an assessment of clinical features for etiologic clues, laboratory testing (eg, complete blood counts, brain natriuretic protein (BNP), blood cultures, peripheral blood and urine tests for viral, fungal, and Legionella infection) and a chest radiograph. Additional testing is based on the timing of symptom onset, acuity of illness, and results of initial evaluation and imaging. (See 'Approach to the patient with respiratory symptoms or signs' above.)

Dyspnea with normal chest radiograph – Patients with a gradual onset of dyspnea and normal chest radiographs should undergo full pulmonary function testing with evaluation of gas transfer (eg, pulse oximetry). Abnormal pulmonary function testing or evidence of impaired gas exchange should be followed by a high resolution computed tomography (HRCT) scan to look for subtle interstitial disease. Echocardiography should be performed in patients with undiagnosed dyspnea to look for cardiac dysfunction. (See 'Approach to the patient with respiratory symptoms or signs' above.)

New opacities on chest imaging – Almost all febrile HCT recipients with new opacities on chest imaging are treated empirically with broad-spectrum antibiotics (with or without antifungal agents), until a causative organism is identified or an alternate diagnosis confirmed. The choice of empiric therapy depends upon the risk for specific infections and the susceptibility patterns at a given institution. (See 'Approach to the patient with respiratory symptoms or signs' above.)

Focal opacities – Patients with focal opacities can often be given a trial of empiric antibiotics with or without antifungal agents; bronchoscopy or other diagnostic procedure can be performed after two to three days if there is no response to empiric therapy and a causative organism has not been identified. (See 'Approach to the patient with respiratory symptoms or signs' above.)

Diffuse pulmonary opacities – Patients with diffuse pulmonary opacities on imaging should undergo bronchoscopy with bronchoalveolar lavage (BAL); sequential lavage is performed to exclude pulmonary hemorrhage and samples are sent for cytologic and microbiologic analysis. A surgical lung biopsy should be strongly considered if a diagnosis is not made bronchoscopically and the patient is not responding to empiric therapy. (See 'Approach to the patient with respiratory symptoms or signs' above.)

Empiric glucocorticoids for lung injury syndromes – After exclusion of infection, heart failure, and fluid overload, systemic glucocorticoids are typically given to patients with peri-engraftment respiratory distress syndrome (PERDS), diffuse alveolar hemorrhage, idiopathic pneumonia syndrome, or suspected drug or irradiation-induced toxicity, although evidence in support of this treatment is limited. (See 'Engraftment syndrome and PERDS' above and 'Diffuse alveolar hemorrhage' above and 'Toxicity from chemotherapy and/or radiotherapy' above and 'Idiopathic pneumonia syndrome' above.)

Prognosis – Acute respiratory failure due to diffuse alveolar hemorrhage or acute pulmonary edema following autologous HCT often requires short term support with noninvasive ventilation or intubation with mechanical ventilation. Respiratory failure requiring prolonged mechanical ventilation is generally associated with a poor prognosis in these patients. (See "Prognosis of cancer patients in the intensive care unit", section on 'Predictors of prognosis'.)

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Topic 4342 Version 23.0

References

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