From 1987 to 1998, 19 of 416 patients (4.6%) who underwent autologous hematopoietic stem cell transplantation experienced peri-engraftment (within 5 days of neutrophil recovery) respiratory distress syndrome (PERDS) not attributable to infection, fluid overload, or cardiac dysfunction. The median time from stem cell infusion to onset of PERDS was 11 days (range 4–25). Risk of PERDS or its outcome was not predicted by any pre- or peri-transplant clinical or laboratory feature. The respective median white blood cell and platelet counts at first symptoms were 1.3 × 109/l and 25 × 109/l. No patients had an infectious etiology by bronchoalveolar lavage. Six of the 19 patients had alveolar hemorrhage, which was significantly correlated with high neutrophil count. PERDS was directly implicated in four deaths (21%). Eleven patients received high-dose corticosteroid therapy, including five of the six who required mechanical ventilation. Ten of these patients experienced clinical improvement, which occurred within 24 h in five. The rapid response to corticosteroid treatment and the fact that such therapy was delayed until after intubation in all the mechanically ventilated cases point to a therapeutic benefit. Bone Marrow Transplantation (2001) 27, 1299–1303.
High-dose chemotherapy with autologous stem cell rescue is increasingly being used for the treatment of a variety of hematologic malignancies as well as solid tumors. Its efficacy in the treatment of various nonmalignant disorders such as systemic lupus erythematosus and rheumatoid arthritis is currently undergoing evaluation in clinical trials. Although the initial source of stem cells was bone marrow, recent years have witnessed a gradual shift toward the use of cytokine-mobilized peripheral blood stem cells. Even though they offer the potential for cure in some of these disorders, these procedures are associated with potentially life-threatening complications, which are related to both the high-dose chemotherapy and the transplant procedure itself. The serious complications associated with autologous transplants include life-threatening bacterial, fungal, and viral infections, veno-occlusive disease of the liver, infectious and non-infectious pulmonary complications, and renal failure. These complications together account for most of the mortality seen with autologous transplants.
Engraftment syndrome, also known as ‘auto aggression syndrome’, is a poorly understood complication of the autologous transplantation process which has only recently been described. Its features include combinations of skin rash, non-infectious pulmonary infiltrates, fever, diarrhea, and capillary leak occurring in the peri-engraftment period. Lee et al1 first noted the temporal clustering of acute graft-versus-host disease-like skin rash, idiopathic neutropenic fever, hypoxic pulmonary infiltrates, and weight gain with hypoalbuminemia around the time of neutrophil recovery and hypothesized that the accompanying cytokine storm may be responsible. This syndrome is being increasingly recognized in transplant centers, especially with the shift toward the use of peripheral blood stem cell transplants.2,3,4,5,6,7 The incidence of this syndrome varies widely between different reports, probably because of differences in the diagnostic criteria utilized. The cause is not well defined but is believed to be a complex interaction between the conditioning-related endothelial damage and the cytokine release associated with neutrophil and lymphocyte recovery.
Cytokines have been thought to have a role in the etiology of many of the early post-transplant complications, including diffuse alveolar hemorrhage, hepatic veno-occlusive disease, and capillary leak syndrome, and cytokine levels have been studied during the development of these complications. Interleukin-2, interferons, and tumor necrosis factors are the cytokines most often incriminated. Earlier studies noted a possible relationship of the engraftment syndrome to underlying disease,3 number of therapies before transplant, stem cell dose,3 stem cell source,3 growth factor use,1 amphotericin use,2 and rate of engraftment.3
We present a retrospective review of our institution's experience with the diagnosis and management of patients with acute respiratory distress that occurs during the time of neutrophil recovery in patients undergoing autologous hematopoietic stem cell transplantation. We also compared the background clinical features of these patients with those of others not experiencing this complication.
Materials and methods
After approval by the institutional review board, the Mayo Clinic bone marrow transplant and pulmonary procedure databases were retrospectively searched to identify patients with clinical, laboratory, and radiographic features compatible with a diagnosis of peri-engraftment respiratory distress syndrome (PERDS) after autologous hematopoietic stem cell transplantation. The medical records of these patients and those undergoing transplantation during the same period but not experiencing PERDS were reviewed for pertinent clinical parameters.
PERDS was considered in the presence of fever (more than 38.3°C) and evidence of pulmonary injury in the form of hypoxia (SaO2 < 90%) and/or pulmonary infiltrates on chest radiographs in the absence of clinical cardiac dysfunction. Confirmation was obtained through either echocardiography or pulmonary artery catheterization. To be diagnosed as PERDS, the symptoms and/or the radiographic findings had to have occurred within 5 days of neutrophil engraftment (defined as an absolute neutrophil count of more than 0.5 × 109/l on 2 or more consecutive days). Tissue infiltration with neutrophils has been shown to occur earlier than the appearance of neutrophils in the peripheral blood,8 and this feature is the rationale for using this time-frame in the definition of PERDS. In addition, the possibility of an infectious etiology for the pulmonary findings was minimized by the demonstration of negative gram stains and cultures from blood, sputum, and bronchoalveolar lavage.
All patients were treated in single rooms with high-efficiency particulate air filters. Standard neutropenic precautions were observed for all patients during the entire neutropenic phase. Patients with neutropenic fever were immediately treated with a third-generation cephalosporin, with vancomycin and amphotericin B added sequentially over the next 48 to 72 h as dictated by the response to initial therapy. Antibiotic therapy was further tailored to the results of blood cultures when they were positive. Red blood cell and platelet transfusions were given to maintain a hemoglobin level of more than 8 g/dl and a platelet count of at least 20 × 109/l, respectively. Cytomegalovirus-negative blood was used for patients with a cytomegalovirus-negative serology, and all patients received irradiated blood.
Bronchoscopy with bronchoalveolar lavage was performed on all patients with PERDS, under strict sterile conditions. All bronchoalveolar lavage samples were evaluated on an immunocompromised host protocol. This consists of special studies for opportunistic fungal infections, Pneumocystis carinii, and cytomegalovirus, in addition to routine bacterial, fungal, and viral cultures. In addition, bronchoalveolar lavage effluent was tested for the presence of hemosiderin-laden macrophages, to identify the presence of diffuse alveolar hemorrhage.
Statistical analysis was done by using Statview software. The chi-square test was used to compare nominal variables and Student's t-test was used for continuous variables. The Kaplan–Meier product limit method was used for comparison of survival. End points included initiation of mechanical ventilation, death, and dismissal from the hospital.
Four hundred and sixteen patients underwent autologous hematopoietic stem cell transplantation at our institution from January 1987 through June 1998. Forty-eight of these patients (11.5%) underwent bronchoalveolar lavage in the first 100 days of the post-transplant period as part of a workup for an undefined pulmonary process. Of these, 19 (4.6%) fulfilled the diagnostic criteria for PERDS. Table 1 outlines the pre- and peri-transplant clinical and laboratory features of these 19 patients compared with those of 368 patients who underwent autologous hematopoietic stem cell transplantation during the same period but did not experience a pulmonary complication that was severe enough to require bronchoalveolar lavage. There was no significant difference between the two groups in demographics, type and stage of underlying disease, conditioning regimen used, graft source, use of cytokines either for stem cell mobilization or after transplant, viral serologies, or pretransplant pulmonary reserve. The median infused mononuclear cell count per kilogram of the recipient's body weight was 1.8 × 108 (0.74–4.4) for the bone marrow and 8.3 × 108 (6–9.8) for the peripheral blood and was similar to those received by the 368 patients without PERDS.
In the 19 patients with PERDS, the median duration to onset of symptoms or pulmonary infiltrates on the chest radiograph from the time of transplant was 11 days (range 4–25). The median duration to neutrophil engraftment was also 11 days after transplant (range 8–25). The onset of symptoms or signs occurred within 5 days of engraftment, varying from 5 days before engraftment to 4 days after. Dyspnea was the initial symptom in all patients. Fever was present in 12 patients (63%) at the onset of symptoms. Chest radiographs showed a bilateral distribution of infiltrates in 13 patients (68%); the remaining six patients had a lobar distribution of the infiltrates on plain radiographs.
The median white blood cell count at the time of onset of symptoms was 1.3 × 109/l (range 0.2–29.6), and the median neutrophil count was 0.7 × 109/l (range 0.1–28.6). The median rise in the white blood cell count during the 48 h before the onset of symptoms was 0.4 × 109/l (range 0.0–17.7). The mean platelet count at the onset of symptoms was 25 × 109/l (range 6–233), and the mean creatinine concentration was 1.1 mg/dl (range 0.8–2.5). Liver function tests at the time of onset of symptoms included mean levels of alkaline phosphatase of 245 ± 88 U/dl (range 126–430) and aspartate aminotransferase, 37.5 ± 20 U/dl (range 7–89). Twelve patients were receiving amphotericin at the time of the onset of symptoms.
All patients underwent bronchoalveolar lavage at a median time of 1 day after the onset of symptoms (range 0–13 days). All 19 lavage samples were negative for any infectious organism. In addition, two patients underwent open lung biopsy of idiopathic infiltrates. Both tests revealed nonspecific alveolar damage. In six patients, lavage fluid was consistent with alveolar hemorrhage, either bloody in appearance (six) or with the presence of hemosiderin-laden macrophages (four). In seven patients, hypoxia was severe enough to warrant admission to the intensive care unit. Six of these seven patients required mechanical ventilatory support, and one was managed with noninvasive ventilation. Five of the 19 patients (26%) died in the immediate post-transplant period; four of these deaths were related to PERDS.
Treatment with corticosteroids was based on the demonstration of either evidence for alveolar hemorrhage or severity of the pulmonary process. Accordingly, 11 of the 19 patients were treated with intravenous methylprednisolone sodium succinate (Solu-Medrol; Pharmacia and Upjohn, Kalamazoo, MI, USA), 1 to 2 g/day for 3 days followed by a rapid taper. Steroid therapy was started after a median period of 2 days (range 0–8) after the onset of symptoms. Five of the six patients who required intubation received steroid therapy, steroids being started after intubation in all patients. These patients were intubated after a median of 2 days (range 0–5) after the onset of symptoms. In 10 patients, institution of steroid therapy was followed by rapid recovery over the next 2 to 4 days, and five of these patients improved within 24 h of the initiation of steroids. In most patients, the improvement consisted of decreased oxygen requirement and lessening of symptoms. One patient, in whom the steroids were started 8 days after the onset of symptoms, did not have any benefit and died of progressive respiratory failure. Seven of the 11 patients treated with steroids survived to dismissal, the cause of death in the other four patients being respiratory failure (two), veno-occlusive disease of the liver (one), and sepsis (one). Patients with evidence of alveolar hemorrhage on bronchoalveolar lavage were more likely to receive steroids (six of six vs five of 13).
Among the eight patients who did not receive treatment with steroids, one patient required transfer to the intensive care unit and mechanical ventilation at the onset of symptoms and subsequently died in the post-transplant period, of progressive pulmonary compromise. All the other seven patients, whose disease was not severe enough to require corticosteroid therapy, recovered from the pulmonary complications and were dismissed from the hospital.
There was no correlation between sex, age, source of stem cells, mononuclear cell count of the graft, use of post-transplant growth factors, white blood cell count at the time of onset of symptoms, rate of rise in white blood cells, or amphotericin use and the need for mechanical ventilation or post-transplant mortality. The mean absolute neutrophil count was significantly higher among the patients who had evidence of alveolar hemorrhage in the form of blood or hemosiderin-laden macrophages on bronchoalveolar lavage (2.8 vs 0.4 × 109/l, P < 0.001).
Forty to sixty percent of bone marrow transplant recipients experience a respiratory complication, which in turn is responsible for 10% to 40% of post-transplant mortality.9 A substantial number of these patients have respiratory failure requiring mechanical ventilation, and their outcome remains poor.10,11,12,13 Although infections constitute the majority of pulmonary injuries in the first 100 days after transplant, alveolar hemorrhage, pulmonary edema, and the idiopathic pneumonia syndrome have been implicated as causing significant morbidity in this patient population. Recently, engraftment syndrome has been described as a non-infectious complication of bone marrow transplantation.1,2,3,4,5,6,7 Although skin rash and fever are considered as cardinal features of ‘engraftment syndrome’,1,6 pulmonary symptoms and signs may be a clinically more important part of the syndrome as we understand it today, and the aim of our study was to emphasize this aspect of the peri-engraftment syndrome, which we refer to as PERDS.
We observed 19 patients with PERDS among 416 transplants performed over a 10-year period. However, we selected our patients from among those who underwent bronchoscopy and bronchoalveolar lavage. Although most patients with unexplained lung infiltrates and respiratory symptoms undergo bronchoalveolar lavage in our transplant unit, this method of selection would have failed to identify patients with milder forms of the syndrome. We did not see the female predominance observed by others.3 The difference might be related to the large number of patients with breast cancer undergoing transplant in those studies, whereas only one of our patients had a transplant because of breast carcinoma. The increased risk of engraftment syndrome seen in breast cancer patients compared to those with lymphoma has been thought to be related to their less heavily pretreated status.6 No correlation was seen between the underlying disease and the severity of the syndrome as measured by the need for mechanical ventilation or risk of death.
The mean time to engraftment was the same as the mean time to onset of symptoms (11 days). Symptoms may precede the appearance of white blood cells in the peripheral blood, as reported elsewhere, probably because tissue infiltration with recovering leukocytes occurs before the peripheral blood starts showing evidence of engraftment.8 Others have demonstrated the appearance of leukocytes in the urine at the time of onset of symptoms in the absence of peripheral blood leukocytes.2
The most common symptoms among our patients were fever and dyspnea, as has been observed in other studies. Chest radiographs revealed a heterogeneous pattern of alveolar infiltrates, either diffuse or in a lobar distribution. Interstitial pulmonary edema and pleural effusions were the most common findings in one study.7 Our patients did not have pleural effusions on chest radiograph at diagnosis. In one-third of patients, progression of the disease necessitated mechanical ventilation. Previous studies have shown a dismal prognosis for bone marrow transplant recipients who require mechanical ventilatory support,10 and this feature was confirmed in our study. Of the six patients who required mechanical ventilation, five died in the post-transplant period. Four of these patients died as a result of pulmonary complications due to the transplant, and one died from sepsis. In the group of patients reported by Cahill et al,2 all 14 patients who required ventilatory support died in the post-transplant period.
Treatment with steroids has been shown to be of benefit in patients with engraftment syndrome.5 Steroids have also been found to be useful in patients experiencing diffuse alveolar hemorrhage in the setting of bone marrow transplants not as a part of PERDS.14,15,16 However, all these studies, including our own, suffer from disadvantages related to their retrospective nature. Nevertheless, the potential benefit of high-dose corticosteroid therapy is suggested by the rapid response we found in five of the 11 patients so treated, and it is possible that a delay in steroid therapy until after intubation contributed to the unfavorable outcome in those patients. However, patients who experience respiratory improvement may still die of other comorbid conditions. One of the patients who died had initially improved on steroids and subsequently succumbed to infection. Among the patients who did not receive steroids, only one died. Obviously, the pulmonary process in this group of patients may have been milder, and this consideration precludes a comparative analysis between those who received steroids and those who did not.
Several factors have been said to predict higher risk for the development of the engraftment syndrome, including female sex, underlying solid tumor, peripheral blood as stem cell source,2,4,6 mononuclear cell count of the graft,3 rate of recovery of neutrophils at the time of recovery,17 and amphotericin therapy. We did not find any correlation between sex, age, underlying disease, source of the graft, use of growth factors for stem cell collection, or use of post-transplant growth factor and the risk of PERDS (Table 1). Given the study design, we could not compare patients who did or did not express the syndrome with respect to other factors, especially the use of amphotericin. Moreover, it is likely that amphotericin use is an associated factor, given that most patients have fever that is unresponsive to antibiotics at the onset of PERDS, which triggers the use of amphotericin. These factors did not correlate with the severity of the illness either, as measured by the need for mechanical ventilation, perhaps because of our relatively small number of patients. Patients who had diffuse alveolar hemorrhage as part of their engraftment syndrome had a higher absolute neutrophil count compared with those who did not. Since diffuse alveolar hemorrhage represents a severe form of acute lung injury, this finding gives credence to the pivotal role that neutrophils have been said to play in the genesis of the engraftment syndrome.
In conclusion, engraftment syndrome developing in the setting of autologous stem cell transplantation is being increasingly recognized as a cause of significant morbidity and mortality. Prompt recognition of this syndrome of pulmonary infiltrates, hypoxia, and non-infectious fever, with or without skin rash and diarrhea, occurring in the peri-engraftment period is important because early treatment with corticosteroids may have a benefit. Recognition of this entity is also important from the point of view of preventing unnecessary antibiotic therapy for presumed infections with which this disorder is often confused.
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Capizzi, S., Kumar, S., Huneke, N. et al. Peri-engraftment respiratory distress syndrome during autologous hematopoietic stem cell transplantation. Bone Marrow Transplant 27, 1299–1303 (2001). https://doi.org/10.1038/sj.bmt.1703075
- autologous transplantation
- respiratory distress syndrome
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