Volume 13, Issue 1 , Pages 26-30, January 2007
Clinical Utility of Autopsy after Hematopoietic Stem Cell Transplantation
Article Outline
Abstract
Autopsy is the gold standard for establishing the cause of death. We present results of the largest retrospective review of complete autopsies of subjects after hematopoietic stem cell transplantation to better define the role of the autopsy in discovering a missed diagnosis. We reviewed the medical chart and autopsy records of 111 patients who had undergone hematopoietic stem cell transplantation from July 1986 to June 2003 from a single center. We compared the cause of death as charted by the clinical team with data obtained from postmortem chart review and autopsy reports. Of 29 (26%) cases when the premortem and postmortem major diagnoses did not agree, only 4 (4%) autopsy records provided data that might have led to the initiation of new treatments, and none of these diagnoses would be missed today with more sensitive and specific diagnostics and improved supportive care. Although autopsies after transplantation can be important educational, research, and epidemiologic tools and provide an emotional benefit to patient’s families, in our series they rarely provided missed diagnoses that would alter the management of subsequent patients. Improvements in noninvasive tests for relapse or occult infections may further erode the role of autopsies in discovering missed diagnoses.
Key words: Autopsy, Hematopoietic stem cell transplantation, Mortality, Cause of death
Introduction
Autopsy remains the gold standard for establishing cause of death. However, rates of performing autopsies have decreased in general medical and surgical wards [1, 2]. Different reasons have been postulated for this decline including lower rates of consent from relatives, legal issues concerning exposing physicians’ errors and lack of reimbursement [3]. However, as autopsy rates decrease, the ability to confirm a clinical diagnosis or document a missed diagnosis may be lost.
It has been reported that the possibility that a given autopsy will reveal important unsuspected diagnoses has decreased over time. Based on their review from 1966 to 2002 in general medical and surgical patients, Shojania et al [1] estimated that a contemporary United States institution could expect missed diagnoses involving a principal cause of death at a rate of 4.1% to 6.7%. Al Saidi et al [4] examined the utility of autopsy in preventing death in 28 patients who underwent hematopoietic stem cell transplantation (HSCT) from 1994 to 1999. They found 10 (35%) discrepancies between pre- and postmortem diagnoses but only 2 discrepancies that would have influenced patient management and none that would have altered patient outcome.
We present the largest review of complete autopsies of subjects after HSCT with a focus on the clinical utility of the autopsy as a method of improving subsequent patient care. We hypothesized that results from autopsies performed specifically on cases after HSCT rarely lead to additional information that would have changed management.
Methods
We performed an institutional review board approved retrospective electronic and paper chart review on 111 subjects after HSCT who underwent autopsy at Loyola University Medical Center from July 1986 to June 2003. Progress notes and death certificates were reviewed to determine the treating team’s proposed cause of death. The autopsy report, electronic and paper medical records, and microbiologic results were reviewed to determine the actual cause of death. A 2-person independent chart review was performed to compare the cause of death as charted in the medical record by the attending or fellow on service with data obtained from chart review and autopsy reports.
Goldman et al [5] published criteria to review autopsy reports for missed diagnoses. Major diagnoses included the principal underlying disease(s) and primary cause(s) of death; minor diagnoses were all other important conditions. A missed major diagnosis was defined as a difference between the clinical team’s main cause of death, documented by the fellow or attending, and the cause of death as determined by review of the electronic and paper charts and the autopsy results. A class I missed major diagnosis was that for which detection before death would in all probability have led to a change in management and this might have resulted in prolonged survival. A class II missed major diagnosis was that for which detection before death would probably not have led to a change in management.
Results
At our center 1780 adult HSCTs were performed from July 1986 to June 2003, of which 1268 (71%) were autologous and 512 (29%) were allogeneic. Of these patients, 122 autopsies were performed, of which 111 complete medical records were available for review. Hematopoietic stem cell sources in our study were 53 (48%) autologous and syngeneic, 45 (41%) sibling, 11 (10%) matched unrelated donor, and 2 (2%) umbilical cord (Table 1). The most common conditioning regimens were total body irradiation-based chemotherapy protocols, most commonly combined with cyclophosphamide with or without etoposide, in 51 patients (46%). The next most common was the combination of busulfan and cyclophosphamide in 25 patients (23%). The remaining 31% of patients received a variety of chemotherapy-based regimens. None of the patients reviewed had received a reduced intensity or nonablative conditioning regimen.
Table 1. Patient Demographics (n = 111)⁎
| Characteristic | n (%) |
|---|---|
| Age, median (range) | 41 (16-71) |
| Sex | |
| Male | 55(49%) |
| Female | 56(51%) |
| Diagnoses | |
| Non-Hodgkin lymphoma | 31(28%) |
| Acute myelogenous leukemia | 14(12%) |
| Acute lymphocytic leukemia | 11(10%) |
| Chronic myelogenous leukemia | 11(10%) |
| Hodgkin lymphoma | 10(9%) |
| Ovarian cancer | 9(8%) |
| Myelodysplastic syndrome | 5(4%) |
| Breast cancer | 5(4%) |
| Severe aplastic anemia | 3(3%) |
| Multiple myeloma | 2(2%) |
| Other | 10(9%) |
| Stem cell sources | |
| Autologous and syngeneic | 53(48%) |
| Sibling | 45(41%) |
| Matched unrelated donor | 11(10%) |
| Umbilical cord | 2(2%) |
⁎Demographics of subjects that underwent an autopsy. Diagnosis is the disease for which the transplantation was performed. Diagnoses not listed include colon cancer (n = 2), myelofibrosis (n = 2), chronic lymphocytic leukemia (n = 2), germ cell tumor (n = 1), renal cell carcinoma (n = 1), neuroblastoma (n = 1), and melanoma (n = 1). Stem cell sources combined 52 autologous and 1 syngeneic transplants. |
Transplantation indications for the 111 patient records reviewed were as follows: non-Hodgkin lymphoma (28%), acute myelogenous leukemia (12%), acute lymphocytic leukemia (10%), chronic myelogenous leukemia (10%), Hodgkin lymphoma (9%), ovarian cancer (8%), myelodysplastic syndrome (4%), breast cancer (4%), and severe aplastic anemia (3%). There were also 2 cases (2%) of multiple myeloma, colon cancer, myelofibrosis, and chronic lymphocytic leukemia. There was 1 case (1%) each of renal cell carcinoma, germ cell tumor, neuroblastoma, and melanoma. Thirty-nine patients (35%) died between day +31 and day +100 after transplantation, 30 (27%) died between day 0 to day +30, 34 (31%) from day +101 to day +365, and 8 (7%) died 1 year after transplantation.
Major diagnostic causes of death after allogeneic and autologous transplantations were reviewed (Table 2). Of the 52 patients who had received an autologous transplant, the most common major diagnosis that led to the patients’ death was nonpseudomonas bacterial sepsis or pneumonia in 9 patients (17%). Disseminated Aspergillus (n = 8, 15%), progressive disease (n = 7, 13%), regimen-related toxicity (n = 5, 10%), and other fungi (n = 4, 8%) made up the next 4 most common causes of death. Although the principal cause of death after allografting was disseminated Aspergillus in 12 patients (20%), steroid-refractory graft-versus-host disease (n = 10, 17%), progressive disease (n = 6, 10%), cytomegalovirus (CMV; n = 6, 10%), and fungi other than Aspergillus (n = 4, 7%) made up the 5 most common causes of death.
Table 2. Causes of Death: Allogeneic versus Autologous⁎
| Postmortem | n (%) |
|---|---|
| After allograft (n = 59) | |
| Aspergillus | 12(20%) |
| Refractory graft-versus-host disease | 10(17%) |
| Progressive disease | 6(10%) |
| Cytomegalovirus | 6(10%) |
| Other fungi (Candida, Cladosporium, Rhizopus, Pseudoallescheria) | 4(7%) |
| Pseudomonas | 3(5%) |
| Bacteria other than Pseudomonas | 3(5%) |
| DAH/engraftment | 3(5%) |
| Bleeding diathesis, TTP | 3(5%) |
| Other causes | 9(15%) |
| After autograft (n = 52) | |
| Bacteria other than Pseudomonas | 9(17%) |
| Aspergillus | 8(15%) |
| Progressive disease | 7(13%) |
| Regimen related | 5(10%) |
| Other fungus | 4(8%) |
| Pneumonia NOS | 3(6%) |
| PCP | 3(6%) |
| DAH/engraftment | 3(6%) |
| Other causes | 10(19%) |
⁎Other causes for allogeneic transplantation include other viruses, PCP, veno-occlusive disease, idiopathic pneumonia syndrome, regimen-related toxicity, diabetic ketoacidosis, and pneumonia. Other causes for autologous transplantation include veno-occlusive disease, pseudomonas, idiopathic pneumonia syndrome, other viruses, myocardial infarction, and Swan-Ganz catheter trauma leading to pulmonary hemorrhage. |
The premortem clinical diagnosis agreed with the retrospective postmortem major diagnosis in 82 patients (74%; Table 3). In 29 cases (26%), postmortem diagnosis was discordant with the providing team’s clinical diagnosis. Of these 29 cases, 25 subjects (86%) were found to have overwhelming systemic infections despite appropriate antimicrobial therapy, rapidly progressive disease with a poor performance status, or a regimen-related toxicity (most commonly dilated cardiomyopathy) in a patient who was not a candidate for aggressive treatment such as solid organ transplantation. In these cases, the autopsy would not have provided data that would suggest an alternative therapy that might have prevented the patient’s death, a class II missed diagnosis according to criteria of Goldman et al [5].
Table 3. Agreement between Premortem and Postmortem Causes of Death
| Postmortem Cause of Death | Discordancy⁎ |
|---|---|
| Aspergillus | 7/20(35%) |
| Progressive disease | 7/13(54%) |
| Regimen-related toxicity | 4/6(67%) |
| Other bacteria | 3/12(25%) |
| Other fungi (Candida, Cladosporium, Rhizopus, Pseudoallescheria) | 3/8(38%) |
| Cytomegalovirus | 3/6(50%) |
| Pneumonia NOS | 1/4(25%) |
| Iatrogenic | 1/1(100%) |
| Steroid-refractory graft-versus-host disease (10) | 0/41 |
| Diffuse alveolar hemorrhage/engraftment syndrome (6) | |
| Pseudomonas sepsis or pneumonia (5) | |
| PCP (5) | |
| Bleeding diathesis/thrombotic microangiopathy (4) | |
| Veno-occlusive disease (3) | |
| Idiopathic pneumonia syndrome (3) | |
| Viral pneumonia or encephalitis (3) | |
| Diabetic ketoacidosis (1) | |
| Acute myocardial infarction (1) | |
| Total | 29/111(26%) |
⁎Discordancy is the number of cases in which the premortem and postmortem causes of death did not agree from the total number of patients with that diagnosis. The postmortem cause of death was derived by review of the electronic and paper medical records and autopsy report. |
Only 4 discrepancies between premortem and postmortem diagnoses (class I missed diagnoses) provided data that would have led to the initiation of new treatments (Table 4). Three cases of disseminated CMV infection were seen and 1 case demonstrated disseminated candidiasis. In these cases, the autopsy provided data that suggested an alternative therapy that might have prevented the patient’s death. Since our hospital started using peripheral blood to test for CMV by a hybrid capture assay in 1999 [6], no further CMV discordant cases have occurred.
Table 4. Treatable Missed Major Diagnoses⁎
| Postmortem Cause of Death | Clinical History |
|---|---|
| CMV | A 24-y-old patient with ALL after sibling transplantation was admitted in 1998 for what was thought to be acute GVHD of the gut and liver. The patient died on day +5 despite negative CMV cultures during the month preceding death. Autopsy revealed disseminated CMV infection that had not been treated. |
| A 38-y-old patient with ALL after sibling transplantation in 1990 developed a new left lung infiltrate while hospitalized for acute GVHD. The patient developed Staphylococcus aureus bacteremia and respiratory failure and died. Autopsy revealed disseminated CMV infection that had not been treated. | |
| A 26-y-old patient with Hodgkin lymphoma after sibling transplantation was admitted on day +48 in 1988 with acute left subclavian DVT. Within 1 d he became asystolic, was resuscitated, but died a week later. Autopsy revealed CMV pneumonia; he was thought to have died from pulmonary hemorrhage and had not received ganciclovir. | |
| Disseminated candidiasis | A 32-y-old patient with relapsed DLBCL day +308 after autografting was admitted with bleeding diathesis and increased transaminases while receiving salvage chemotherapy in 1993. Autopsy revealed systemic candidiasis involving the gastrointestinal tract, heart, and lungs. The patient was thought to have died of chemotherapy-induced liver failure and did not receive antifungal therapy. |
⁎After reviewing the records of 111 subjects, there were only 4 cases in which the results from chart review and autopsy report provided information that would have led to the initiation of new treatment had the information been available before death. |
Discussion
Our study provides the largest published review to date of complete autopsies of subjects after HSCT. We focused specifically on class I missed diagnoses to highlight the utility of the autopsy with regard to improving future patient care. Our findings are similar to other reported data in that the most frequent autopsy discrepancies were occult infections. Infections are widely recognized as the most common cause of death among peripheral blood stem cell and marrow transplant recipients [4, 7, 8, 9]. Most of our patients died from disseminated fungal infections, similar to previously reported cohorts [8, 10].
Only 4 (4%) autopsies reviewed in our study provided data that might have prevented a patient’s death. One discrepancy involved a subject with untreated systemic aspergillosis who was clinically diagnosed with pulmonary hemorrhage, other hemorrhagic complications and multiple system organ failure secondary to idiopathic thrombocytopenic purpura and disseminated enterococcal infection. Another discrepancy detailed an untreated coagulase-negative staphylococcus catheter infection in a patient who died from diffuse pulmonary hemorrhage secondary to thrombocytopenia.
Although infections are the most common causes of death in autopsy studies after HSCT, newer diagnostic methods may decrease the risk of missed infectious diagnoses. Chandrasekar et al [9] reported in 1995 autopsy results of 56 subjects after HSCT and found that the presence of infection was not identified or proved before death in 9 of 14 patients with CMV, 6 of 13 patients with yeast, and 4 of 6 patients with Aspergillus. It is unclear in this trial if diagnosing these infections would have prevented death in those patients. However, in the past decade several newly developed noninvasive tests to detect opportunistic infections have been routinely used such as galactomannan for the diagnosis of Aspergillus [11] and polymerase chain reaction assays to detect CMV infection [12, 13, 14, 15, 16]. New assays to detect disease recurrence can assess BCR-ABL transcripts in chronic myelogenous leukemia [17, 18] and quantitate chronic leukemia disease levels [19]. In our study, which spanned 1986 to 2003, most of these noninvasive tests were not available. Noninvasive methods to test for CMV including peripheral blood polymerase chain reaction, antigenemia, and hybrid capture may have allowed earlier effective antiviral treatments.
There are several limitations to our retrospective study. Determining the root cause of death in the HSCT population can be complex because it is often multifactorial and the proximate cause of death is often related to remote causes of death such as graft-versus-host disease [20]. In our study, we tried to identify this remote factor and use it as the cause of death, whereas other studies may not have used this exact method [2, 4, 9]. In our study, there was subjectivity involved in deciding whether or not a discrepancy was significant to have provided data that could have prevented a patient’s death; we attempted to limit this by 2-person independent chart review and discussion of every case. We hypothesize that families who consented for autopsies were those who were most concerned about management or outcome, presumably because the diagnosis was felt to be in question or after a patient’s unexpected demise. This selection biases the study to show a falsely increased rate of missed diagnoses. Selection bias must be also be acknowledged because only 111 complete patient records of 122 autopsies performed were available for review.
Although autopsies typically cost approximately US $2000 per autopsy that is rarely billed to the patient’s insurance, autopsies can have other important roles beyond the discovery of missed diagnoses. Autopsies can play an important educational role [21, 22], provide valuable tissue for research purposes [23], and supply important data for hospital microbiology and epidemiology sections. Autopsies may also provide an emotional benefit to patient’s families because it may put family members’ minds at ease in certain cases [24, 25, 26, 27].
In most cases, autopsies performed after HSCT did not provide additional information that would have changed management. Recently developed noninvasive methods for diagnosing disease and occult infections may further erode the role of autopsies in discovering missed diagnoses.
Acknowledgments
We thank Mala Parthasarathy for providing demographic information about Loyola’s stem cell transplantation program; Penny Bleffer-Riding, an analyst at Loyola University’s Center for Clinical Effectiveness, for obtaining a rough autopsy rate of our patients with HSCT; and Preeti Jaggi, MD, for critical review of the manuscript.
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PII: S1083-8791(06)00641-0
doi:10.1016/j.bbmt.2006.09.006
© 2007 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
Volume 13, Issue 1 , Pages 26-30, January 2007
