Biomedical subjects
Publications and source records attributed to L Nichols.
We describe a case of acute invasive sinusitis due to an unusual moniliaceous fungus, Trichoderma longibrachiatum Rifai 1969 (a member of the class Hyphomycetes), in a small bowel and liver transplant recipient treated with tacrolimus (FK-506) and prednisone. The patient was successfully treated with surgical debridements and amphotericin B followed by oral itraconazole.
To determine the current frequency of discovering important diagnoses at autopsy, the diagnoses made in all complete or "no head" autopsies during 1994 at a major tertiary care transplantation referral center were retrospectively compared with the diagnoses made antemortem. Of 176 autopsies, 79 (44.9%) revealed 1 or more undiagnosed causes of death. Of the 123 undiagnosed causes of death, 13 were sole immediate causes of death, 72 were one of multiple immediate causes, 22 were intervening causes, and 16 were underlying causes. The causes of death were as follows: infections, 34; infarctions, 11; malignant neoplasms, 8; pulmonary emboli, 7; gastrointestinal ulcers, 7; hemorrhages, 6; thromboses, 3; amyloidosis, 1; genetic hemochromatosis, 1; and cardiac tamponade, 1. Of 35 autopsies of transplant recipients, 16 (46%) disclosed undiagnosed causes of death, compared with 63 (44.7%) of 141 autopsies of patients who had not received transplants. Approximately two thirds of the undiagnosed causes of death were judged to be treatable conditions. This and similar studies suggest that old-fashioned low-technology autopsies can uncover many important diagnoses missed by modern high-technology medicine.
Liver transplantation is an established treatment for multiple end-stage liver diseases, yet little information is available on the autopsy-determined causes of death in liver transplant recipients. We undertook a retrospective study of the immediate causes of death in all liver transplant recipients who underwent autopsy at the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, from January 1982 to January 1997. Infections were the most frequent cause of death, present in 64% of a total of 321 cases. Overall, the infections were bacterial in 48% of the cases, fungal in 22%, and viral in 12%. The ratio of infectious to noninfectious causes of death did not change significantly during the 15-year study period, and the relative percentages of bacterial, fungal, and viral infections showed relatively little variation on a year-to-year basis. Two-thirds of all infections occurred during the first 100 days post transplantation. A precipitous drop in the number of infections (and the number of deaths) occurred by Day 90. Other major causes of death included liver failure (12%), pulmonary failure (10%), multiple organ system (8%), and cardiovascular causes (6%). Infections were the most frequent cause of death in this study population, suggesting that improvement in the prevention and treatment of infections is an important way to improve survival of liver transplant recipients.
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Bronchoalveolar lavage (BAL) and transbronchial biopsies from 351 human immunodeficiency virus (HIV)-positive patients with presumed Pneumocystis pneumonia were analyzed to determine the spectrum and frequency of interstitial lung disease mimicking Pneumocystis pneumonia. Among 67 patients without Pneumocystis, nonspecific interstitial pneumonitis (NSIP) was the most common histologic diagnosis (n = 16). Tissue sections from patients with NSIP were tested by in situ hybridization for Epstein-Barr virus, cytomegalovirus (CMV), and HIV; sections were also tested with the polymerase chain reaction (PCR) for HIV env and gag protein DNA. In patients with NSIP, Epstein-Barr virus and CMV could not be detected by in situ hybridization; HIV nucleic acid was amplifiable with PCR in 10 of 15 formalin-fixed, paraffin-embedded tissue sections. Symptoms, physical findings, and blood gas values were similar in patients with NSIP and matched controls with Pneumocystis. Patients with NSIP presented earlier in the course of HIV, with higher weight, serum albumin levels, and CD4+ T-lymphocyte counts (492 +/- 828 cells/mm3 versus 57 +/- 60 cells/mm3), and more normal lactate dehydrogenase (LDH) levels (280 +/- 113 IU/L versus 432 +/- 141 IU/L; means +/- SD). Seven to 10 d later, improvement in blood gas values was of similar magnitude for the two groups. Only one other unequivocal, treatable infection was diagnosed only with transbronchial biopsy. These results indicate that NSIP may be the most common diagnosis mimicking Pneumocystis pneumonia in acquired immune deficiency syndrome (AIDS), and that NSIP may improve during empiric therapy.
Chronic hepatitis B is a widespread viral illness with the serious sequelae of cirrhosis and hepatocellular carcinoma. Current therapy with interferon is not universally efficacious, and this has led to the evaluation of other antiviral agents. A recent Phase II trial of the nucleoside analogue, fluoroiodoarabinofuranosyluracil (fialuridine, FIAU) was halted because of the sudden development of severe multisystem toxicity characterized by hepatic failure, lactic acidosis, and pancreatitis, which resulted in the deaths of five patients. We systematically evaluated pre- and post-therapy biopsy, explant, and autopsy specimens from the 15 patients involved in this trial to define the hepatic changes of fialuridine toxicity and to determine whether the degree of pre-existing hepatitis contributed to the severity of toxicity. Severe hepatotoxicity from fialuridine was characterized by hepatomegaly with diffuse, predominantly microvesicular steatosis, hepatocellular glycogen depletion, marked bile ductular proliferation, and cholestasis. Ultrastructural examination revealed intracytoplasmic lipid droplets and marked mitochondrial injury. Patients in whom severe toxicity did not develop mainly showed changes caused by the underlying chronic hepatitis B alone. There was a subtle increase in the amount of microvesicular steatosis in two of six patients with mild or no symptoms of toxicity. The microscopic and ultrastructural pattern of injury and systemic symptoms in patients with fialuridine toxicity are consistent with severe mitochondrial and metabolic derangements. Similar hepatic pathologic findings have been reported rarely for other antiviral nucleoside analogues, which suggests that the mechanisms of toxicity might be related.
Injection drug use is a major risk factor for human immunodeficiency virus (HIV) infection and drug treatment is widely recognized as a core component of the public health effort to limit the spread of HIV. The assumption is frequently made that lack of immediate access to treatment is a significant barrier to the success of this effort. However, little empirical data exist to support this belief. We conducted a trial of no-cost outpatient drug-free treatment made available on demand to a cohort of out-of-treatment injection drug users (IDUs) in Portland, Oregon, through a coupon program. Of 824 IDUs, 272 (33%) expressed an interest in treatment, 225 (27%) accepted a coupon, 66 (8%) redeemed a coupon, and 9 (1%) remained in treatment for 6 months. These numbers indicate that simply enhancing access is not adequate. Additional strategies to increase motivation to enter and remain in treatment are needed if drug treatment is to play an important role in reducing the spread of HIV among injection drug users, their sexual partners, and their infants.
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Trimetrexate is a powerful inhibitor of the dihydrofolate reductase of Pneumocystis carinii. AIDS patients (n = 215) with moderate to severe P. carinii pneumonia were enrolled in a double-blind study of trimetrexate plus leucovorin versus trimethoprim-sulfamethoxazole (TMP-SMZ) for 21 days. By study day 10, study therapy failed because of lack of efficacy in 16% of patients assigned to TMP-SMZ and 27% assigned to trimetrexate (P = .064), and the PAO2-PaO2 improved significantly faster with TMP-SMZ. By study day 21, failure rates were 20% with TMP-SMZ and 38% with trimetrexate (P = .008), with respective mortality rates of 12% and 20% (P = .088). By study day 49, the difference in mortality (16% vs. 31%) was significant (P = .028). The cumulative incidence of serious and treatment-terminating adverse events including hematologic toxicities was less with trimetrexate (P < .001). Thus, trimetrexate plus leucovorin was effective, albeit inferior to TMP-SMZ, for moderately severe P. carinii pneumonia but was better tolerated than TMP-SMZ.
OBJECTIVE: To determine changes in causes of death, survival, and organ system distribution of major opportunistic infections and neoplasms in adults dying with the acquired immunodeficiency syndrome (AIDS) following the widespread use of antiretroviral therapy and prophylaxis for opportunistic infections since 1988. DESIGN: A retrospective review of autopsy records with gross and microscopic pathologic findings, laboratory data, and clinical histories in cases of AIDS, comparing findings from 1982 through 1988 with those from 1989 through May 1993. SETTING: All autopsies were performed on persons dying in the metropolitan Los Angeles, Calif, area from January 1982 through May 1993. RESULTS: In 565 adult cases of AIDS at autopsy, Pneumocystis carinii pneumonia (PCP) remained the most common cause of death, but both the frequency of and number of deaths of PCP declined over time. Deaths from bacterial sepsis, cytomegalovirus infection, Mycobacterium avium complex infection, and toxoplasmosis also declined during this period, but mortality from fungal infections, tuberculosis, encephalopathy, and causes unrelated to AIDS increased. The death rate from malignant lymphoma remained high. Kaposi's sarcoma (KS) continued to occur more frequently in patients whose risk factor for human immunodeficiency virus infection (HIV) was homosexuality or bisexuality, but the death rate from KS was greatest for patients with a risk factor of blood exposure to HIV. Survival was shorter and deaths from tuberculosis more common in patients with a history of intravenous drug use. Overall survival of patients in other AIDS risk groups increased over time, particularly in those treated with antiretroviral therapy. The organ system distribution of major opportunistic infections and neoplasms was similar throughout the years of the study. The lung was the most frequent organ involved by AIDS-associated diseases leading to death, followed by the gastrointestinal tract and the central nervous system. CONCLUSIONS: The causes of death in AIDS have evolved since 1988 following the widespread use of prophylactic and antiretroviral therapies in patients with HIV infection. This has occurred primarily from changes in overall frequency and death rates from infections. Organ system involvement by AIDS-associated diseases has not changed significantly over time.
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With over 15,000 solid organ transplants performed in the United States last year, it is exciting to follow trends in this field. The United Network for Organ Sharing is carefully studying the availability of organs and new methods to enhance organ donation. In the forefront at this time are new antirejection medications being tested throughout the United States. In the basic science and immunology arena are many studies on graft tolerance, whereby organs are accepted by the body with minimal or no immunosuppression. The real answers to many transplantation questions are still being answered through the efforts of ongoing research.
Thirty-one single lung transplantations were performed between March 17, 1988, and November 1, 1990. Postoperative infection, especially with cytomegalovirus, has been the major cause of morbidity and mortality. Eighteen of the 31 patients were receiving prednisone before transplantation. Every patient was prepared preoperatively with oral cyclosporine 5 mg/kg and azathioprine (Imuran) 2 mg/kg. Every patient received methylprednisolone for 3 days postoperatively, followed by prednisone 1.0 mg/kg/day, oral cyclosporine, and azathioprine. Ten patients additionally had cytolytic therapy with OKT3 and 12 with antilymphocyte globulin. Nine patients had no cytolytic therapy. Cytolytic therapy was chronologic, not randomized. Postoperative infection occurred in 20 patients, 13 of whom had cytomegalovirus infection. Preoperative use of prednisone did not correlate with postoperative infection, cytomegalovirus, or death. Postoperative infection occurred in 17 of 22 patients with cytolytic therapy compared with three of nine without cytolytic therapy (p = 0.035). Cytomegalovirus infection occurred in 13 of 22 with cytolytic therapy and in none of the nine without cytolytic agents (p = 0.003). Therefore preoperative prednisone does not appear to be a contraindication to single lung transplantation. Cytolytic therapy with either OKT3 or antilymphocyte globulin increases the prevalence of postoperative infection with cytomegalovirus and should not be used in patients undergoing lung transplantation.
The authors evaluated the use of direct Gram-stained smears, 1- and 24-hour urease broth tests, histologic examination, and culture to detect Helicobacter pylori in 100 gastric biopsy specimens from 97 patients with epigastric symptoms. Twenty-six patients had positive cultures and 27 had H. pylori identifiable in hematoxylin and eosin-stained sections. The gastric biopsy specimens from the 29 patients with culture and/or histologic findings positive for H. pylori showed active gastritis in 27 cases (93%), compared with 26 cases (37%) without H. pylori (P less than 0.0001). Chronic gastritis was present in 25 cases (86%) with H. pylori and 40 cases (56%) without H. pylori (P less than 0.01). Twenty patients had positive Gram-stained smears. Fifteen patients had positive 1-hour urease tests, and 3 had delayed positive 24-hour urease tests. There were no false-positive Gram's stain results, three false-positive 24-hour urease tests, two false-negative histologic results, and three false-negative cultures (one inadvertently incubated anaerobically). The sensitivities of the methods were as follows: 62% for the 24-hour urease test, 69% for direct Gram's stain, 90% for culture, and 93% for histologic examination. The authors conclude that the urease test used in this study has low sensitivity and limited specificity; that the direct Gram-stained smear is a useful, highly specific, rapid screening test; and that the lengthier methods of culture and histologic examination have comparably high sensitivity for the definitive diagnosis of H. pylori gastritis.
In a series of 342 bone marrow examinations from 314 patients with human immunodeficiency virus infection, 70 examinations (20%) detected opportunistic mycobacterial or fungal infections. One hundred eleven of the 314 patients had such infections, and, hence, 63% (70/111) were detected by bone marrow examination. Special stains for microorganisms detected 16 (32%) of 50 Mycobacterium avium complex infections, 10 (22%) of 45 Mycobacterium tuberculosis infections, eight (73%) of 11 Histoplasma capsulatum infections, and five (83%) of six Cryptococcus neoformans infections. Bone marrow cultures detected 36 (72%) of the 50 M avium complex infections, 13 (29%) of the 45 M tuberculosis infections, and 63% of the fungal infections. Marrow examination revealed infection in only one of the 70 specimens (1%) collected to evaluate thrombocytopenia alone or hematologic malignancy, but in 69 (25%) of 274 with fever, neutropenia, anemia, or miscellaneous other indications for marrow examination. Granulomas were detected in 102 (30%) of the biopsy specimens, including 71 (64%) of those in cases with mycobacterial or fungal infection. The granulomas showed caseous necrosis in nine cases, all in patients with tuberculosis, and the 27 cases with tuberculosis-associated granulomas tended to show large, tightly cohesive granulomas. The presence of granulomas correlated with opportunistic infection in 82 (80%) of 102 cases. Without granulomas, special stains were positive in only eight (3%) of 240 specimens. These results suggest that (1) bone marrow granulomas are a common and valuable histologic clue to opportunistic infection; (2) without them, special stains may not be a cost-efficient way to diagnose such infection; and (3) bone marrow examination can be a useful method of diagnosing opportunistic mycobacterial and fungal infections in patients with fever, anemia or neutropenia, and underlying human immunodeficiency virus infection.
Twenty-two patients have undergone 23 single lung transplants between March 1980 and April 1990 at the University of Texas Health Science Center at San Antonio. The actuarial survival rate is 77.27% at 12 months and 72.73% at 24 months. There have been no instances of bronchial dehiscence or stenosis, even though 13 of the patients were on a program of preoperative prednisone, every patient had high-dose perioperative methylprednisolone, and omental wraps were not used on any bronchial anastomosis. Of particular interest is the fact that three patients had primary pulmonary hypertension, three had secondary pulmonary hypertension, and 10 patients had chronic obstructive pulmonary disease, due in five cases to an alpha 1-antitrypsin deficiency. Each of these entities was previously thought to contraindicate single lung transplantation. Donor selection was based on an oxygen tension/inspired oxygen concentration ratio greater than 300, donor/recipient chest circumference within 3 inches, clear chest x-ray film, negative sputum Gram stain, and less than 6-hour estimated ischemic time. Harvest technique included donor prostaglandin E1 500 micrograms, topical slush, and pulmonoplegia with cold Euro-Collins solution. The heart and lung were separated in situ rather than the heart lung block being removed. A telescoping bronchial anastomosis was performed with 4-0 Prolene (not absorbable) sutures. We conclude that single lung transplantation has evolved into a simple operation, necessitating meticulous preoperative and postoperative care, which can be performed on a wide spectrum of critically ill patients with an acceptable mortality rate.
Respiratory failure in syringomyelia has rarely been reported. We report a patient with syringomyelia who showed some neurological improvement after intermittent respiratory support with negative and positive pressure ventilation.