Tanya R. Flohr

Aggressive versus conservative initiation of antimicrobial treatment in critically ill surgical patients with suspected intensive-care-unit-acquired infection: a quasi-experimental, before and after observational cohort study

BACKGROUND Antimicrobial treatment in critically ill patients can either be started as soon as infection is suspected or after objective data confirm an infection. We postulated that delaying antimicrobial treatment of patients with suspected infections in the surgical intensive care unit (SICU) until objective evidence of infection had been obtained would not worsen patient mortality. METHODS We did a 2-year, quasi-experimental, before and after observational cohort study of patients aged 18 years or older who were admitted to the SICU of the University of Virginia (Charlottesville, VA, USA). From Sept 1, 2008, to Aug 31, 2009, aggressive treatment was used: patients suspected of having an infection on the basis of clinical grounds had blood cultures sent and antimicrobial treatment started. From Sept 1, 2009, to Aug 31, 2010, a conservative strategy was used, with antimicrobial treatment started only after objective findings confirmed an infection. Our primary outcome was in-hospital mortality. Analyses were by intention to treat. FINDINGS Admissions to the SICU for the first and second years were 762 and 721, respectively, with 101 patients with SICU-acquired infections during the aggressive year and 100 patients during the conservative year. Compared with the aggressive approach, the conservative approach was associated with lower all-cause mortality (13/100 [13%] vs 27/101 [27%]; p=0·015), more initially appropriate therapy (158/214 [74%] vs 144/231 [62%]; p=0·0095), and a shorter mean duration of therapy (12·5 days [SD 10·7] vs 17·7 [28·1]; p=0·0080). After adjusting for age, sex, trauma involvement, acute physiology and chronic health evaluation (APACHE) II score, and site of infection, the odds ratio for the risk of mortality in the aggressive therapy group compared with the conservative therapy group was 2·5 (95% CI 1·5-4·0). INTERPRETATION Waiting for objective data to diagnose infection before treatment with antimicrobial drugs for suspected SICU-acquired infections does not worsen mortality and might be associated with better outcomes and use of antimicrobial drugs. FUNDING National Institutes of Health.

The use of stem cells in liver disease

Purpose of reviewCell transplantation to restore liver function as an alternative to whole liver transplantation has thus far not been successful in humans. Recent findingsAdult mature hepatocytes and various populations of liver progenitors and stem cells are being studied for their regenerative capabilities. Hepatocyte transplantation to treat metabolic deficiencies has shown promising early improvement in liver function; however, long-term success has not been achieved. Liver progenitor cells can now be identified and were shown to be capable to differentiate into a hepatocyte-like phenotype. Despite evidence of mesenchymal stem cell fusion in animal models of liver regeneration, encouraging results were seen in a small group of patients receiving autologous transplantation of CD133+ mesenchymal stem cells to repopulate the liver after extensive hepatectomy for liver masses. Ethical issues, availability, potential rejection and limited understanding of the totipotent capabilities of embryonic stem cells are the limitations that prevent their use for restoration of liver function. The effectiveness of embryonic stem cells to support liver function has been proven with their application in the bioartificial liver model in rodents. SummaryThere is ongoing research to restore liver function in cell biology, animal models and clinical trials using mature hepatocytes, liver progenitor cells, mesenchymal stem cells and embryonic stem cells.

Diagnosis-Dependent Relationships between Cytokine Levels and Survival in Patients Admitted for Surgical Critical Care

BACKGROUND Death after trauma, infection, or other critical illness has been attributed to unbalanced inflammation, in which dysregulation of cytokines leads to multiple organ dysfunction and death. We hypothesized that admission cytokine profiles associated with death would differ based on admitting diagnosis. STUDY DESIGN This 5-year study included patients admitted for trauma or surgical intensive care for more than 48 hours at 2 academic, tertiary care hospitals between October 2001 and May 2006. Cytokine analysis for interleukin (IL)-1, -2, -4, -6, -8, -10, -12, interferon-gamma, and tumor necrosis factor (TNF)-alpha was performed using ELISA on specimens drawn within 72 hours of admission. Mann-Whitney U test was used to compare median admission cytokine levels between alive and deceased patients. Relative risks and odds of death associated with admission cytokines were generated using univariate analysis and multivariate logistic regression models, respectively. RESULTS There were 1,655 patients who had complete cytokine data: 290 infected, nontrauma; 343 noninfected, nontrauma; and 1,022 trauma. Among infected patients, nonsurvivors had higher median admission levels of IL-2, -8, -10, and granulocyte macrophage-colony stimulating factor; noninfected, nontrauma patients had higher IL-6, -8, and IL-10; and nonsurviving trauma patients had higher IL-4, -6, -8, and TNF-alpha. IL-4 was the most significant predictor of death and carried the highest relative risk of dying in trauma patients, and IL-8 in nontrauma, noninfected patients. In infected patients, no cytokine independently predicted death. CONCLUSIONS Cytokine profiles of certain disease states may identify persons at risk of dying and allow for selective targeting of multiple cytokines to prevent organ dysfunction and death.

Moraxella osloensis bacteremia in a kidney transplant recipient

The combination of contemporary potent immunosuppressive agents and antimicrobial prophylactic regimens are simultaneously increasing the susceptibility of organ transplant recipients to opportunistic infections and altering the range of causative microbial pathogens [1]. New molecular diagnostical methods are being increasingly used to identify previously unrecognized opportunistic pathogens [1,2]. Moraxella are aerobic, pleomorphic Gram negative bacteria that are common commensal organisms of the human upper respiratory tract. Moraxella catarrhalis is typically considered to have the greatest ability to act as a pathogen; other species such as Moraxella osloensis are considered to be rare pathogens in humans and most reported cases were found in immunocompromised patients [3,4]. Thus far no case of M. osloensis infection after solid organ transplantation (SOT) has been published. Of note, correlating clinical disease with other species such as M. osloensis has been hampered by the complexity of differentiating Moraxella by biochemical and phenotypic testing [3,4]. Therefore, M. osloensis may be an underappreciated pathogen. A 60-year-old man underwent a living-unrelated kidney transplant for end-stage renal disease because of systemic sclerosis. His past medical history also included renal cell carcinoma, for which he underwent a left nephrectomy three years prior to the transplant. He required peritoneal dialysis from the time of the nephrectomy up to the transplant. The transplant was performed without complications. Immunosuppression included induction with antithymocyte globulin (ATG, 1.5 mg/kg on four consecutive days), mycophenolate mofetil (1.5 g/day), tacrolimus (trough levels 8–12 ng/ ml) and a steroid taper. The peritoneal dialysis catheter and ureteral stent were removed three weeks after the transplant. Cultures of peritoneal fluid drawn before catheter removal were negative for bacterial growth. A urine culture obtained before stent removal grew vancomycin-resistant Enterococcus faecium, which was treated with a 3-day course of linezolid. Ten days later, he presented with abdominal pain, nausea, vomiting, fever and chills of one day’s duration. He had a temperature of 36.3 C, pulse of 106/min, and blood pressure of 179/122 mmHg. His physical exam was remarkable for abdominal distension, tenderness and reduced bowel sounds. Initial laboratory test results were notable for a white blood cell count at 16 900/ll with 89% neutrophils, creatinine of 1.3 mg/dl, and normal hepatic and pancreatic enzyme levels. Abdominal computed tomography scans revealed postoperative changes around the allograft, no ascites, and mild distension of the small bowel consistent with an ileus. Cultures were obtained before empirical treatment with vancomycin and cefepime was started. Urinalysis and urine culture were unremarkable. On day 2, a non-catarrhalis Moraxella species was isolated from a set of the admission blood cultures. PCR sequencing of genomic DNA using a set of 16S rDNA primers confirmed that the isolate was Moraxella osloensis (99% identity over 443 bp, e-value 0). Antimicrobial susceptibility testing was performed by the E-test (AB Biodisk, Solna, Sweden) and Kirby–Bauer disk diffusion methods. Using CLSI breakpoints for Haemophilus influenzae for interpretation, the isolate was sensitive to penicillin, cefotaxime, cefepime, ciprofloxacin, and trimethoprim-sulfamethoxazole and was resistant to tetracycline. Blood cultures obtained after the initiation of antibiotics were negative. The patient’s abdominal pain progressively improved and his bowel function returned to normal with conservative management. He was discharged on the fourth day of the admission on a two-week course of oral ciprofloxacin. He recovered without further difficulties and was doing well on 9-month post-transplant clinic visit. Genetic analysis has become an effective tool for the taxonomic identification of Moraxella species and may prove to be a powerful method to elucidate relationships between different species and clinical disease [5]. In addition to being a human respiratory tract saprophyte [3,4], M. osloensis has also been recovered from environmental samples and is a mutualist of Phasmarhabditis hermaphrodita (Nematoda: Rhabditidae), a parasitical roundworm that infects and kills terrestrial mollusks [6–11]. In garden slugs infected by P. hermaphrodita, M. osloensis is thought to act as the primary killing agent [7,12]. Historically M. osloensis has rarely been implicated in systemic disease

Nocardiosis in solid-organ transplant recipients: Spectrum of imaging findings

Nocardiosis is an infrequent but severe infection that primarily affects the lung and thence is able to produce disseminated disease. Prompt diagnosis of pulmonary and disseminated nocardiosis is of utmost importance in solid-organ transplant recipients to reduce mortality. Knowledge of the different radiological manifestations in the appropriate clinical setting is key to successful management of these patients. The aim of this review is to describe the radiological features of nocardiosis in immunosuppressed patients, particularly in solid-organ transplant recipients.

Nocardiosis in a renal transplant recipient following rituximab preconditioning

Sir, With great interest we read the recent article ‘Pulmonary nocardiosis with brain abscess in a sensitized kidney transplant recipient with history of repeated graft loss and human leukocyte antigen HLA-antibody depletion treatment—a case report’ by Ali-Reza Biglarnia et al. (1). This report is important in the light of an increased exposure of renal transplant recipients to more intense immunosuppression, in particular to depleting antibodies such as rituximab. Rituximab is unique, as in contrast to antithymocyte globulin (ATG), muromunab OKT3, and alemtuzumab it targets B cells (2) but may cause profound hypogammaglobulinemia. We would like to add another case of nocardiosis after renal transplantation (RT) and exposure to rituximab that largely mimics the case reported by Biglarnia and should support the findings and emphasize the risk for opportunistic infections in such patients. Our patient was a 45-year-old female with end stage renal disease secondary to streptococcal glomerulonephritis. She underwent living related RT in 1978 but ceased taking her immunosuppression during the early 1990s for an unknown period. In 1997, she presented with an elevation in her serum creatinine from 1.5 to 5.0 mg/dL. This non-compliance-associated rejection was initially treated with a course of methylprednisolone (500 mg daily for three doses), then with a course of OKT3 (5 mg daily for five days). The rejection could not be reversed, and she was started on hemodialysis in 1998. The patient tested repeatedly positive for preformed panel-reactive antibodies (PRA) with high titers, and on several occasions the donor/recipient cross-match was positive, preventing a cadaveric RT. The option for living related donation was evaluated; however, the cross-match was again incompatible. Therefore, the patient underwent preconditioning for RT with rituximab (375 mg/m2), intravenous immunoglobulin (IVIG) at a dose of 0.5–4.0 mg/kg/min, and whole plasma exchange (WPE). During the waiting time for RT she was maintained on mycophenolate mofetil (MMF) at a dose of 2 g/day. Her subsequent titer of PRAs was found to be suitable to proceed with RT. Living related RT from a cousin was performed without complication in 2006, and immunosuppression consisted of ATG induction (1.5 mg/kg for three days) followed by tacrolimus (TAC) with trough levels of 6–12 ng/mL, with continuation of MMF and a steroid taper. Two weeks post RT, a biopsy revealed humoral rejection. She was treated with ATG, IVIG, and nine courses of WPE. Rejection resolved, and she was discharged with stable graft function. Pneumocystis jirovecii prophylaxis consisted of dapsone due to her sulfa allergy; She was hospitalized multiple times for anasarca, urinary tract infection, and pneumonia. Despite several attempts to counsel the patient, she continued smoking and missed several follow-up appointments. Three months post RT she developed another episode of pneumonia presenting with shortness of breath, cough, and fever. Chest X-ray revealed a left upper lobe lesion consistent with infection in the context of the clinical history. No pathogen could be isolated from sputum. She received a 10-day course of empiric therapy with linezolid (600 mg daily) and ciprofloxacin (500 mg twice daily), and immunosuppression was temporarily reduced. She rapidly improved and was discharged with stable graft function. Two months later, she again deteriorated; her left upper lobe lesion appeared unresolved and cavitary on chest X-ray and CT scan (Figure 1). Bronchoalveolar lavage cultures revealed Nocardia nova. She was desensitized and started on twice daily double-strength trimethoprim/sulfamethoxazole (TMPS); immunosuppression was again temporarily reduced. She was discharged with resolved respiratory symptoms and stable graft function, however, again deteriorated requiring readmission six months after first diagnosis of nocardiosis. She developed respiratory failure requiring mechanical ventilation. Nocardia could not be isolated, however, TMPS was continued. She again improved and was discharged with stable graft function. Subsequently, she was hospitalized another two times for respiratory infections. Her chest CT scan continued to reveal a lung lesion with slow resolution. She is currently alive with good graft function, no further rejection episodes and no signs of recurrent nocardiosis. Figure 1. Chest X-ray (A) and CT scan (B) show left lobe infiltrates. Similar to the reported case by Biglarnia et al. our patient had a re-RT, and the first RT was complicated by steroid-resistant rejection and OKT3 treatment. In addition both patients had elevated PRA and underwent preconditioning using WPE and rituximab. Both received TAC, MMF, and steroids for maintenance immunosuppression. Our patient may have received even more intense immunosuppression (ATG versus interleukin IL-2 receptor antagonist induction), and in addition she had rejection requiring a second course of ATG and WPE. On the other hand our patient was 14 years younger. Both patients had no prophylaxis against Nocardia as their Pneumocystis jirovecii prophylaxis included dapsone and inhaled pentamidine. Recent findings by the Pittsburgh group suggested that in a subset of patients, TMPS may be ineffective in terms of prophylaxis against Nocardia (3). The application of linezolid for pneumonia may have temporarily controlled Nocardia growth. This new agent may be a good treatment option in transplant recipients, and one patient in the publication from the Innsbruck group was successfully treated with linezolid (3). In our patient, we assume that the continuous smoking was a significant contributor. Nocardiosis has been reported in a RT recipient who was a smoker (4). We have recently encountered an increasing number of transplant recipients with nocardiosis. In addition, extrapulmonary manifestations have become more common, and species other than Nocardia asteroides are on the rise. Our patient had only pulmonary involvement in contrast to the previously reported case, and in both cases non-asteroides Nocardia were the causing organism (Nocardia nova and Nocardia farcinica). A common denominator in 11 transplant recipients who developed nocardiosis between 1995 and 2008 at our center was the use of depleting antibodies. Transplant physicians should be aware of this rare infection and include nocardiosis in the differential diagnosis in patients presenting with pneumonia.

Benign Transient Hyperphosphatasemia Associated With Epstein-Barr Virus Enteritis in a Pediatric Liver Transplant Patient: A Case Report

Transient hyperphosphatasemia was found in a 3-year-old male liver transplant recipient. The condition was associated with diarrheal disease due to the Epstein-Barr virus (EBV). Immunosuppression was tapered and valganciclovir prescribed for 3 months, after which the diarrhea resolved and the EBV polymerase chain reaction assays became negative. After 6 months, alkaline phosphatase levels normalized. Isolated elevation of alkaline phosphatase in conjunction with enteric infection is a rare condition. No further diagnostic or therapeutic interventions except treatment of the underlying infection are needed, as this has been shown to be a benign, transient condition.

Herpes simplex virus hepatitis after renal transplantation

To the Editor We were excited to see the recent case series and review of herpes simplex virus (HSV) hepatitis by Duckro et al. (1) and would like to report an additional case of mildly symptomatic HSV hepatitis in a kidney transplant recipient from our center. The patient is a 23 -year-old womanwith a history of multiple genital and urological abnormalities as the result of Mayer-Rokitansky-Kˇster-Hauser syndrome. She underwent a living-related kidney transplant 5 years earlier as the result of renal hypoplasia with an uneventful posttransplant course. Donor and recipient were cytomegalovirus (CMV) negative and the patient tested negative for HSV antibodies before transplantation. Six months before admission she developed steroid-resistant acute cellular rejection, which may have been due to noncompliance, and received 4 cycles of anti-thymocyte globulin (ATG) therapy. Valgancyclovir (450 g/day) was administered during therapy but was discontinued a few weeks after the ¢nal dose of ATG because of persistent neutropenia. Her renal function returned to baseline, and she was maintained on a regimen of tacrolimus, mycophenolate mofetil (MMF), and prednisone. She then presented with a fever of 39.21C, nausea, graft tenderness, and acute renal failure. She was admitted and found to have Escherichia coli acute graft pyelonephritis. Of note, she also reported having a new sexual partner in the month preceding the admission and stated recently developing oral ulcers that would ‘come and go.’ No tests were performed to con¢rm HSV infection.While the graft tenderness improved on antibiotic therapy, the patient developed new right upper quadrant abdominal pain on hospital day 8. Laboratory testing demonstrated that her alanine aminotransferase and aspartate aminotransferase had risen from 12 to 15 U/L, respectively, on admission to 296 and 503 U/L on hospital day 8, and 1252 and 2892 U/L on hospital day 10. Examination revealed a fever of 38.81C, right upper quadrant tenderness, and vesicular and ulcerating lesions on buccal and neo-labial mucosae, but no tests with regard to HSV were performed. Leukopenia and thrombocytopenia (white blood cell count of 1660/mL, platelet count of 56,000/mL) were also noted on laboratory testing. Serum CMV DNA polymerase chain reaction (PCR), serum hepatitis C RNA, serology for acute hepatitis A and C, and serology for HSV types 1 and 2 were all negative. The patient was previously vaccinated for hepatitis B r 2008 Wiley Periodicals, Inc.

Elderly Recipients of Hepatitis C Positive Renal Allografts Can Quickly Develop Liver Disease

Our institution explored using allografts from donors with Hepatitis C virus (HCV) for elderly renal transplantation (RT). Thirteen HCV- elderly recipients were transplanted with HCV+ allografts (eD+/R-) between January 2003 and April 2009. Ninety HCV- elderly recipients of HCV- allografts (eD-/R-), eight HCV+ recipients of HCV+ allografts (D+/R+) and thirteen HCV+ recipients of HCV- allografts (D-/R+) were also transplanted. Median follow-up was 1.5 (range 0.8-5) years. Seven eD+/R- developed a positive HCV viral load and six had elevated liver transaminases with evidence of hepatitis on biopsy. Overall, eD+/R- survival was 46% while the eD-/R- survival was 85% (P = 0.003). Seven eD+/R- died during follow-up. Causes included multi-organ failure and sepsis (n = 4), cancer (n = 1), failure-to-thrive (n = 1) and surgical complications (n = 1). One eD+/R- died from causes directly related to HCV infection. In conclusion, multiple eD+/R- quickly developed HCV-related liver disease and infections were a frequent cause of morbidity and mortality.

Liver transplantation in a patient with primary sclerosing cholangitis suffering from lipomatous pseudohypertrophy of the pancreas

Although the pathogenesis of lipomatous pseudohypertrophy (LiPH) of the pancreas is not clear, findings of previous 10 cases support the hypothesis that hepatic disorders are closely linked to this condition [1–3]. The first case dates back to 1953 and was published by Robson et al. [4]. They described the lesion as an abundance of mature adipose tissue with widely separated fibrous septae investing remnants of pancreas parenchyma. The pathogenesis of this disorder remained unknown; however, over the following decades more and more evidences were collected that LiPH may be caused by liver disorders [5]. Sasaki reported a patient with chronic hepatitis B and such a lesion, and Kuroda et al. [6,7] confirmed these findings. In both cases, there was no evidence for obesity but both patients suffered form liver cirrhosis. Most published cases come from Japan. Bralet et al., on the other hand, found that LiPH was associated with a squamous cancer of the pancreas in a patient without liver disease and the disorder has been reported in association with chronic pulmonary disease by Siegler et al. [8,9] In another case, the disease caused obstruction of the bile duct and required surgical treatment by a hepaticojejunostomy. LiPH also has been reported in the submandibular gland [10]. A case from Russia suggested a congenital disorder associated with this obscure lesion [11]. LiPH can grow to gigantic masses; histology of the pancreas reveals almost complete replacement of the acinar cells by adipocytes with preservation of the islets. Insulin-dependent diabetes mellitus is not a typical feature of this obscure disorder. Although closely linked to liver cirrhosis, thus far not a single case of LiPH associated with primary sclerosing cholangitis (PSC) or liver transplantation (LT) has been reported. Our patient was a 32-year-old male who was diagnosed with PSC 2001. His presenting symptoms included weight loss, watery diarrhea, pruritus, and scleral icterus. His family history included a father diagnosed with PSC who underwent LT. Liver biopsy in 2001 showed chronic hepatitis with bridging fibrosis and early cirrhosis and typical features of PSC. Endoscopic retrograde cholangiopancreatography (ERCP) findings for the patient at the time of diagnosis revealed diffuse areas of narrowing and dilation of the biliary tree. During the following years, multiple biliary stents were placed. He had at least one documented episode of cholangitis with sepsis. He developed significant ascites, which was treated with routine paracentesis and continued to have abdominal pain. In February 2007, the patient underwent routine ERCP with removal of his biliary stents. New stents could not be placed because of a tight ductal stricture. A few days after his procedure, he was admitted for increased abdominal pain and multiple loose, light-colored stools. Upon admission, laboratory values included mildly elevated liver enzymes (AST 61 IU/ml, ALT 108 IU/ml), a total serum bilirubin of 8.1 mg/dl and alkaline phosphatase of 357 IU/ml. Also serum amylase was mildly elevated with 141 mg/dl. Magnetic resonance cholangiopancreatography (MRCP) and Magnetic resonance imaging (MRI) of the abdomen were performed revealing typical features of the PSC and in addition an intramesenteric lipomatous mass emanating from the pancreatic head (Fig. 1a and b). This mass had been present on MRI studies 5 years prior with size unchanged, measuring 18 cm at the greatest diameter. Despite the mass effect that the tumor exerted on the head and distal body of the pancreas, there was no pancreatic ductal dilation noted. The patient was evaluated and listed for LT with a model for end stage liver disease (MELD) score of 17; biopsy of the mass was planned to be performed during LT. Few days later while still hospitalized, a cadaveric graft became available. On exploration of the abdominal cavity, the intramesenteric lipomatous mass was found and a wedge resection was performed prior to hepatectomy. Histology showed mature adipose tissue with admixed with benign pancreatic elements (Fig. 2a and b). The final pathology was LiPH of the pancreas. Resection of the mass did not occur during the operation because its location originating from the pancreatic head would have required a Whipple procedure. Following the confirmation that the