Invasive aspergillosis in liver transplant recipients, an infectious complication with low incidence but significant mortality.

BACKGROUND: Infections, including invasive fungal infections (IFIs), are among the leading causes of mortality in liver transplant recipients during the first year post-transplantation. AIM: To investigate the epidemiology, clinical manifestations, risk factors, treatment outcomes, and mortality rate of post-liver transplantation invasive aspergillosis (IA). METHODS: In this case-control study, 22 patients with IA were identified by reviewing the archived and electronic medical records of 850 patients who received liver transplants at the Imam Khomeini Hospital complex in Tehran, Iran, between 2014 and 2019. The control group comprised 38 patients without IA infection matched for age and sex. The information obtained included the baseline characteristics of liver transplant patients, operative reports, post-transplantation characteristics of both groups and information about the fungal infection of the patient group. RESULTS: The prevalence rate of IA among liver transplant recipients at Imam Khomeini Hospital was 2.7%. The risk factors of IA among studied patients included high serum creatinine levels before and post-transplant, renal replacement therapy, antithymocyte globulin induction therapy, post-transplant bile leakage, post-transplant hepatic artery thrombosis, repeated surgery within 30 d after the transplant, bacterial pneumonia before the aspergillosis diagnosis, receiving systemic antibiotics before the aspergillus infection, cytomegalovirus infection, and duration of post-transplant hospitalization in the intensive care unit. The most prevalent form of infection was invasive pulmonary aspergillosis, and the most common chest computed tomography scan findings were nodules, pleural effusion, and the halo sign. In the case group, prophylactic antifungal therapy was administered more frequently than in the control group. The antifungal therapy response rate at 12 wk was 63.7%. The 3- and 12- mo mortality rates of the patients with IA were 36.4% and 45.4%, respectively (compared with the mortality rate of the control group in 12 mo, which was zero). CONCLUSION: In this study, the prevalence of IA among liver transplant recipients was relatively low. However, it was one of the leading causes of mortality following liver transplantation. Targeted antifungal therapy may be a factor in the low incidence of infections at our facility. Identifying the risk factors of IFIs, maintaining an elevated level of clinical suspicion, and initiating early antifungal treatment may significantly improve the prognosis and reduce the mortality rate of liver transplant recipients.

Statin Use May Be Associated With a Lower Risk of Invasive Aspergillosis in Lung Transplant Recipients.

BACKGROUND: Statins are competitive inhibitors of 3-hydroxy-3methylglutaryl coenzyme A reductase (HMG-CoA reductase) that catalyses HMG-CoA conversion to mevalonate, a process involved in synthesizing cholesterol in humans and ergosterol in fungi. The effect of statin use on the risk of development of invasive aspergillosis (IA) in lung transplant recipients (LTRs) is not well documented. METHODS: This retrospective study included LTRs from 2010 to 2017 who were followed for one-year post-transplant. Proven or probable IA was diagnosed as per ISHLT criteria. We performed a multivariable Cox proportional hazards model of the association between IA and statin use (minimum of 2 weeks duration prior to IA), adjusting for other known IA risk factors. RESULTS: We identified 785 LTRs, 44% female, mean age 53 years old, the most common underlying disease being pulmonary fibrosis (23.8%). In total, 451 LTRs (57%) received statins post-transplant, atorvastatin was the most commonly used statin (68%). The mean duration of statins post-transplant was 347 days (interquartile range [IQR]: 305 to 346). And 55 (7%) LTRs developed IA in the first-year post-transplant. Out of these 55 LTRs, 9 (16.3%) had received statin before developing IA. In multivariable analysis, statin use was independently associated with a lower risk of IA (P = .002, SHR 0.30, 95% confidence interval [CI] 95% .14-.64). Statin use was also associated with a lower incidence of post-transplant Aspergillus colonization, 114 (34%) in the no statin group vs 123 (27%) in the statin group (P = .038). CONCLUSIONS: The use of statin for a minimum of two weeks during the first-year post-transplant was associated with a 70% risk reduction of IA in LTRs.

Antifungal prophylaxis in adult lung transplant recipients: Uncertainty despite 30 years of experience. A systematic review of the literature and network meta-analysis.

BACKGROUND: Invasive fungal infections (IFI), particularly invasive aspergillosis (IA), cause significant morbidity and mortality in lung transplant (LTx) recipients. The optimum strategy and antifungal agents for prevention are unclear. METHODS: We performed a comprehensive literature search, systematic review, and network meta-analysis using a frequentist framework to compare the efficacy of various antifungal drugs on the incidence of IA/IFI in the setting of universal prophylaxis or no prophylaxis following lung transplantation. RESULTS: We included 13 eligible studies comprising of 1515 LTx recipients and 12 different prophylaxis strategies/antifungal combinations. The greatest number of direct comparisons were between the inhaled amphotericin formulations. The top three ranked treatments were inhaled liposomal amphotericin B (L-AmB), inhaled amphotericin deoxycholate (AmBd), and itraconazole plus inhaled amphotericin B (AmB). Among the azoles, isavuconazole ranked highest. The certainty of the evidence, assessed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) framework, was very low. CONCLUSION: Although universal antifungal prophylaxis post lung transplantation is commonly used, robust data from randomized controlled trials (RCTs) to inform the choice of antifungal agent and prophylaxis strategy are lacking. This exploratory network meta-analysis provides insight into the probable relative effectiveness of various antifungal agents in preventing IA, and this analysis should serve as a guide when selecting antifungals to be assessed in a RCT.

Late Onset Invasive Pulmonary Aspergillosis in Lung Transplant Recipients in the Setting of a Targeted Prophylaxis/Preemptive Antifungal Therapy Strategy.

BACKGROUND: Invasive pulmonary aspergillosis (IPA) is a significant cause of morbidity and mortality in lung transplant recipients (LTRs). It is unclear how a targeted prophylaxis/ preemptive antifungal therapy strategy impacts the incidence of IPA beyond the first-year posttransplant. METHODS: This is a retrospective cohort of LTRs from January 2010 to December 2014. We included all LTRs who survived beyond the first year and followed them until death or 4 years postoperatively. Incidence of probable/proven IPA and Aspergillus colonization were assessed as per International Society for Heart and Lung Transplantation (ISHLT) criteria. Patients with risk factors, positive Aspergillus cultures, or galactomannan (GM) received targeted prophylaxis/preemptive therapy within the first-year posttransplant. RESULTS: During the study period, 350 consecutive LTRs underwent 1078 bronchoscopies. Positive bronchoalveolar lavage for GM or Aspergillus cultures was reported for 15% (52/350) of LTRs between 2 and 4 years after transplantation. Among them, the median time to positive Aspergillus culture or GM positivity was 703 days (interquartile range, 529-754 d). The incidence rate of IPA and Aspergillus colonization was 30 of 1000 patient-y, and 63 of 1000 patient-y, respectively. The mortality rate was significantly higher in patients with IPA than without IPA (107/1000 patient-years versus 18/1000 patient-years; P < 0.0001). Rate of first-year colonization and IPA was 33% and 9%, respectively. Among the 201 patients who had a negative bronchoscopy during the first year posttransplant, only 6 (3%) developed IPA during the follow-up. CONCLUSIONS: A targeted prophylaxis/preemptive therapy strategy within the first-year posttransplant resulted in 4% incidence of IPA at 4-years after transplantation. However, IPA was associated with higher mortality.

Inferior Epigastric Artery Pseudoaneurysm Following Paracentesis in a Liver Graft Recipient: A Case Report.

Pseudoaneurysm happens when the artery wall is injured and the blood is contained by the surrounding tissues with eventual formation of a fibrous sac communicating with the artery. We report a case of a 39-year-old man with inferior epigastric artery (IEA) pseudoaneurysm after paracentesis. The pseudoaneurysm was diagnosed by Doppler ultrasound and treated by surgical intervention regarding the patient's underlying comorbidity. IEA false aneurysm must be included in the differential diagnosis during investigation of the cause of any swelling after paracentesis. Cirrhotic patients may be more prone to this complication because of thin rectus muscle that could not confine the hematoma.

Detection of Emergence Cyclospora cayetanensis in A HIV(+) / AIDS Patient with Diarrhea from Tehran: A Case Report.

Coccidian protozoa of Cyclospora cayetanensis are obligate intracellular apicomplexan parasites that infect the mucosal epithelium of the small intestine of immunocompetent and immunocompromised persons. A 25- years old woman from around, Tehran with complaint of faintness and fatigue with HIV positive/AIDS confirmed eight months ago was admitted in Imam Khomeini Hospital, Tehran, Iran in 2014. The patient suffered from intestinal and lung symptoms like watery diarrhea, flu-like symptoms. The stool was examined by direct preparation and concentration technique, stained with modified acid-fast staining method, and observed with light and then Immunofluorescence microscope. The stool cultivation was made in dichromate potassium medium and diagnosis of Cyclospora infection was finally made according to observation of Cyclospora oocysts almost 10 µm in acid-fast staining method and autofluorescence of Cyclospora under Immunofluorescence microscope. The patient was initially treated with azithromycin, tazocin and fluconazol because of lung lesions and diarrhea and relative remission was observed. Cyclospora sp. causes an intestinal infection particularly in immunocompromised patients.

Healthcare-associated outbreaks due to Mucorales and other uncommon fungi.

BACKGROUND: Healthcare-associated outbreaks of fungal infections, especially with uncommon and emerging fungi, have become more frequent in the past decade. MATERIALS AND METHOD: Here, we reviewed the history and definition of healthcare-associated outbreaks of uncommon fungal infections and discussed the principles of investigating, containing and treatment of these outbreaks. RESULTS: In case of these uncommon diseases, occurrence of two or more cases in a short period is considered as an outbreak. Contaminated medical devices and hospital environment are the major sources of these outbreaks. Care must be taken to differentiate a real infection from colonization or contamination. Defining and identifying cases, describing epidemiologic feature of cases, finding and controlling the source of the outbreak, treating patients, and managing asymptomatic exposed patients are main steps for outbreak elimination. These fungal outbreaks are not only difficult to detect but also hard to treat. Early initiation of appropriate antifungal therapy is strongly associated with improved outcomes in infected patients. Choice of antifungal drugs should be made based on spectrum, pharmacodynamic and pharmacokinetic characteristics and adverse effects of available drugs. Combination antifungal therapy and surgical intervention may be also helpful in selected cases. CONCLUSIONS: A multidisciplinary approach and close collaboration between all key partners are necessary for successful control of fungal outbreaks.

A long-term survivor of disseminated Aspergillus and mucorales infection: an instructive case.

Invasive fungal infections remain major causes of infection-related mortality in hematopoietic stem cell transplantation (HSCT) patients. Mixed infections and multiple organ involvement have been reported in these patients. Here, we report a case of mixed Aspergillus and Mucorales infection involving the lungs, brain, spleen and bone in a HSCT patient with relapsed acute myeloid leukemia, who finally improved with triple antifungal therapy and neurosurgical evacuation of brain abscesses. She was put on lifelong secondary prophylaxis with posaconazole with excellent compliance and no sign of toxicity despite over 10 years of drug administration. Serial galactomannan measurements and positron emission tomography/computed tomography were used and were helpful for disease activity monitoring. This is an instructive case of long-term survival after a severe combined mould infection.

Cytomegalovirus reactivation and preemptive therapy after liver transplant.

OBJECTIVES: Cytomegalovirus is the most common viral infection after orthotopic liver transplant. The purpose of the present study was to determine the incidence of cytomegalovirus reactivation in Iranian liver transplant recipients at our center and to evaluate outcomes with preemptive therapy with ganciclovir for pp65 antigenemia. MATERIALS AND METHODS: There were 145 patients who had liver transplant and who survived > 2 weeks after transplant. All patients were evaluated for pp65 antigenemia weekly until 90 days after transplant. The diagnosis of cytomegalovirus reactivation was made when a recipient had pp65 antigenemia ≥ 1/50,000 leukocytes. In patients who had cytomegalovirus infection, preemptive therapy with ganciclovir (5 mg/kg, intravenous, twice daily) was started immediately after diagnosis and continued for ≥ 21 days and until cytomegalovirus antigen became undetectable on 2 consecutive tests. RESULTS: All patients in our study were seropositive for cytomegalovirus before transplant. Follow-up at mean 27 ± 20 months (range, 5.2 to 80.6 mo) after transplant showed that 46 patients (32%) had cytomegalovirus reactivation at mean 56 ± 67 days after transplant (range, 12 to 445 d). There was a higher frequency of female patients in the cytomegalovirus reactivation than non-reactivation group (odds ratio, 2.3; P ≤ .02). The most common causes of liver failure in the cytomegalovirus reactivation group were autoimmune hepatitis, cryptogenic cirrhosis, and hepatitis B virus cirrhosis. There was no significant relation between cause of liver failure, use of steroids before or after transplant, and frequency of acute rejection and cytomegalovirus reactivation. Only 1 patient (2%) developed cytomegalovirus disease at 22 days after transplant, and this patient was treated successfully. There were 6 patients (13%) who developed a second episode of cytomegalovirus reactivation at median 43 days (range, 10 to 176 d) after the first episode; all 6 patients were treated successfully with ganciclovir. CONCLUSIONS: Preemptive treatment with ganciclovir may be an effective approach against cytomegalovirus in seropositive recipients after liver transplant.

Patient outcomes in a liver transplant program in Iran.

OBJECTIVES: The first liver transplant program in Tehran was started at Tehran University of Medical Sciences in 2002. The purpose of this study was to evaluate patient outcomes in this program. MATERIALS AND METHODS: From January 2002 to February 2013, there were 172 deceased-donor orthotopic liver transplants performed in 166 patients, including revision transplant in 6 patients. Outcomes were evaluated for 4 phases of the program: (1) phase 1 (2002 to 2005; 9 transplants); (2) phase 2 (2006 to 2009; 41 transplants); (3) phase 3 (2010 to 2011; 49 transplants); and (4) phase 4 (2012 to 2013; 73 transplants). RESULTS: The most frequent indications for liver transplant included cryptogenic cirrhosis, autoimmune hepatitis, and hepatitis B and C cirrhosis. During the progression from phase 1 to 4, there were significant decreases in median cold ischemia time, operative time, and transfusions (platelets, packed red blood cells, and fresh frozen plasma). The most frequent complications included infection and acute rejection. The overall median follow-up for all patients was 26 months (range, 9-144 mo). Frequency of 1-month, 3-month, 1-year, and 2-year survival increased from phase 1 to 4. Kaplan-Meier plots showed significant improvement in patient survival from phase 1 to 4 (P ≤ .001). The most common causes of death were sepsis and bleeding. CONCLUSIONS: Clinical outcomes with deceased-donor liver transplant may be improved with a cooperative multidisciplinary team, coordinated care from different specialties, increased experience, and modifications of anesthetic and surgical techniques. Comprehensive unified written protocols for preoperative, perioperative, and postoperative treatment may help improve outcomes after sufficient experience is achieved.

Establishing a liver transplantation program at Tehran University of Medical Sciences, Iran: a report of ten years of experience.

In 2001, a Liver Transplantation (LT) program was commenced in Imam Khomeini Hospital Complex as the first one in the capital city of Tehran which is the second liver transplantation center in Iran. This study presents the results of our 10-year experience with LT.

Diagnostic value of interferon-gamma assay in tuberculosis pericardial effusions: study on a cohort of Iranian patients.

Tuberculosis pericarditis as a potentially fatal complication of tuberculosis requires effective diagnosis and treatment. We evaluated the efficacy of interferon-gamma (IFN-gamma) and adenosine deaminase (ADA) for diagnosing tuberculosis pericarditis in a cohort of Iranian patients presenting with pericarditis. We enrolled 38 patients with presentation of pericarditis. All patients underwent diagnostic and therapeutic pericardiostomy with drainage and biopsy. Adenosine deaminase and interferon-gamma levels were determined in pericardial fluid samples of all patients. Pericardial tissue samples were submitted for histopathologic and microbiologic studies. Polymerase chain reaction (PCR) was performed on all pericardial fluid samples to detect Mycobacterium tuberculosis. From 38 patients with pericarditis, 7 cases were diagnosed as having tuberculosis pericarditis (18.4%). Mean concentration of interferon-gamma in tuberculosis group was significantly higher compared to non-tuberculosis group (69257 pg/l [range: 26600-148000] vs. 329 pg/l [range: 0-2200], P<0.000). Receiver operating characteristic (ROC) curve showed a value of 14400 pg/l as the cutoff point with a sensitivity of 100% and specificity of 100% for diagnosing tuberculosis pericardial effusion. Adenosine deaminase was not found to be significantly higher in tuberculosis group in comparison with non-tuberculosis causes of pericardial effusion (35.7 [range: 9-69] vs. 36.03 [range: 8-420], P=0.28). In this study interferon-gamma showed to be a valuable diagnostic test for detection of tuberculosis pericarditis among a cohort of Iranian patients. We suggest using interferon-gamma to diagnose tuberculosis pericarditis to make diagnose in case of suspicion. While in this study, adenosine deaminase measurement did not prove to have the characteristics of an accurate diagnostic test for tuberculosis pericarditis.

Fever and psychosis as an early presentation of Brucella-associated meningoencephalitis: a case report.

OBJECTIVE: To describe a case with Brucella-associated meningoencephalitis. In addition, we report drug-induced hepatotoxicity due to acyclovir. CLINICAL PRESENTATION AND INTERVENTION: A young woman was admitted with fever and psychosis and neuroimaging findings indicative of meningoencephalitis. Serology was positive for Brucella. She was treated with doxycycline, rifampin, and trimethoprim-sulfamethoxazole. CONCLUSION: This case reminds physicians in endemic regions to consider neurobrucellosis as a differential diagnosis in patients with any unexplained neurologic symptoms or atypical psychosis. Early diagnosis and treatment of neurobrucellosis will be helpful in decreasing the sequelae of this complication.

Pro-inflammatory cytokine profile of critically ill septic patients following therapeutic plasma exchange.

UNLABELLED: Severe sepsis involves a generalized inflammatory response, mediated by a number of various cytokines and factors. Plasma exchange (PE) has been proposed as a therapeutic approach to improve survival of patients with severe sepsis and septic shock. The theory is that removing harmful excessive endogenous inflammatory mediators is beneficial. Upon establishment of a diagnosis of severe sepsis, twelve patients received PE plus conventional sepsis treatment. Interleukin (IL)-6, IL-1ß and tumor necrosis factor (TNF)-α were assayed before and after each session of PE. RESULTS: There were no significant changes in cytokine plasma levels after each PE session compared to pre-procedure levels. Among measured pro-inflammatory cytokines, only the plasma levels of IL-6 before the 2nd and 3rd PE sessions were lower than baseline levels (p=0.011 and p=0.012, respectively). All patients tolerated PE therapy well without any adverse effects or homodynamic instability. The results of this study showed that PE does not have a direct and rapid effect on plasma level of TNF-α, IL-1ß and IL-6.

Application of fnbA gene as new target for the species-specific and quantitative detection of Staphylococcus aureus directly from lower respiratory tract specimens by real time PCR.

Staphylococcus aureus is a significant cause of hospital-acquired pneumonia (HAP), particularly in mechanically ventilated patients. We used the fibronectin-binding protein A gene (fnbA) for the species-specific and quantitative detection of S. aureus directly from lower respiratory tract (LRT) specimens by a Taq Man real time PCR. For this reason, a total of 269 lower respiratory tract (LRT) specimens collected from patients with hospital-acquired pneumonia were assayed. Amplification of fnbA in serial dilutions ranged from 10(9) CFU/ ml to 10(2) CFU/ml. Standard curve of triplicate every dilution had slope 3.34±0.1 and R2>0.99 with SD 0.1. Based on these data, the sensitivity and specificity of the newly developed real time PCR targeting the fnbA gene were both 100%. The Cohen's Kappa test showed the Kappa value of 1.0. The fnbA gene is a potential marker for the species-specific detection of S. aureus and can be used to detect this bacterium in any clinical specimens by real time PCR. Moreover, this method reduces the time needed for quantitative detection of Staphylococcus aureus from LRT specimens to nearly 2 hours compared to 1 to 4 days for culture and provided sensitivity equal to or greater than culture.

Prevalence of hepatitis A virus infection in a HIV positive community.

Hepatitis A is acute and usually self-limiting disease, but sometimes it can be dangerous such as in immunosuppressed patients. Purpose of this study is to investigate the prevalence of hepatitis A serology in HIV/AIDS Patients. 247 HIV positive patients from March 2005 to September 2006 were entered in this study. Participants completed questionnaires to elicit demographic, drug and sex risk information, and were (tested for hepatitis A. They were all referred to Counseling center for behavioral diseases in Imam Khomeini Hospital. Cases were chosen from volunteers with no history of jaundice or acute hepatitis. Data were analyzed by SPSS version 13 and results were compared between seropositive and seronegative groups using T test and chi square. Statistical significance was accepted at a level of P < 0.05.200 (80.98%) were male and 47 (19.02) were female. The mean age was 36 +/- 9.3. 238 (96.3%) of patients were seropositive. One hundred percent and 96% who were born in rural and urban areas were seropositive, respectively. Also, 85.7% and 96.6% who reside in rural and urban areas were seropositive, respectively. Iran is an endemic country for hepatitis A in which most people has asymptomatic infectious during childhood. According to high prevalence of hepatitis A positive serology in HIV/AIDS patients, routine vaccination seems to be unnecessary. But special sub populations like HIV infected infants should be evaluated more precisely and different approaches may be needed for them.

CD4+ cell counts in patients with different clinical manifestations of tuberculosis

Tuberculosis is the prototype of infections that require a cellular immune response for their control. It has been shown that CD4+ T-lymphocytes are most important in the protective response against Mycobacterium tuberculosis. CD8+ T-lymphocytes are also important for effective T-cell immune response. This study compares CD4+ and CD8+ baseline values in patients with different manifestations of tuberculosis. CD4+ and CD8+ in three groups of patients with tuberculosis (pulmonary, lymphadenitis, meningitis/milliary involvement) and a group of healthy volunteers were enumerated using flowcytometry. Twenty-six patients with pulmonary tuberculosis, 10 with adenitis, 16 with meningitis or milliary tuberculosis and 16 healthy volunteers entered the study. Mean CD4 in meningitis/milliary group was significantly lower than all other groups (p<0.05). Mean CD4 counts of patients with pulmonary tuberculosis was also significantly lower than control group (p=0.01). Mean CD8 in meningitis/milliary group was significantly lower than control group (p=0.02). No relation was found between results of TSTs and CD4 values in three groups. CD4 depletion is an expectable phenomenon in patients with tuberculosis. This study shows that patients with more severe form of disease had the lowest number of both CD4 and CD8 cells which can be a sign of suppressed cellular immunity in these patients.

CD4+ cell counts in patients with different clinical manifestations of tuberculosis.

Tuberculosis is the prototype of infections that require a cellular immune response for their control. It has been shown that CD4+ T-lymphocytes are most important in the protective response against Mycobacterium tuberculosis. CD8+ T-lymphocytes are also important for effective T-cell immune response. This study compares CD4+ and CD8+ baseline values in patients with different manifestations of tuberculosis. CD4+ and CD8+ in three groups of patients with tuberculosis (pulmonary, lymphadenitis, meningitis/milliary involvement) and a group of healthy volunteers were enumerated using flowcytometry. Twenty-six patients with pulmonary tuberculosis, 10 with adenitis, 16 with meningitis or milliary tuberculosis and 16 healthy volunteers entered the study. Mean CD4 in meningitis/milliary group was significantly lower than all other groups (p<0.05). Mean CD4 counts of patients with pulmonary tuberculosis was also significantly lower than control group (p=0.01). Mean CD8 in meningitis/milliary group was significantly lower than control group (p=0.02). No relation was found between results of TSTs and CD4 values in three groups. CD4 depletion is an expectable phenomenon in patients with tuberculosis. This study shows that patients with more severe form of disease had the lowest number of both CD4 and CD8 cells which can be a sign of suppressed cellular immunity in these patients.