Joseph A. Hilinski

Predictors of cytomegalovirus disease among pediatric transplant recipients within one year of renal transplantation

Abstract: Cytomegalovirus (CMV) is the most important opportunistic infection in renal transplant recipients and is associated with an increased risk of rejection. Infection can be acquired post‐operatively (from the transplanted organ) or from re‐activation of latent disease. To identify risk factors for CMV disease in a pediatric population within 1 yr of renal transplant, and to generate hypotheses for the pathogenesis of CMV disease in this population, a review of all recipients from 1992 to 1998 in a childrens hospital in Atlanta, Georgia, was undertaken. Medical records of 73 transplants performed on 72 patients were reviewed: nine (12.7%) of 72 individuals, after 73 procedures developed CMV disease. Median time to onset of CMV disease was 52 days post‐transplant (range = 15–95 days). Receipts of mycophenolate mofetil (MMF), demographic factors, and use of cadaveric kidneys were not associated with a significantly elevated risk of CMV disease. Positive donor CMV serostatus was associated with CMV disease (uni‐variate relative risk [RR] = 8.52, Fishers Exact Test [FET] p = 0.010). Patients with transplants in October or November had a higher risk of developing CMV disease (four of 13; 30.8%) than patients transplanted in other months (five of 60, 8.3%); RR = 3.69; p = 0.047, FET). Most transplants of patients who did not develop CMV disease were performed in January through August (48/64; 75.0%); only 25.0% were performed in September through December. In contrast, six of nine (66.7%) transplants in patients who subsequently developed CMV disease were performed in September through December (p = 0.018, FET). Donor CMV‐positive serostatus and transplant in October and November continued to be independently associated with an increased risk of CMV disease when controlled for other factors. The association of transplant in October and November with CMV disease in November–January may be related to an increased risk of seasonal community CMV exposure and primary CMV infection during the peak season for CMV circulation, with subsequent immune suppression promoting progression to disease. Alternatively, co‐infection with seasonal pathogens after exposure from an infected donor during the period of immune suppression may promote progression from CMV infection to CMV disease. Further studies should be undertaken to explore these and other hypotheses, which may have implications for determination of a need for anti‐viral prophylaxis.

Risk Factors for Lower Respiratory Tract Infection Death Among Infants in the United States, 1999–2004

OBJECTIVE: To describe maternal and birth-related risk factors associated with lower respiratory tract infection (LRTI) deaths among infants. METHODS: Records for infants with LRTI as a cause of death were examined by using the linked birth/infant death database for 1999–2004. Singleton infants dying with LRTI and a random sample of surviving singleton infants were compared for selected characteristics. RESULTS: A total of 5420 LRTI-associated infant deaths were documented in the United States during 1999–2004, for an LRTI-associated infant mortality rate of 22.3 per 100000 live births. Rates varied according to race; the rate for American Indian/Alaska Native (AI/AN) infants was highest (53.2), followed by black (44.1), white (18.7), and Asian/Pacific Islander infants (12.3). Singleton infants with low birth weight (<2500 g) were at increased risk of dying with LRTI after controlling for other characteristics, especially black infants. Both AI/AN and black infants born with a birth weight of ≥2500 g were more likely to have died with LRTI than other infants of the same birth weight. Other risk factors associated with LRTI infant death included male gender, the third or more live birth, an Apgar score of <8, unmarried mother, mother with <12 years of education, mother <25 years of age, and mother using tobacco during pregnancy. CONCLUSIONS: Low birth weight was associated with markedly increased risk for LRTI-associated death among all of the racial groups. Among infants with a birth weight of ≥2500 g, AI/AN and black infants were at higher risk of LRTI-associated death, even after controlling for maternal and birth-related factors. Additional studies and strategies should focus on the prevention of maternal and birth-related risk factors for postneonatal LRTI and on identifying additional risk factors that contribute to elevated mortality among AI/AN and black infants.

24 weeks of valganciclovir prophylaxis in children after renal transplantation: a 4-year experience.

Background. Cytomegalovirus (CMV) is the most common opportunistic infection after solid-organ transplant. Valganciclovir prophylaxis significantly reduces disease, but limited data are available on its use in children. Recently, an increase in delayed-onset CMV disease has been noted with some arguing that longer prophylaxis may decrease late-onset disease. Methods. Single-center, retrospective analysis of pediatric renal transplant patients receiving 24 weeks valganciclovir prophylaxis (15 mg/kg/day, maximum 900 mg/day) from January 2004 to December 2008, aiming to measure the incidence of CMV disease and toxicity of valganciclovir. Results. We enrolled 111 patients, 60% males, 46% African Americans, and median age at transplant 14.5 years (range 1.4–20.4 years). Sixty-nine percent of donors and 44% of recipients were seropositive pretransplant. Median duration of valganciclovir use was 5.9 months (range 0.5–24 months). CMV viremia and disease occurred in 27% and 4.5%, respectively. All patients with disease presented after prophylaxis ended and all were D+/R−. Thymoglobulin use (P=0.04) and positive donor CMV status (P=0.02) were associated with a higher risk of CMV viremia. Twenty-four percent had hematologic toxicity directly associated with valganciclovir. Conclusions. Valganciclovir use in children was effective as prophylaxis against CMV disease; no children at our institution developed disease while on therapy. Our regimen of 24 weeks of prophylaxis was associated with a lower rate of late-onset disease than previous reports with 12-week regimens. Further controlled studies should be considered to compare longer versus shorter periods of prophylaxis and dose reductions and their impact on prevention of late-onset disease, resistance, cost, and toxicity.

Evaluation and treatment of mastitis in infants.

We reviewed cases of mastitis in infants treated at Children’s Healthcare of Atlanta from 2005 to 2011. Among infants with breast cultures, Staphylococcus aureus was the most common cause. No infant with a positive breast culture had a concordant positive culture elsewhere. Our findings argue that urine, blood and spinal fluid cultures are unnecessary in well-appearing afebrile infants with mastitis.

Mycobacterium tuberculosis Infection of the placenta: a study of the early (innate) inflammatory response in two cases.

Infections with Mycobacterium tuberculosis (MTb) are globally prevalent in many countries, yet descriptions of placental pathology in tuberculous patients are scanty. The usual necrotizing granulomatous response associated with tuberculous infections requires an activation of the adaptive immune system. However, before this system is turned on, the 1st encounter with the tubercle bacillus is mediated by the innate immune system. This pathway utilizes innate surface receptors in neutrophils and histiocytes predominantly and does not produce a granulomatous pattern of inflammation. In this report we describe 2 cases of placental involvement with MTb in which an acute abscess-like inflammatory response with Myeloperoxidase and CD68-positive neutrophils and histiocytes causing acute villitis and intervillitis, with abundant acid-fast mycobacteria, were identified. Other cellular markers consistent with adaptive immunity were negative. These nongranulomatous lesions are seen in primary tuberculous infections occurring in a naïve woman and, obviously, a naïve fetus. These cases with early response inflammation in the placenta are frequently missed precisely because the mother is not known to be infected or has been recently diagnosed and because the symptoms in the newborn may not develop for several weeks, by which time the placenta may have been discarded. This report also shows that the differential diagnosis of acute villitis and intervillitis in the placenta should include tuberculosis aside from the more common bacterial infections such as listeriosis.

Respiratory Decompensation and Immunization of Preterm Infants

BACKGROUND: Concern for respiratory decompensation after immunization in premature infants, particularly those with bronchopulmonary dysplasia (BPD), may lead to delayed and altered immunization schedules. METHODS: A retrospective cohort of premature infants at <32 weeks’ gestational age cared for in a tertiary level 4 NICU and immunized during their hospital stay were evaluated for respiratory decompensation within 72 hours of immunization. Respiratory measurements including change in respiratory support, mean fraction of inspired oxygen, and apnea, bradycardia, and desaturation events were compared between those infants with BPD and those without. The primary outcome was the difference in respiratory decompensation defined as a composite of increased respiratory support or increased fraction of inspired oxygen ≥10% within 72 hours of immunization. RESULTS: Of 403 infants admitted to the NICU and immunized, 240 met the study criteria. Of those infants, 172 had a diagnosis of BPD. There was no difference in the primary outcome of respiratory decompensation after immunization between groups (P = .65). There was also no significant difference in apnea, bradycardia, and desaturation events between groups (P = .51). CONCLUSIONS: In this cohort, respiratory decompensation requiring clinical intervention after immunization of preterm infants both with and without BPD was uncommon and not significantly different between groups. Consideration for immunization of this vulnerable population should not be delayed out of concern for clinical deterioration.

Development, implementation and evaluation of a fourth-year medical school elective course in clinical microbiology using case-based vignettes.

Knowledge of clinical microbiology is an integral component in the management of patients with infectious diseases. Clinical microbiologists validate, implement and ensure quality control of all the tests and cultures performed in the clinical microbiology laboratory servicing hospitals and outpatient clinics. Typically, microbiology is taught to medical students by basic science microbiologists or infectious diseases physicians with minimal input from clinical laboratory specialists. Emory University School of Medicine implemented a course in the final month of the senior year of medical school to ensure that students are ready for postgraduate residency. As part of this course and emphasizing the Systems-Based Practice core competency of the Accreditation Council for Graduate Medical Education (Gregory et al., 2009), one full day was allotted to the Department of Pathology and Laboratory Medicine. During this ‘Laboratory Medicine Experience’, students toured different hospital clinical laboratories and solved cases designed to stimulate discussions that emphasized laboratory medicine fundamentals as delineated by the Academy of Clinical Laboratory Physicians and Scientists (Smith et al., 2010; Molinaro et al., 2012). Using case-based learning (Srinivasan et al., 2007), an additional 4 h elective in clinical microbiology was offered 1 day after the ‘Laboratory Medicine Experience’.

Bacillary Angiomatosis in Patients With Cancer: A Pediatric Case Report and a Review of the Literature

Anita K. McElroy, Joseph A. Hilinski, Carlos R. Abramowsky, Ronald Jaffe, Sunita I. Park, Bahig M. Shehata, and ToddM. Cooper Divisions of Infectious Diseases and Hematology/Oncology, Department of Pediatrics, and Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia;, and Department of Pathology, University of Pittsburgh School of Medicine, Pennsylvania

Rifaximin for preventing acute graft-versus-host disease: impact on plasma markers of inflammation and T-cell activation.

In murine allogeneic hematopoietic cell transplantation models, inhibiting bacterial translocation stemming from conditioning-induced damage to the gut mucosa abrogates inflammatory stimulation of donor T cells, preventing acute graft-versus-host disease (AGVHD). We conducted a phase I trial to begin testing the hypothesis that rifaximin, a broadly acting oral antibiotic, would reduce systemic inflammation and T-cell activation. We administered rifaximin to 20 adolescents and younger adults (day –10 through day +30) receiving intensive conditioning. We measured the plasma level of interleukin-6, as a marker of conditioning-induced inflammation, and the levels of soluble tumor necrosis factor receptor-1 and soluble interleukin-2 receptor, as surrogate markers of AGVHD. We formed a historical control group (n=24), from a previous study of biomarkers in AGVHD. The increase in the treatment group’s mean interleukin-6 level from baseline to day 0 was 73% less than that in the control group (P=0.006). The increase from baseline to day 15 in the treatment group’s mean soluble tumor necrosis factor-1 and soluble interleukin-2 receptor levels was similar to the control group. Incidences of grade 2 to 4 AGVHD also did not differ. This suggests that rifaximin may abrogate bacterial translocation and resultant inflammation, but in alternative donor transplants this does not prevent downstream activation of donor T cells.

Refractory Pneumonia in a Mexican American Infant

The traditional practice of administering oral or nasal vegetable or animal oil substances has been used in various cultures for treatment of common symptoms, including constipation, colic, and even nasal congestion. As a result of this practice, oil aspiration pneumonia or lipoid pneumonia is a possible complication in countries where infants and children are given these traditional folk remedies. In addition to compromising the integrity of the pulmonary epithelium, lipids play an integral role in predisposing otherwise healthy lungs to a variety of infectious agents. Lipoid pneumonia has been reported to predispose to the development of pulmonary disease caused by nontuberculous mycobacteria (NTM). Lipids are thought to enhance the pathogenicity of mycobacteria, though the mechanism by which this occurs is poorly understood. Some authors believe that lipids serve as mechanical protectors for these organisms and enhance their growth. Others argue that the high concentration of free fatty acids may favor development of a necrotizing hemorrhagic pneumonia with secondary superinfection. Treatment for lipoid pneumonia is primarily supportive, along with antimicrobials as required. Some reports have described successful outcomes with the use of corticosteroids; however, controlled trials have found no benefit. Treatment for NTM varies depending on the nature of the disease. Therapy for pulmonary disease includes the use of multiple antimicrobial agents. As with other mycobacterial infections, long-term therapy ranging between 6 and 12 months is necessary for cure. Here we report the case of a 3-month-old Mexican American male infant who received mineral oil for constipation and subsequently developed respiratory failure secondary to lipoid pneumonia with Mycobacterium fortuitum superinfection.