Early blood stream infection following allogeneic hematopoietic stem cell transplantation is a risk factor for acute grade III-IV GVHD in children and adolescents.

BACKGROUND: Graft-versus-host disease (GVHD) remains a major cause of mortality and morbidity in allogeneic hematopoietic stem cell transplantation (HSCT). In adults, early blood stream infection (BSI) and acute GVHD (AGVHD) have been reported to be related. The impact of BSI on risk for AGVHD, however, has not been assessed in pediatric patients. PROCEDURE: We conducted a retrospective analysis to test the hypothesis that early BSI (before day +30) predisposes allogeneic pediatric transplant patients to severe AGVHD. We analyzed 293 allogeneic HSCT performed at Children's Healthcare of Atlanta between 2005 and 2014 that met eligibility criteria. RESULTS: The cumulative incidence of acute grade III-IV GVHD at 100 days after HSCT was 17.1%. In multivariate analysis, risk for acute grade III-IV GVHD was associated with HLA-mismatched donor (hazard ratio [HR] = 4.870, P < 0.001), and BSI between day 0 and +30 prior to AGVHD (HR = 3.010, P = 0.001). CONCLUSIONS: These results indicate that early BSI appears to be a risk factor for acute grade III-IV GVHD. Further research is needed to determine if the link is causal.

African American Race Is a Newly Identified Risk Factor for Postengraftment Blood Stream Infections in Pediatric Allogeneic Blood and Marrow Transplantation.

Blood stream infections (BSI) are a major source of morbidity and mortality both in allogeneic blood and marrow transplant (BMT) recipients. Various risk factors for BSI in BMT have been identified. The impact of race and cytomegalovirus (CMV) viremia, a common complication after engraftment, however, has not been rigorously assessed. This is important because both CMV infection and ganciclovir, the mainstay of pre-emptive therapy, have myelosuppressive and immunosuppressive effects. We conducted a retrospective analysis to test the hypothesis that race and CMV viremia predispose allogeneic BMT patients to postengraftment BSI. We analyzed 278 allogeneic BMT performed at Children's Healthcare of Atlanta between January 1, 2005 and December 31, 2014 that met eligibility criteria. We performed a multivariate analysis to estimate the effect of CMV viremia on risk for BSI in the postengraftment period (days +30 to 100). Risk for BSI was associated with CMV viremia (hazard ratio [HR], 3.34; 95% confidence interval [CI], 1.51 to 7.36; P = .003); grade III and IV acute graft-versus-host disease (HR, 3.28; 95% CI, 1.55 to 6.92; P = .002), and African American race (HR, 2.22; 95% CI, 1.09 to 4.51; P = .027). The results of our study highlight the importance of a novel risk factor for postengraftment BSI, not previously considered-African American race.

Candida quercitrusa Candidemia in a 6-Year-Old Child.

We present the first case of candidemia due to Candida quercitrusa in a pediatric patient. The identification of the isolate was protracted and ultimately dependent upon sequence analysis of the internal transcribed spacer region. To further define the antifungal susceptibility characteristics of this species, we performed antifungal susceptibility testing of clinical and type strains. In light of the antifungal susceptibility testing results, we caution against the use of fluconazole for treating C. quercitrusa infections.

Risk for CMV reactivation in children undergoing allogeneic hematopoietic stem cell transplantation.

Tailoring pre-emptive CMV therapy to hematopoietic cell transplant recipients' risk for reactivation could make this approach more cost-effective. To determine the feasibility of creating a risk classification system for this purpose, we analyzed 169 pediatric HCTs involving seropositive recipients or donors. Using risk factors derived from multivariable analysis, we stratified patients as having no risk factors, any one, any two, or all three risk factors (age, donor type, and presence of GVHD). The cumulative incidence of reactivation was 4.7%, 10.1%, 21.1%, and 40.9%, respectively (P ≤ 0.001). These results demonstrate the feasibility of creating a risk classification schema. Pediatr Blood Cancer 2015;62:364-366. © 2014 Wiley Periodicals, Inc.

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.

High prevalence of inducible clindamycin resistance among Staphylococcus aureus isolates from patients with cystic fibrosis.

BACKGROUND: Staphylococcus aureus (SA) is an important pathogen among patients with cystic fibrosis (CF). Inducible clindamycin resistance (ICR) has been described as a cause of treatment failure in non-CF related infections. The prevalence of ICR among SA from patients with CF is unknown. METHODS: We compared clindamycin susceptibilities of SA isolated from patients with and without cystic fibrosis (CF) using hospital microbiology data. Patients with CF were primarily identified using CF registry data. We evaluated all patients who had SA isolated at the Children's Healthcare of Atlanta microbiology laboratory during May 2004-May 2005. We performed antimicrobial susceptibility testing using broth microdilution and performed D-zone testing for ICR in accordance with the Clinical Laboratory Standards Institute (CLSI) document M100-S16. Proportions were compared using a 2-sided Pearson's Chi-square test or Fisher's exact test to assess for significance. RESULTS: Of 703 patients with methicillin-resistant SA (MRSA), 48% of CF patients (68/143) had at least one isolate demonstrating ICR, compared to 8% of non-CF patients (43/560) (P<0.01). Of 762 patients with methicillin-susceptible SA (MSSA), 29% of CF patients (73/254) had at least one isolate demonstrating ICR compared to 17% of non-CF patients (88/508) (P<0.01). CONCLUSIONS: SA demonstrating ICR are significantly more prevalent among patients with CF than among those without CF.

Pediatric Dental Clinic-Associated Outbreak of Mycobacterium abscessus Infection.

BACKGROUND: Mycobacterium abscessus is an uncommon cause of invasive odontogenic infection. METHODS: M abscessus-associated odontogenic infections occurred in a group of children after they each underwent a pulpotomy. A probable case-child was defined as a child with facial or neck swelling and biopsy-confirmed granulomatous inflammation after a pulpotomy between October 1, 2013, and September 30, 2015. M abscessus was isolated by culture in confirmed case-children. Clinical presentation, management, and outcomes were determined by medical record abstraction. RESULTS: Among 24 children, 14 (58%) were confirmed case-children. Their median age was 7.3 years (interquartile range, 5.8-8.2 years), and the median time from pulpotomy to symptom onset was 74 days (range, 14-262 days). Clinical diagnoses included cervical lymphadenitis (24 [100%] of 24), mandibular or maxillary osteomyelitis (11 [48%] of 23), and pulmonary nodules (7 [37%] of 19). Each child had ≥1 hospitalization and a median of 2 surgeries (range, 1-6). Of the 24 children, 12 (50%) had surgery alone and 11 (46%) received intravenous (IV) antibiotics. Nineteen of the 24 (79%) children experienced complications, including vascular access malfunction (7 [64%] of 11), high-frequency hearing loss (5 [56%] of 9), permanent tooth loss (11 [48%] of 23), facial nerve palsy (7 [29%] of 24), urticarial rash (3 [25%] of 12), elevated liver enzyme levels (1 [20%] of 5), acute kidney injury (2 [18%] of 11), incision dehiscence/fibrosis (3 [13%] of 24), and neutropenia (1 [9%] of 11). CONCLUSIONS: M abscessus infection was associated with significant medical morbidity and treatment complications. Unique manifestations included extranodal mandibular or maxillary osteomyelitis and pulmonary nodules. Challenges in the identification of case-children resulted from an extended incubation period and various clinical manifestations. Clinicians should consider the association between M abscessus infection and pulpotomy in children who present with subacute cervical lymphadenitis. The use of treated/sterile water during pulpotomy might prevent further outbreaks.

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.

Instinctive Clinical Teaching: Erasing the Mental Boundary Between Clinical Education and Patient Care to Promote Natural Learning.

Effective clinical teaching is essential in physician education, yet faculty members rarely receive formal training in clinical teaching. Formal models for training clinical educators are often tedious and require significant time and effort. Instinctive clinical teaching allows clinicians to seamlessly integrate and promote effective teaching into their clinical practice. The approach is guided by similarities between the components of Kolb's experiential learning cycle-concrete experience, reflective observation, abstract conceptualization, and active experimentation-and the elements of the patient care process-history and physical, initial assessment, differential, hypothesis, final diagnosis, management, and follow-up. Externalization of these clinical thought processes allows for inclusion of learners and promotes effective clinical teaching.

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.

Sixteen-Year-Old Boy From Nigeria With a Rash.

DATE: Thursday, October 20, 2011. SESSION TITLE: Pediatric Fellows' Day Workshop Hosting Organization: Infectious Diseases Society of America. HOSTING EVENT: 49th Annual Meeting of the Infectious Diseases Society of America. LOCATION: Boston, Massachusetts.

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.

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.

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 100,000 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 > or =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 > or =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.

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

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 children's 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, Fisher's 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.