Toxoplasmosis in Pediatric Hematopoietic Stem Cell Transplantation Patients.

Infection due to the protozoa Toxoplasma gondii can be life-threatening in hematopoietic stem cell transplantation (HSCT) recipients. Most cases of toxoplasmosis in HSCT recipients result from reactivation of latent infection in individuals who were Toxoplasma-seropositive before transplantation and did not receive appropriate prophylaxis. Pretransplantation screening with Toxoplasma IgG and IgM antibodies is suggested for all allogeneic HSCT recipients and their donors and all autologous HSCT recipients. Prevention of toxoplasmosis in T. gondii-seropositive HSCT recipients requires primary prophylaxis, preemptive screening, or both. Trimethoprim-sulfamethoxazole (TMP-SMX) is the preferred agent for Toxoplasma prophylaxis and should be continued for 6 months or until the patient is no longer receiving immunosuppression, whichever is longer, assuming that immune reconstitution has occurred. Preemptive weekly screening with whole blood Toxoplasma PCR should be considered for seropositive HSCT recipients if prophylaxis cannot be given or if prophylaxis other than TMP-SMX is used. The signs, symptoms, and radiographic findings of toxoplasmosis in HSCT recipients can be nonspecific, and the diagnosis requires a high degree of suspicion. Common presentations include fever, encephalopathy with mental status changes or seizures, and pneumonia. A Toxoplasma PCR analysis from whole blood (and other body fluids/tissues according to clinical symptoms) should be obtained in patients in whom there is a concern for toxoplasmosis. Treatment with oral pyrimethamine, sulfadiazine, and leucovorin for at least 6 weeks is the first-line therapy and should be followed by secondary prophylaxis. In this article, we review the published literature regarding the epidemiology, clinical presentation, treatment, and prevention of toxoplasmosis in HSCT recipients.

Toxoplasmosis Among 38 751 Hematopoietic Stem-cell Transplant Recipients: A Systematic Review of Disease Prevalence and a Compilation of Imaging and Autopsy Findings.

BACKGROUND: Toxoplasmosis in hematopoietic stem-cell transplant (HSCT) recipients can be life threatening if not promptly diagnosed and treated. METHODS: We performed a systematic review (PubMed last search March 29, 2020) of toxoplasmosis among HSCT recipients and calculated the toxoplasmosis prevalence across studies. We also created a compilation list of brain imaging, chest imaging, and autopsy findings of toxoplasmosis among HSCT recipients. RESULTS: We identified 46 eligible studies (47 datasets) with 399 toxoplasmosis cases among 38 751 HSCT recipients. There was large heterogeneity in the reported toxoplasmosis prevalence across studies, thus formal meta-analysis was not attempted. The median toxoplasmosis prevalence among 38 751 HSCT recipients was 2.14% (range 0%-66.67%). Data on toxoplasmosis among at-risk R+HSCT recipients were more limited (25 studies; 2404 R+HSCT recipients [6.2% of all HSCT recipients]), although the median number of R+HSCT recipients was 56.79% across all HSCT recipients. The median toxoplasmosis prevalence across studies among 2404 R+HSCT was 7.51% (range 0%-80%) versus 0% (range 0%-1.23%) among 7438 R-HSCT. There were limited data to allow meaningful analyses of toxoplasmosis prevalence according to prophylaxis status of R+HSCT recipients. CONCLUSIONS: Toxoplasmosis prevalence among HSCT recipients is underestimated. The majority of studies report toxoplasmosis prevalence among all HSCT recipients rather than only among the at-risk R+HSCT recipients. In fact, the median toxoplasmosis prevalence among all R+//R- HSCT recipients is 3.5-fold lower compared with the prevalence among only the at-risk R+HSCT recipients and the median prevalence among R+HSCT recipients is 7.51-fold higher than among R-HSCT recipients. The imaging findings of toxoplasmosis among HSCT recipients can be atypical. High index of suspicion is needed in R+HSCT recipients with fever, pneumonia, or encephalitis.

Treatment options for acute sinusitis in children.

Much controversy exists regarding the best diagnostic method for acute sinusitis, the efficacy of antibiotics, the best choice of antibiotics, the most appropriate duration of therapy, and the efficacy of ancillary measures and nasal corticosteroids. The therapeutic goal is to identify those children who are more likely to have bacterial sinusitis and unlikely to resolve spontaneously, who may require treatment with antibiotics. The inaccuracy of clinical signs and symptoms complicates further the management of these children. Acute sinusitis is expected to resolve spontaneously in most cases, including many cases of bacterial sinusitis. Antibiotics are needed only for a minority of non-self-resolving infections. Based on current resistance considerations, approximately 80% of bacterial infections are expected to respond to standard doses of amoxicillin. High-dose amoxicillin, amoxicillin/clavulanate, or other b-lactam antibiotics should be considered for children at high risk for carrying resistant organisms. Evidence for the effectiveness of ancillary measures is limited.

Extended-interval aminoglycoside administration for children: a meta-analysis.

BACKGROUND: There has been a long-standing debate regarding whether aminoglycosides should be administered on a multiple daily dosing (MDD) or once-daily dosing (ODD) schedule. Several unique characteristics of the aminoglycosides make ODD an attractive and possibly superior alternative to MDD. These include concentration-dependent bactericidal activity; postantibiotic effect, which allows continued efficacy even when serum concentrations fall below expected minimum inhibitory concentrations; decreased risk of adaptive resistance; and diminished accumulation in renal tubules and inner ear. OBJECTIVE: To assess the relative efficacy and toxicity of ODD, compared with MDD, of aminoglycosides among pediatric patients. STUDY SELECTION: Randomized, controlled trials among children, evaluating the relative efficacy and toxicity of ODD versus MDD of aminoglycosides, with similar total daily doses in the compared arms, were selected. DATA SOURCES: PubMed (1966-2003) and Embase (1982-2003) databases, the Cochrane Controlled Trials Registry (2003), and references of eligible studies and pediatric review articles were searched. DATA EXTRACTION: Study population characteristics and outcome data were extracted independently in duplicate, and consensus was reached on all items. The following outcome data were considered: (1) clinical or microbiologic failure, as defined in each study; (2) clinical failure; (3) microbiologic failure; (4) primary nephrotoxicity, ie, any rise in serum creatinine or decrease in creatinine clearance with thresholds as defined in each study; (5) secondary nephrotoxicity, ie, urinary excretion of proteins or phospholipids; and (6) ototoxicity based on pure tone audiometry, brainstem auditory evoked responses, or otoacoustic emissions for neonates and infants, vestibular testing, clinical impression, or any other method. All of the efficacy and toxicity outcomes were evaluated at the end of therapy. RESULTS: Identification of eligible studies and study characteristics: 24 eligible studies published between 1991 and 2003 were identified. Aminoglycosides were used in different clinical settings (neonatal intensive care unit: 6 studies; cystic fibrosis: 3 studies; cancer: 5 studies; urinary tract infections: 4 studies; diverse infectious indications: 5 studies; pediatric intensive care unit: 1 study). Aminoglycosides used included amikacin (9 studies), gentamicin (11 studies), tobramycin (2 studies), netilmicin (2 studies), and tobramycin or netilmicin (1 study). EFFICACY: There was no significant difference between ODD and MDD in the clinical failure rate, microbiologic failure rate, and combined clinical or microbiologic failure rates, but trends favored ODD consistently. There was no between-study heterogeneity for any outcome. Efficacy analysis of all trials indicating either clinical or microbiologic failures demonstrated pooled failure rates of 4.6% (23 of 501 cases) in the ODD arms and 6.9% (34 of 494 cases) in the MDD arms. The fixed-effects risk ratio was 0.71 (95% confidence interval [CI]: 0.45-1.11). A statistically significant benefit was seen with ODD over MDD in trials using amikacin, whereas no statistical significance was seen in trials using other antibiotics. The pooled clinical failure rates were 6.7% (22 of 330 cases) in the ODD arms and 10.4% (34 of 327 cases) in the MDD arms. The fixed-effects risk ratio was 0.67 (95% CI: 0.42-1.07). The pooled microbiologic failure rates were 1.8% (5 of 283 cases) with ODD and 4.0% (11 of 275 cases) with MDD. The fixed-effects risk ratio was 0.51 (95% CI: 0.22-1.18). NEPHROTOXICITY: There was no significant difference between ODD and MDD in the primary nephrotoxicity outcomes. Secondary nephrotoxicity outcomes were significantly better with ODD. The pooled primary nephrotoxicity rates were 1.6% (15 of 955 cases) in the ODD arms and 1.6% (15 of 923 cases) in the MDD arms. The fixed-effects risk ratio was 0.97 (95% CI: 0.55-1.69). The pooled secondary nephrotoxicity rates were 4.4% (3 of 69 cases) in the ODD arms and 15.9% (11 of 69 cases) in the MDD arms, suggesting a statistically significant superiority of ODD. The fixed-effects risk ratio was 0.33 (95% CI: 0.12-0.89). Results were consistent across types of clinical settings and aminoglycosides. OTOTOXICITY: There was no significant difference between ODD and MDD in the primary ototoxicity outcomes. The pooled ototoxicity rates for studies that provided auditory testing results were 2.3% (10 of 436 cases) in the ODD arms and 2.0% (8 of 406 cases) in the MDD arms. The fixed-effects risk ratio was 1.06 (95% CI: 0.51-2.19). In studies that provided clinical vestibular function testing results, no toxicity was documented among 209 patients given ODD and 206 patients given MDD. Studies noting only the clinical impression of hearing impairment also failed to identify any toxicity (ODD: 114 cases; MDD: 114 cases). SUBGROUP AND BIAS ANALYSES: We detected no statistically significant differences between ODD and MDD in any of the examined subgroups (neonatal intensive care unit, cystic fibrosis, cancer, or urinary tract infection), with respect to combined clinical or microbiologic failure outcomes, primary nephrotoxicity outcomes, or ototoxicity (based on auditory testing), when sufficient data were available. Moreover, there was no significant relationship between the effect size (risk ratio) and the trial size for any of the outcomes. DATA INTERPRETATION: Clinical failures were uncommon in the pediatric trials, regardless of the regimen used. If anything, fewer clinical failures tended to occur with ODD. Moreover, we observed a trend toward decreased bacteriologic failures. One meta-analysis of adult data suggested that ODD might reduce nephrotoxicity, whereas other meta-analyses showed nonsignificant trends or no difference in nephrotoxicity outcomes. In our meta-analysis, we were not able to show any reduction in the risk of primary nephrotoxicity outcomes with ODD. However, the event rate was much lower among children, compared with adults, and the secondary nephrotoxicity outcomes favored ODD. Finally, although the 2 regimens seemed equivalent with respect to ototoxicity, reporting on ototoxicity outcomes was incomplete. Reassuringly, even in the trials that performed auditory testing, the rates of ototoxicity in the MDD arms were very low. These results were consistent with meta-analyses of adult data, which showed no difference in ototoxicity rates between ODD and MDD. CONCLUSIONS: Although single trials have been small, the available randomized evidence supports the general adoption of ODD of aminoglycosides in pediatric clinical practice. This approach minimizes cost, simplifies administration, and provides similar or even potentially improved efficacy and safety, compared with MDD of these drugs.