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In this article, we describe a novel case of SARS-CoV-2-associated-hemophagocytic lymphohistiocytosis (HLH) complicated by posterior reversible encephalopathy syndrome (PRES). Initially diagnosed with multisystem inflammatory response in children (MIS-C), the patient received a large corticosteroid dose days before the onset of neurological symptoms. After developing PRES, the patient was treated with antihypertensives, antiepileptics, dexamethasone, and anakinra, leading to neurologic normalization. We propose that given the challenging diagnostic picture of PRES developing in patients with HLH or MIS-C, institutionalized standards for blood pressure management during corticosteroid induction may significantly improve outcomes in patients being treated for hyperinflammatory syndromes who develop neurological symptoms.
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Juvenile myelomonocytic leukemia (JMML) is an aggressive pediatric leukemia with few effective treatments and poor outcomes even after stem cell transplantation, the only current curative treatment. We developed a JMML patient-derived xenograft (PDX) mouse model and demonstrated the in vivo therapeutic efficacy and confirmed the target of trametinib, a RAS-RAF-MEK-ERK pathway inhibitor, in this model. A PDX model was created through transplantation of patient JMML cells into mice, up to the second generation, and successful engraftment was confirmed using flow cytometry. JMML PDX mice were treated with trametinib versus vehicle control, with a median survival of 194 days in the treatment group versus 124 days in the control group (p = 0.02). Trametinib's target as a RAS pathway inhibitor was verified by showing inhibition of ERK phosphorylation using immunoblot assays. In conclusion, trametinib monotherapy significantly prolongs survival in our JMML PDX model by inhibiting the RAS pathway. Our model can be effectively used for assessment of novel targeted treatments, including potential combination therapies, to improve JMML outcomes.
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Leucemia Mielomonocítica Juvenil , Piridonas , Pirimidinonas , Ensayos Antitumor por Modelo de Xenoinjerto , Pirimidinonas/uso terapéutico , Pirimidinonas/farmacología , Piridonas/uso terapéutico , Piridonas/farmacología , Animales , Leucemia Mielomonocítica Juvenil/tratamiento farmacológico , Humanos , Ratones , Proteínas ras/metabolismo , Masculino , Femenino , Ratones SCIDRESUMEN
Acute lymphocytic leukemia (ALL) is a common pediatric cancer diagnosis with excellent survival outcomes but significant morbidity, particularly during the induction phase of chemotherapy. Central venous sinus thrombosis (CVST) is a known potential complication of induction therapy; however, it occurs rarely and may be difficult to diagnose, particularly in young children who have limited verbal skills. Herein, we report a case of CVST in a child with B-cell ALL undergoing induction chemotherapy whose main symptoms were headache and a change in the appearance of his artwork noticed by his parents. This astute observation by the child's parents played a critical role in his diagnosis, allowing prompt treatment and eventual recovery.
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Anomalías Cardiovasculares , Leucemia-Linfoma Linfoblástico de Células Precursoras , Trombosis de los Senos Intracraneales , Trombosis de la Vena , Enfermedad Aguda , Niño , Preescolar , Cefalea/etiología , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Trombosis de los Senos Intracraneales/diagnóstico por imagen , Trombosis de los Senos Intracraneales/etiología , Trombosis de la Vena/complicacionesRESUMEN
BACKGROUND: Acanthamoeba keratitis is challenging to treat and thought to result in poor outcomes, but very few comparative studies exist to assess whether ulcers caused by Acanthamoeba are worse than those caused by bacteria or fungus. METHODS: In a retrospective cohort study, all cases of smear- or culture-proven Acanthamoeba keratitis diagnosed from January 2006 to June 2011 at an eye hospital in South India were identified from the microbiology database. Random samples of the same number of cases of bacterial and fungal keratitis, matched by year, were identified from the same database in order to compare outcomes between the three types of organism. The main outcomes were the time until the following events: re-epithelialization, discontinuation of antimicrobials, perforation/keratoplasty, elevated intraocular pressure, and new cataract. RESULTS: The median time until re-epithelialization was 113 days for Acanthamoeba keratitis, 30 days for fungal keratitis, and 25 days for bacterial keratitis, and the median time until discontinuation of antimicrobial therapy was 100 days for Acanthamoeba keratitis, 49 days for fungal keratitis, and 40 days for bacterial keratitis. Compared to the other two organisms, Acanthamoeba ulcers took significantly longer to re-epithelialize (adjusted HR 0.4, 95% CI 0.3 to 0.6 relative to bacterial ulcers and HR 0.3, 95% CI 0.2 to 0.5 relative to fungal ulcers; overall p<0.001) and had significantly longer courses of antimicrobials (adjusted HR 0.3, 95% CI 0.2 to 0.6 relative to bacterial ulcers and HR 0.5, 95%CI 0.3 to 0.8 relative to fungal ulcers; overall p<0.001). No statistically significant difference was observed between the three organisms for the other time-to-event outcomes. CONCLUSIONS: Acanthamoeba keratitis was more difficult to treat and had worse clinical outcomes than bacterial or fungal ulcers, highlighting the lack of adequate treatment regimens for this infection.
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Queratitis por Acanthamoeba/patología , Antiinfecciosos/uso terapéutico , Infecciones Bacterianas del Ojo/patología , Infecciones Fúngicas del Ojo/patología , Repitelización , Acanthamoeba/aislamiento & purificación , Queratitis por Acanthamoeba/tratamiento farmacológico , Queratitis por Acanthamoeba/parasitología , Adulto , Bacterias/aislamiento & purificación , Infecciones Bacterianas del Ojo/tratamiento farmacológico , Infecciones Bacterianas del Ojo/microbiología , Infecciones Fúngicas del Ojo/tratamiento farmacológico , Infecciones Fúngicas del Ojo/microbiología , Femenino , Hongos/aislamiento & purificación , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Background: A rise in hospital-acquired venous thromboembolism (HA-VTE) in children has led to increased awareness regarding VTE prophylaxis and risk assessment. Despite no consensus exists regarding these practices in pediatrics. Objective: To describe common practices in VTE prophylaxis, VTE risk assessment models, and anticoagulation dosing strategies in pediatric hospitals that are members of the Children's Hospital Acquired Thrombosis (CHAT) Consortium. Methods: An electronic survey of 44 questions evaluating practices surrounding pediatric HA-VTE risk assessment and prevention was distributed between August 9, 2021, and August 30, 2021, to the primary investigators from the 32 institutions within the CHAT Consortium. Results: The survey response rate was 100% (n = 32). In total, 85% (n = 27) of the institutions assess HA-VTE, but only 63% (n = 20) have formal hospital guidelines. Within the institutions with formal guidelines, 100% (n = 20) include acute systemic inflammation or infection and presence of a central venous catheter (CVC) as risk factors for VTE. Pharmacologic prophylaxis is prescribed at 87% (28) of institutions, with enoxaparin being the most frequent (96%, n = 27). Variability in responses persisted regarding risk factors, risk assessment, thromboprophylaxis, dosing of prophylactic anticoagulation or anticoagulant drug monitoring. A majority of providers were comfortable providing thromboprophylaxis across all age groups. In addition, the global coronavirus disease 2019 increased the providers' use of prophylactic anticoagulation 78% (n = 25). Conclusion: Practices among institutions are variable in regard to use of HA-VTE prophylaxis, risk assessment, or guideline implementation, highlighting the need for further research and a validated risk assessment model through groups like the CHAT Consortium.
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We reviewed three very similar cases of acute-onset heart failure in children with acute myeloid leukemia who received anthracyclines during their treatment. All three children were diagnosed with recent Streptococcus viridans bacteremia and had persistent tachycardia prior to acute-onset heart failure with near-complete resolution within weeks. We hypothesize their heart failure was secondary to sepsis-induced cardiomyopathy with anthracycline-induced cardiac myocyte damage as a predisposing factor. We suggest prophylaxis and methods of early detection to prevent and better treat acute heart failure in pediatric oncology patients receiving anthracyclines.
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Bacteriemia , Cardiomiopatías , Insuficiencia Cardíaca , Leucemia Mieloide Aguda , Antraciclinas/efectos adversos , Antibióticos Antineoplásicos/uso terapéutico , Bacteriemia/complicaciones , Bacteriemia/etiología , Cardiomiopatías/inducido químicamente , Niño , Insuficiencia Cardíaca/inducido químicamente , Insuficiencia Cardíaca/tratamiento farmacológico , Humanos , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/tratamiento farmacológico , Estreptococos ViridansRESUMEN
Infections with Rothia mucilaginosa are rare. We present an unusual case of Rothia mucilaginosa in an immunocompromised host, which is usually considered a low virulence pathogen. The objective of this report is to highlight spectrum of clinical presentations in an immunocompromised individual and discuss various antimicrobial treatment options in the light of lack of definitive treatment guidelines for this organism.
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BACKGROUND: Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure syndrome characterized by anemia, short stature, congenital anomalies, and cancer predisposition. Most cases are due to mutations in genes encoding ribosomal proteins (RP) leading to RP haploinsufficiency. Effective treatments for the anemia of DBA include chronic red cell transfusions, long-term corticosteroid therapy, or hematopoietic stem cell transplantation. In a small patient series and in animal models, there have been hematologic responses to L-leucine with amelioration of anemia. The study objectives of this clinical trial were to determine feasibility, safety, and efficacy of L-leucine in transfusion-dependent patients with DBA. PROCEDURE: Patients ≥2 years of age received L-leucine 700 mg/m2 orally three times daily for nine months to determine a hematologic response and any improvement in growth (NCT01362595). RESULTS: This multicenter, phase I/II study enrolled 55 subjects; 43 were evaluable. There were 21 males; the median age at enrollment was 10.4 years (range, 2.5-46.1 years). No significant adverse events were attributable to L-leucine. Two subjects had a complete erythroid response and five had a partial response. Nine of 25, and 11 of 25, subjects experienced a positive weight and height percentile change, respectively, at the end of therapy. CONCLUSIONS: L-leucine is safe, resulted in an erythroid response in 16% of subjects with DBA, and led to an increase in weight and linear growth velocity in 36% and 44% of evaluable subjects, respectively. Further studies will be critical to understand the role of L-leucine in the management of patients with DBA.
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Anemia de Diamond-Blackfan/terapia , Transfusión Sanguínea/métodos , Leucina/uso terapéutico , Adolescente , Adulto , Anemia de Diamond-Blackfan/patología , Niño , Preescolar , Terapia Combinada , Estudios de Factibilidad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Pronóstico , Adulto JovenRESUMEN
Importance: Corneal opacity is a leading cause of visual impairment worldwide; however, the specific features of corneal scars, which decrease visual acuity, have not been well characterized. Objective: To investigate which features of a postfungal keratitis corneal scar contribute to decreased visual acuity after an episode of infectious keratitis and evaluate whether any corneal features may be used as outcomes for clinical trials. Design, Setting, and Participants: In this ancillary, prospective cross-sectional study, a subset of study participants treated for fungal keratitis (n = 71) as part of the Mycotic Ulcer Treatment Trial I (MUTT I) underwent best spectacle-corrected visual acuity (BSCVA) and best contact lens-corrected visual acuity examination, Scheimpflug imaging, and anterior segment optical coherence tomography at a referral hospital in India approximately 2 years after enrollment. Data were collected from December 3, 2012, to December 19, 2012, and analyses were performed from December 2, 2013, to October 2, 2019. Main Outcomes and Measures: Linear regression models were used to evaluate the importance of various corneal features for BSCVA and to assess whether these features could be used to differentiate the 2 treatment arms of the MUTT I trial. Results: Seventy-one patients (42 men [59.1%]; median age, 48 [range, 39-60] years) were examined at a median (IQR) time of 1.8 (1.4-2.2) years after enrollment. The mean (SD) logMAR BSCVA was 0.17 (0.19) (Snellen equivalent, 20/32). In multivariable linear regression models, BSCVA was most associated with irregular astigmatism (1.0 line of worse BSCVA per 1-line difference between BSCVA and contact lens visual acuity; 95% CI, 0.6-1.4) and corneal scar density (1.5 lines of worse vision per 10-unit increase in the mean central corneal density; 95% CI, 0.8-2.3). The thinnest point of the cornea was the metric that best discriminated between the natamycin- and voriconazole-treated ulcers in MUTT I, with 29.3 µm (95% CI, 7.1-51.6 µm) less thinning in natamycin-treated eyes. Conclusions and Relevance: Both irregular astigmatism and corneal scar density may be important risk factors for BSCVA in a population with relatively mild, healed fungal corneal ulcers. The thinnest point of the corneal scar may be a cornea-specific outcome that could be used to evaluate treatments for corneal ulcers.
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Lesiones de la Cornea/fisiopatología , Infecciones Fúngicas del Ojo/fisiopatología , Queratitis/fisiopatología , Agudeza Visual/fisiología , Adulto , Córnea/patología , Estudios Transversales , Femenino , Humanos , Queratitis/microbiología , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
PURPOSE: To report 2 patients with colonization of therapeutic contact lens with dematiaceous fungi. METHODS: Case report. RESULTS: The first patient had a retained soft contact lens on an opaque cornea for 4 years with brownish black multiple colonies on the soft contact lens and culture grew Bipolaris spp. The second patient was on therapeutic contact lens for pseudophakic bullous keratopathy for 4 months and developed a brownish colonization of contact lens with unidentified dematiaceous fungi. Both the patients had conjunctivitis but did not develop fungal keratitis. CONCLUSION: Judicious use of therapeutic contact lens is required in agrarian countries with adequate emphasis on strict adherence to the standard protocols and frequent replacement of the lens.
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Lentes de Contacto Hidrofílicos/microbiología , Infecciones Fúngicas del Ojo/microbiología , Hongos/aislamiento & purificación , Micosis/microbiología , Administración Oftálmica , Anciano , Antifúngicos/uso terapéutico , Quimioterapia Combinada , Infecciones Fúngicas del Ojo/diagnóstico , Infecciones Fúngicas del Ojo/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Moxifloxacino/uso terapéutico , Micosis/diagnóstico , Micosis/tratamiento farmacológico , Natamicina/uso terapéutico , Soluciones Oftálmicas , Microscopía con Lámpara de HendiduraRESUMEN
Purpose: To determine the repeatability and reproducibility of anterior segment optical coherence tomography (AS-OCT) and Scheimpflug photography for several measurements of corneal scars, including scar size, scar depth, and corneal thickness. Methods: A series of patients treated for fungal keratitis at a tertiary eye care center in South India were recalled two years after successful treatment. Eyes with corneal scars had a slit lamp examination performed by two ophthalmologists masked to the other's examination. For AS-OCT and Scheimpflug photography, each eye had two scans taken by one technician and a third scan taken by a separate technician. Scar measurements were subsequently assessed from AS-OCT images by three graders masked to each other's results. Repeatability and reproducibility were assessed by calculating the intra-class correlation coefficient (ICC) from mixed effects linear regression models. Results: Fifty eyes had all measurements taken. The corneal scar size, measured as the geometric mean of the two longest perpendicular meridians, ranged from 0.8 to 5.4 (mean 2.8 mm, 95%CI 2.6 to 3.1). Scar size measurements taken by two separate individuals were most reproducible when the border of the scar was traced from the OCT (ICC 0.90, 95%CI 0.86 to 0.94), and least repeatable when assessed from slit lamp examination (ICC 0.80, 95%CI 0.70 to 0.90). Conclusions: AS-OCT and Scheimpflug imaging of corneal scars produced measurements with acceptable reproducibility that could be useful as cornea-specific outcomes for clinical trials.
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Cicatriz/diagnóstico , Córnea/patología , Paquimetría Corneal/métodos , Úlcera de la Córnea/complicaciones , Infecciones Fúngicas del Ojo/complicaciones , Microscopía con Lámpara de Hendidura/métodos , Tomografía de Coherencia Óptica/métodos , Adulto , Antifúngicos/uso terapéutico , Cicatriz/etiología , Úlcera de la Córnea/diagnóstico , Úlcera de la Córnea/tratamiento farmacológico , Infecciones Fúngicas del Ojo/diagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los ResultadosRESUMEN
Central vein thrombosis as a cause of chylothorax is uncommon, and in a few cases in the literature was related to thrombotic complications of central venous access devices (CVAD). Superior vena cava (SVC) occlusion-induced chylothorax has been described in adult sickle cell disease (SCD) in a setting of chronic indwelling CVAD. There are limited reports on chylothorax induced by central venous thrombosis secondary to chronic CVAD in children with SCD. We describe an 8-year-old male patient, with a history of SCD, maintained on long term erythrocytapheresis for primary prevention of stroke, and whose clinical course was complicated by chylothorax which was successfully treated with a pleuroperitoneal shunt.
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Argiria/patología , Enfermedades de la Conjuntiva/patología , Enfermedades de la Córnea/patología , Enfermedades Profesionales/patología , Exposición Profesional/efectos adversos , Compuestos de Plata/efectos adversos , Anciano , Argiria/etiología , Enfermedades de la Conjuntiva/inducido químicamente , Enfermedades de la Córnea/inducido químicamente , Humanos , Masculino , Enfermedades Profesionales/inducido químicamenteRESUMEN
BACKGROUND: Successful treatment of both pediatric autoimmune hemolytic anemia (AIHA) and immune thrombocytopenic purpura (ITP), specifically those that are refractory to first-line therapies, remains unsatisfactory in terms of long-term remission and medication side effects. Here, we propose a novel combination therapy of mycophenolate mofetil (MMF), an adjunct immunosuppressive, and short-term corticosteroids for the treatment of persistent or chronic autoimmune cytopenias in children. This combination may allow for rapid decrease of steroid usage as well as prolonged count stabilization with minimal toxicity to the patient. PROCEDURE: Prospective case series of nine patients, six with persistent or chronic ITP and three with persistent or chronic AIHA, between the ages of 5 and 19 years who are being treated with combination therapy consisting of corticosteroids and MMF. RESULTS: All patients with ITP (Patients 4-9) and AIHA (Patients 1-3) met complete response (CR) criteria, as they all initially achieved platelet counts 100 × 109 l-1 or more or hemoglobin level greater than or equal to 10 g/dl, respectively, while on combination therapy and then maintained this level or higher while on MMF alone after steroids were discontinued. CONCLUSIONS: Our results are very promising, as MMF appears to be an effective and well-tolerated adjunct immunosuppressant that allows for rapid weaning of steroid usage, minimal adverse side effects to the patients, and long-term stabilization of counts, a goal that has not been achieved successfully with other secondary treatment modalities. Therefore, this novel combination therapy may be an excellent alternative for the treatment of persistent or chronic autoimmune cytopenias in the pediatric population.
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Corticoesteroides/uso terapéutico , Anemia Hemolítica Autoinmune/tratamiento farmacológico , Inmunomodulación , Ácido Micofenólico/uso terapéutico , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Adolescente , Adulto , Anemia Hemolítica Autoinmune/inmunología , Antibióticos Antineoplásicos/uso terapéutico , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Masculino , Pronóstico , Estudios Prospectivos , Púrpura Trombocitopénica Idiopática/inmunología , Inducción de Remisión , Adulto JovenRESUMEN
BACKGROUND: Erythrocytapheresis procedures are increasingly used in sickle cell disease. Serum ferritin and noninvasive magnetic resonance imaging measurements of liver iron concentration (LIC) are frequently used to monitor iron overload secondary to hypertransfusion. There is a paucity of data describing the impact of long-term erythrocytapheresis (LTE) on LIC. MATERIALS AND METHODS: We measured magnetic resonance imaging liver and cardiac iron on LTE subjects and stratified them into 2 groups: higher LIC (>3 mg/g) and lower LIC (<3 mg/g). χ(2) and t test were used to test for differences between the 2 groups. Logistic regression and generalized linear mixed-effects models were used to test what impacted LIC. RESULTS: None of 29 sickle cell disease subjects maintained on LTE had high cardiac iron concentration. LIC was associated with serum ferritin (r=0.697, P<0.001) but was not associated with the total number of LTE procedures (r=-0.088, P=0.656) or total number of simple transfusions (r=0.316, P=0.108). The total number of LTE procedures was not associated with serum ferritin (r=0.040, P=0.838), the total number of simple transfusions (r=-0.258, P=0.184), or LIC group (r=-0.111, P=0.566). CONCLUSION: There was no significant correlation between duration of LTE maintenance and LIC.
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Anemia de Células Falciformes/terapia , Citaféresis/métodos , Eritrocitos , Sobrecarga de Hierro/prevención & control , Hígado/química , Adolescente , Niño , Femenino , Ferritinas/sangre , Humanos , Sobrecarga de Hierro/etiología , MasculinoRESUMEN
PURPOSE: Using in vivo confocal microscopy, we established that unique hyperreflective structures in the anterior limbal stroma of healthy individuals represent the limbal stromal niche. The aim of this study was to characterize the limbal stromal microarchitecture in patients with limbal stem cell deficiency (LSCD). METHODS: After obtaining informed consent, 10 patients with LSCD and 3 with macular corneal dystrophy were recruited. In vivo confocal imaging of the limbus and cornea of the affected and normal eyes was performed using an HRT III laser scanning microscope, beyond the epithelium deep into the stroma. RESULTS: In the case of LSCD, the limbal epithelium was replaced by conjunctival epithelium. A large number of inflammatory and dendritic cells were identified along with blood vessels from the epithelium to deep stromal layers. The unique hyperreflective niche structures were replaced by homogenously bright fibrous structures in all eyes with total LSCD. In patients with partial LSCD, even the clinically defined normal limbus had fibrotic stroma. In a patient with focal LSCD, only the affected limbal stroma remained fibrotic, whereas the adjacent clinically normal limbus had the unique hyperreflective structures. Although the opaque corneal stroma appeared bright because of proteoglycan deposition, it was possible to identify the normal limbal epithelial and stromal architecture in macular corneal dystrophy. CONCLUSIONS: In the case of LSCD, the limbal stromal niche was replaced by bright fibrotic structures indicating persistence of damage several months after injury. Further studies are required to characterize the sequential events occurring in the anterior limbal stroma after injury using this noninvasive method.
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Distrofias Hereditarias de la Córnea/patología , Opacidad de la Córnea/patología , Sustancia Propia/patología , Epitelio Corneal/patología , Limbo de la Córnea/patología , Células Madre/patología , Adulto , Recuento de Células , Sustancia Propia/citología , Femenino , Humanos , Limbo de la Córnea/citología , Masculino , Microscopía Confocal , Persona de Mediana Edad , Trasplante de Células MadreAsunto(s)
Colorantes/efectos adversos , Conjuntivitis Alérgica/inducido químicamente , Conjuntivitis Alérgica/cirugía , Opacidad de la Córnea/terapia , Tatuaje/efectos adversos , Adulto , Biopsia con Aguja , Ceguera , Opacidad de la Córnea/diagnóstico , Estudios de Seguimiento , Humanos , Inmunohistoquímica , Masculino , Procedimientos Quirúrgicos Oftalmológicos/métodos , Medición de Riesgo , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
BACKGROUND: Tacrolimus is an immunosuppressive drug that is used to lower the activity of the patient's immune system to prevent organ rejection. Unfortunately, there is limited data regarding the therapeutic equivalency of generic tacrolimus formulations especially in children. We report the case of a pediatric patient having an inability to achieve a therapeutic trough level for tacrolimus after conversion from brand name to the generic formulation. CASE PRESENTATION: A 17-month-old male patient diagnosed with T-cell acute lymphoblastic leukemia underwent allogeneic stem cell transplantation. The patient initially received intravenous (i.v.) tacrolimus for graft-versus-host disease (GVHD) prophylaxis and achieved therapeutic levels. The patient was then switched to an oral brand formulation of tacrolimus, and was able to maintain trough levels within the therapeutic range. After being discharged, the patient received the generic formulation of tacrolimus from an outside pharmacy and the care team was unable to reach therapeutic levels despite multiple dose escalations. Returning to brand name tacrolimus resulted in prompt achievement of therapeutic levels. CONCLUSIONS: A likely etiology for the inability to achieve therapeutic trough levels in this patient is the change in formulation from brand formulation to generic version. Other factors including drug-drug interaction, preparation of the medication by a different pharmacy, drug-food interaction and genetic factors were also considered. Physicians and pharmacists must be aware of the inability to achieve targeted therapeutic concentrations of tacrolimus resulting from the conversion of brand name to the generic formulation until these generic formulations are tested in clinical trials in a pediatric population.