BCG Infection in Patients With Inborn Errors of Immunity Receiving the Russian BCG Strain.

BACKGROUND: Bacillus Calmette-Guierin (BCG) vaccination complications are common in inborn errors of immunity (IEI) due to the inability to clear live attenuated Mycobacterium bovis. Various BCG-vaccine strains are used worldwide, and the profile of the Russian BCG strain vaccine complications in IEI is poorly characterized. OBJECTIVE: To evaluate risks of BCG infection in a large cohort of patients with IEI vaccinated with the Russian BCG strain. METHODS: We evaluated 778 patients with IEI vaccinated with the Russian BCG strain. RESULTS: A total of 114 (15%) developed BCG infection, 41 (36%) with local, 19 (17%) with regional, and 54 with (47%) disseminated disease. BCG infection was seen in 58% of the patients with severe combined immunodeficiency (SCID), 82% with chronic granulomatous disease, 50% with innate immune defects, 5% with combined immunodeficiency, and 2% with other IEI. BCG infection presented at a median age of 4 to 5 months in SCID, chronic granulomatous disease, combined immunodeficiency, and other IEI groups versus 12 months in patients with innate immune defects (P < .005). We found no influence of specific genetic defects, CD3+ and natural killer cell numbers in SCID, or dihydrorhodamine test stimulation index values in chronic granulomatous disease on the BCG-infection risks. All patients with SCID received antimycobacterial therapy at SCID diagnosis even in the absence of active BCG infection. More antimycobacterial agents were required in disseminated relative to local or regional infection (P < .0001). Only 1 of 114 patients (with SCID) died of BCG-related complications (<1%). CONCLUSIONS: BCG infection is common in patients with IEI receiving BCG vaccination. Rational early antimycobacterial therapy, combined with anticytokine agents for posttransplant inflammatory syndrome prevention, and treatment in SCID may prevent BCG-related mortality.

SARS-CoV-2 in children with cancer or after haematopoietic stem cell transplant: An analysis of 131 patients.

PURPOSE: There are limited data on SARS-CoV-2 (COVID-19) infection in children with cancer or after haematopoietic stem cell transplant (HSCT). We describe the severity and outcomes of SARS-COV-2 in these patients and identify factors associated with severe disease. METHODS: This was a multinational, observational study of children (aged <19 years) with cancer or HSCT and SARS-CoV-2 confirmed by polymerase chain reaction. COVID-19 was classified as asymptomatic, mild, moderate, severe or critical (≥1 organ support). Exact polytomous regression was used to determine the relationship between clinical variables and disease severity. RESULTS: One hundred and thirty-one patients with COVID-19 across 10 countries were identified (median age 8 years). Seventy-eight (60%) had leukaemia/lymphoma, 48 (37%) had solid tumour and five had primary immunodeficiency and HSCT. Fever (71%), cough (47%) and coryza (29%) were the most frequent symptoms. The median duration of detectable virus was 16 days (range, 1-79 days). Forty-nine patients (37%) were hospitalised for COVID-19 symptoms, and 15 (11%) required intensive care unit-level care. Chemotherapy was delayed/modified in 35% of patients. COVID-19 was asymptomatic in 32% of patients, mild in 47%, moderate in 8%, severe in 4% and critical in 9%. In 124 patients (95%), a full recovery was documented, and four (3%) died due to COVID-19. Any comorbidity (odds ratio, 2.94; 95% confidence interval [CI], 1.81-5.21), any coinfection (1.74; 95% CI 1.03-3.03) and severe baseline neutropenia (1.82; 95% CI 1.13-3.09) were independently and significantly associated with increasing disease severity. CONCLUSION: Although most children with cancer had asymptomatic/mild disease, 13% had severe COVID-19 and 3% died. Comorbidity, coinfection and neutropenia may increase the risk of severe disease. Our data may help management decisions in this vulnerable population.

Antibiotic Resistant Bloodstream Infections in Pediatric Patients Receiving Chemotherapy or Hematopoietic Stem Cell Transplant: Factors Associated with Development of Resistance, Intensive Care Admission and Mortality.

Bloodstream infections (BSI) are a severe complication of antineoplastic chemotherapy or hematopoietic stem cell transplantation (HSCT), especially in the presence of antibiotic resistance (AR). A multinational, multicenter retrospective study in patients aged ≤ 18 years, treated with chemotherapy or HSCT from 2015 to 2017 was implemented to analyze AR among non-common skin commensals BSI. Risk factors associated with AR, intensive care unit (ICU) admission and mortality were analyzed by multilevel mixed effects or standard logistic regressions. A total of 1291 BSIs with 1379 strains were reported in 1031 patients. Among Gram-negatives more than 20% were resistant to ceftazidime, cefepime, piperacillin-tazobactam and ciprofloxacin while 9% was resistant to meropenem. Methicillin-resistance was observed in 17% of S. aureus and vancomycin resistance in 40% of E. faecium. Previous exposure to antibiotics, especially to carbapenems, was significantly associated with resistant Gram-negative BSI while previous colonization with methicillin-resistant S. aureus was associated with BSI due to this pathogen. Hematological malignancies, neutropenia and Gram-negatives resistant to >3 antibiotics were significantly associated with higher risk of ICU admission. Underlying disease in relapse/progression, previous exposure to antibiotics, and need of ICU admission were significantly associated with mortality. Center-level variation showed a greater impact on AR, while patient-level variation had more effect on ICU admission and mortality. Previous exposure to antibiotics or colonization by resistant pathogens can be the cause of AR BSI. Resistant Gram-negatives are significantly associated with ICU admission and mortality, with a significant role for the treating center too. The significant evidence of center-level variations on AR, ICU admission and mortality, stress the need for careful local antibiotic stewardship and infection control programs.

SARS-CoV-2 convalescent plasma therapy in pediatric patient after hematopoietic stem cell transplantation.

Immunocompromised patients, including HSCT recipients, may have a poor prognosis after contracting COVID-19 due to the absence of a pathogen-specific adaptive immune response. One of the possible options for severe COVID-19 treatment may be the transfusion of hyperimmune SARS-CoV-2 convalescent plasma. A 9-month-old girl with juvenile myelomonocytic leukemia received an HSCT from a haploidentical donor. On day +99, during routine virologic monitoring, SARS-CoV-2 was detected without any clinical symptoms. On day +144, the child developed a polysegmental bilateral viral pneumonia with 60 % damage to the lung tissue and confirm a positive SARS-Cov-2 results in throat swab. The patient was treated with tocilizumab and three doses of fresh frozen plasma obtained from a SARS-CoV-2 convalescent patient. Therapy with tocilizumab and three doses of fresh frozen plasma was well tolerated. In spite of full resolution of the lung lesions, complete elimination of SARS-CoV-2 has not been achieved 4 months after the first detection, which is due to persistence of secondary immunodeficiency after HSCT and the lack of reconstitution of the adaptive immune response. This case represents a demonstration of an atypical course of COVID-19 and the delayed development of lung lesions, which was most likely associated with the features of the patient's immune status after HSCT. SARS-CoV-2 convalescent plasma in combination with other therapeutic approaches is one of the possible curative options for this clinical situation.

Disseminated Fusariosis in Immunocompromised Children-Analysis of Recent Cases Identified in the Global Fungiscope Registry.

Disseminated fusariosis is a rare disease, and data are scant in pediatric patients. In the FungiScope registry, we identified 10 children with disseminated fusariosis between 2006 and 2015. Our analysis of the largest pediatric case series reported to date adds pediatric-specific experience to the management of this opportunistic infection in children.

Control of thrombotic thrombocytopenic purpura by sirolimus in a child with juvenile myelomonocytic leukemia and somatic N-RAS mutation.

We describe an infant who developed juvenile myelomonocytic leukemia (JMML) at the age of 6 months. Myeloproliferation was effectively controlled by low-dose cytosine arabinoside and 13-cis retinoic acid therapy. Two years after therapy for JMML was stopped, at the age of 5 years, the patient developed autoimmune thrombotic thrombocytopenic purpura (TTP). TTP was transiently controlled by plasma exchange, prednisolone, rituximab, and cyclophosphamide, but relapsed within a short time. Long-term control of TTP was established by sirolimus. Somatic N-RAS G38A→Gly13Asp substitution was restricted to hematopoietic cells. The somatic N-RAS mutation may link myeloproliferation and autoimmunity.

Development of T-cell acute lymphoblastic leukemia in a patient in very long lasting complete remission of juvenile myelomonocytic leukemia.

Juvenile myelomonocytic leukemia (JMML) occurs with an incidence of 1.2 per million children a year, and represents 18% to 30% of all myelodysplastic (MDS) and myeloproliferative (MPS) disorders in the age group below 15, being by far the most common MDS/MPS in children younger than 4 years. The only therapeutic approach which results in a definitive cure of patients with JMML is myeloablative chemo-therapy/radio-therapy, followed by allogeneic hematopoietic cell transplantation. Few cases of transformation of JMML in acute lymphoblastic leukemia have been reported. We describe a child with JMML diagnosed at the age of 4 months in whom complete remission was achieved with 13-cis retinoic acid and cytosine-arabinoside and was sustained for 7 years with no maintenance therapy. Ninety-eight months after the diagnosis of JMML was established, overt T-cell leukemia developed. Treatment with acute lymphoblastic leukemia (ALL)-directed chemotherapy induced complete restoration of normal hemopoiesis, but testicular involvement persisted. The patient died after transplantation with unrelated cord blood. This case suggests that JMML is a true stem cell disorder and that stem cell transplantation should be considered, even in patients with a very favorable clinical course.