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STAT2 is a transcription factor that plays an essential role in antiviral immunity by mediating the activity of type I and III interferons (IFN-I and IFN-III). It also has a recently established function in the negative regulation of IFN-I signaling. Homozygous STAT2 deficiency is an ultra-rare inborn error of immunity which provides unique insight into the pathologic consequence of STAT2 dysfunction. We report here a novel genetic cause of homozygous STAT2 deficiency with several notable clinical features. The proband presented aged 12 months with hemophagocytic lymphohistiocytosis (HLH) closely followed by clinical varicella, both occurring within three weeks of measles, mumps, and rubella (MMR) and varicella vaccinations. There was a history of life-threatening influenza A virus (IAV) disease 2 months previously. Genetic investigation uncovered homozygosity for a novel nonsense variant in STAT2 (c. 1999C>T, p. Arg667Ter) that abrogated STAT2 protein expression. Compatible with STAT2 deficiency, dermal fibroblasts from the child demonstrated a defect of interferon-stimulated gene expression and a failure to mount an antiviral state in response to treatment with IFN-I, a phenotype that was rescued by lentiviral complementation by wild type STAT2 . This case significantly expands the phenotypic spectrum of STAT2 deficiency. The occurrence of life-threatening influenza, which has not previously been reported in this condition, adds STAT2 to the list of monogenetic causes of this phenotype and underscores the critical importance of IFN-I and IFN-III to influenza immunity. The development of probable vaccine-strain varicella is also a novel occurrence in STAT2 deficiency, implying a role for IFN-I/III immunity in control of attenuated varicella zoster virus in vivo and reinforcing the susceptibility to pathologic effects of live-attenuated viral vaccines in disorders of IFN-I immunity. Finally, the occurrence of HLH in this case reinforces emerging links to hyperinflammation in patients with STAT2 deficiency and other related defects of IFN-I signaling—highlighting an important avenue for further scientific enquiry.

Background Central and peripheral nervous system symptoms and complications are being increasingly recognized among individuals with pandemic SARS-CoV-2 infections, but actual detection of the virus or its RNA in the central nervous system has rarely been sought or demonstrated. Severe or fatal illnesses are attributed to SARS-CoV-2, generally without attempting to evaluate for alternative causes or co-pathogens. Case presentation A five-year-old girl with fever and headache was diagnosed with acute SARS-CoV-2-associated meningoencephalitis based on the detection of its RNA on a nasopharyngeal swab, cerebrospinal fluid analysis, and magnetic resonance imaging findings. Serial serologic tests for SARS-CoV-2 IgG and IgA showed seroconversion, consistent with an acute infection. Mental status and brain imaging findings gradually worsened despite antiviral therapy and intravenous dexamethasone. Decompressive suboccipital craniectomy for brain herniation with cerebellar biopsy on day 30 of illness, shortly before death, revealed SARS-CoV-2 RNA in cerebellar tissue using the Centers for Disease Control and Prevention 2019-nCoV Real-Time Reverse Transcriptase-PCR Diagnostic Panel. On histopathology, necrotizing granulomas with numerous acid-fast bacilli were visualized, and Mycobacterium tuberculosis complex DNA was detected by PCR. Ventricular cerebrospinal fluid that day was negative for mycobacterial DNA. Tracheal aspirate samples for mycobacterial DNA and culture from days 22 and 27 of illness were negative by PCR but grew Mycobacterium tuberculosis after 8 weeks, long after the child’s passing. She had no known exposures to tuberculosis and no chest radiographic findings to suggest it. All 6 family members had normal chest radiographs and negative interferon-γ release assay results. The source of her tuberculous infection was not identified, and further investigations by the local health department were not possible because of the State of Michigan-mandated lockdown for control of SARS-CoV-2 spread. Conclusion The detection of SARS-CoV-2 RNA in cerebellar tissue and the demonstration of seroconversion in IgG and IgA assays was consistent with acute SARS-CoV-2 infection of the central nervous infection. However, the cause of death was brain herniation from her rapidly progressive central nervous system tuberculosis. SARS-CoV-2 may mask or worsen occult tuberculous infection with severe or fatal consequences.

COVID-19 is generally a benign or asymptomatic infection in children, but can occasionally be severe or fatal. Delayed presentation of COVID-19 with hyperinflammation and multi-organ involvement was recently recognized, designated the Multisystem Inflammatory Syndrome in Children (MIS-C). Six children with MIS-C with molecular and serologic evidence of SARS-CoV-2 infection were admitted to our hospital between May 5, 2020 and June 25, 2020. All had fever and weakness; 4/6 presented with gastrointestinal symptoms. Two children had features of complete Kawasaki disease, 3 had incomplete Kawasaki disease, while 1 had terminal ileitis with delayed onset of circulatory shock. Treatment consisted of intravenous immunoglobulin and aspirin for Kawasaki-like disease. Remdesivir, corticosteroids, and infliximab were used when indicated. Median hospitalization was 7 days. Immediate treatment resulted in rapid clinical improvement. In children presenting with hyperinflammatory syndromes without cardiac manifestations, testing for SARS-CoV-2 RNA and antibodies, with close cardiac monitoring should be pursued due to the manifold presentations of SARS-CoV-2 infection in children.

Moraxella lacunata, a low-virulence Gram-negative coccobacillus, is classically associated with conjunctivitis and upper respiratory tract infections; systemic infections such as sepsis have rarely been reported, especially in children. We describe a 28-month-old girl with atypical hemolytic uremic syndrome and stage II chronic kidney disease on long-term eculizumab therapy who presented with systemic inflammatory response syndrome and was found to have Moraxella lacunata bloodstream infection. Eculizumab, a humanized monoclonal anti-C5 antibody, has been associated with susceptibility to infections with encapsulated bacteria, especially Neisseria meningitidis. This is the first report of an invasive bacterial infection with Moraxella lacunata in a pediatric eculizumab recipient.

We enrolled 200 infants and older children with bacterial meningitis in two prospective double-blind, placebo-controlled trials to evaluate the efficacy of dexamethasone therapy in addition to either cefuroxime (Study 1) or ceftriaxone (Study 2). Altogether, 98 patients received placebo and 102 received dexamethasone (0.15 mg per kilogram of body weight every six hours for four days). At the beginning of therapy, the clinical and demographic characteristics of the patients in the treatment groups were comparable. The mean increase in the cerebrospinal fluid concentration of glucose and the decreases in lactate and protein levels after 24 hours of therapy were significantly greater in those who received dexamethasone than in those who received placebo (glucose, 2.0 vs. 0.4 mmol per liter [36.0 vs. 6.9 mg per deciliter], P<0.001; lactate, 4.0 vs. 2.1 mmol per liter [38.3 vs. 19.8 mg per deciliter], P<0.001; and protein, 0.64 vs. 0.25 g per liter [64.0 vs. 25.3 mg per deciliter], P<0.05). One patient in the placebo group in Study 1 died. As compared with those who received placebo, the patients who received dexamethasone became afebrile earlier (1.6 vs. 5.0 days; P<0.001) and were less likely to acquire moderate or more severe bilateral sensorineural hearing loss (15.5 vs. 3.3 percent; P<0.01). Twelve patients in the two placebo groups (14 percent) had severe or profound bilateral hearing loss requiring the use of a hearing aid, as compared with 1 (1 percent) in the two dexamethasone groups (P<0.001). We conclude that dexamethasone is beneficial in the treatment of infants and children with bacterial meningitis, particularly in preventing deafness. (N Engl J Med 1988; 319:964–71.) BACTERIAL meningitis affects an estimated 15,000 infants and children in the United States each year. 1 The case fatality rates for these patients range from 5 to 10 percent, and as many as 25 to 50 percent of those who survive have long-term sequelae. 2 In recent years, the use of newer antimicrobial agents with superior bactericidal action against infecting organisms in the cerebrospinal fluid has not produced tangible reductions in morbidity or case fatality rates for bacterial meningitis, as compared with conventional therapy. 3 The severe pathophysiologic alterations in the brains of children with bacterial meningitis are believed to contribute substantially to . . .

STAT2 is a transcription factor activated by type I and III IFNs. We report 23 patients with loss-of-function variants causing autosomal recessive (AR) complete STAT2 deficiency. Both cells transfected with mutant STAT2 alleles and the patients' cells displayed impaired expression of IFN-stimulated genes and impaired control of in vitro viral infections. Clinical manifestations from early childhood onward included severe adverse reaction to live attenuated viral vaccines (LAV) and severe viral infections, particularly critical influenza pneumonia, critical COVID-19 pneumonia, and herpes simplex virus type 1 (HSV-1) encephalitis. The patients displayed various types of hyperinflammation, often triggered by viral infection or after LAV administration, which probably attested to unresolved viral infection in the absence of STAT2-dependent types I and III IFN immunity. Transcriptomic analysis revealed that circulating monocytes, neutrophils, and CD8+ memory T cells contributed to this inflammation. Several patients died from viral infection or heart failure during a febrile illness with no identified etiology. Notably, the highest mortality occurred during early childhood. These findings show that AR complete STAT2 deficiency underlay severe viral diseases and substantially impacts survival.

Background Sequence type 131 (EC-ST131) is a prevalent cause of extraintestinal Escherichia coli infection, including in neonates, and accounts for a majority of multidrug-resistant strains. Rare reports of neonatal unit outbreaks have emerged, with one linking the source to freshly expressed breast milk (BM) sharing. We report on premature twin girls whose infection was linked to their mother’s contaminated frozen BM. Methods Blood culture isolates were from twin girls born at 24–1/7 weeks’ gestation who developed severe sepsis caused by ampicillin- and gentamicin-resistant E. coli on days 11 (Baby A; died) and 8 (Baby B; survived) of life; both neonates had sterile blood cultures at birth, and received orogastric feeds using frozen BM provided by their mother. Five remaining frozen BM samples predating onset of sepsis were thawed and cultured; E. coli resistant to ampicillin and gentamicin was recovered from 1 collected on day 5 of life. DNA was extracted from cultured isolates using the Zymo Research Quick-DNA™ Fungal/Bacterial Miniprep kit, sequencing libraries prepared (Nextera® XT PE), and sequencing (Illumina MiSeq® with V2 2 X 250 bp chemistry) completed for the 2 blood and 1 BM isolates. Multilocus Sequence Typing (MLST) and core genome MLST (cgMLST) analyses were performed using SeqSphere+, version 5.1.0 (Ridom, Munster, DE) software, with 2513 alleles analyzed for cgMLST. Results The 2 blood and 1 BM isolates were typed as ST131 by MLST and were indistinguishable by cgMLST. Of the 2513 alleles queried, only 263 (10.5%) differed from the ST131 strain SCB34 (figure). Thus, our EC-ST131 cluster isolates belong to the same clonal complex as, but are genetically divergent from, SCB34. In addition to the E. coli described above isolated from a BM sample, all 5 frozen BM samples grew multiple morphotypes of coagulase-negative staphylococci. The mother had acute chorioamnionitis and was treated with intravenous ampicillin, gentamicin, and metronidazole for 48 hours immediately after delivery. Conclusion Despite frozen BM’s persistent antibacterial activity, it is a potential source of multidrug-resistant bacteria for neonates, as evidenced by this report of EC-ST131 neonatal sepsis in premature twins. Disclosures Robin Patel, MD, ASM and IDSA: Other Financial or Material Support, Travel reimbursement, editor’s stipends; CD Diagnostics, Merck, Hutchison Biofilm Medical Solutions, Accelerate Diagnostics, ContraFect, TenNor Therapeutics Limited, Shionogi: Grant/Research Support; Curetis, Specific Technologies, NextGen Diagnostics, PathoQuest, Qvella: Consultant; NBME, Up-to-Date, the Infectious Diseases Board Review Course: Honorarium recipient, Other Financial or Material Support; Patent on Bordetella pertussis/parapertussis PCR issued, a patent on a device/method for sonication with royalties paid by Samsung to Mayo Clinic, and a patent on an anti-biofilm substance issued: Other Financial or Material Support, Patents.

Ibia et al present findings from a nationwide survey of Board-certified pediatric infectious disease specialists (PIDS). The purpose of the survey was to learn about PIDS' antibiotic-prescribing habits for children with upper respiratory tract infections, using clinical vignettes followed by multiple-choice questions.

Amalia Voureka was a physician, bacteriologist, and Greek Resistance activist who joined the laboratory of Sir Alexander Fleming in 1946 on a scholarship. She had nine research publications between May 1947 and August 1952, four of which were as the single author and three as the first author. Only three were coauthored with Sir Fleming. Her research focus was bacteria and antimicrobial agents. She demonstrated variable endpoints for the bacteriostatic power of streptomycin depending on media used, inoculum size, salt concentration, and atmospheric conditions. She worked on bacterial antibiotic resistance, demonstrating the induction of bacterial variants following chloramphenicol treatment. In another paper, she showed that penicillin‐resistant bacteria can be made sensitive by coculture with other organisms that are either penicillin sensitive or insensitive. In a study of staphylococcal strains from the anterior nares of patients, she documented a low rate of penicillin resistance (7.6%). Elsewhere, she showed that toxin production by staphylococci is important for virulence. She determined that bacterial flagella can be critical for movement and not simply attachments resulting from cell distress. She refined and invented new laboratory techniques, improving on flagellar staining. Dr. Voureka married Sir Fleming in 1953, despite a 31‐year age difference. Her marriage to Sir Fleming was brief (he died of a heart attack in 1955). She later returned to Greece but was exiled and stripped of her citizenship by the military junta for her political activities. After the junta fell, she returned to Greece and was elected to Parliament in 1977, 1981, and 1985. She died in 1986.