Bilirubin Measurement Through a Smartphone Application in Preterm Infants.

BACKROUND: Aim of the present study is to evaluate the feasibility and reliability of an smartphone application for monitore of bilirubin levels in preterm infants. METHODS: Preterm infants hospitalized in the neonatal intensive care unit with gestational age of<35 weeks were included. Exclusion criteria were parental reluctance and requirement of phototherapy in the last 12 hours. Measurements were obtained through a smartphone application (BiliScan) along with simultaneous transcutaneous device (Dräger JM 105) and venous blood biochemistry. RESULTS: Mean gestational age was 30.8±2.4 weeks and birth weight was 1622±566 g. Measurements were obtained at a median of 4 (1-21) days of life. Twenty-five infants (19.4%) had ABO and/or Rh incompatibility and 39 infants (30.2%) required phototherapy. None of the cases required exchange transfusion. Mean total serum bilirubin (TSB) level was 8.16±2.60 mg/dL, mean transcutaneous bilirubin (TcB) level was 8.60±2.70 mg/dL, and the mean bilirubin level measured by BiliScan was 7.26±2.68 mg/dL. For TSB and TcB measurements, the intraclass correlation coefficient (ICC) was found to be 0.915 (95% confidence interval 0.835-0.951; p<0.001) and a strong positive correlation was found between these two measurements. When TSB and BiliScan measurements were compared, ICC was found to be significant as 0.512 (95% confidence interval 0.353-0.638; p<0.001), with a moderate correlation. CONCLUSIONS: In this study, we evaluated the feasibility and reliability of a smartphone application for monitoring bilirubin levels in preterm infants. Although BiliScan measurements reported to display high correlation in term infants, a moderate correlation was found in the preterm infants. It is an emerging low-cost, non-invasive alternative for neonatal jaundice monitoring, however, results should be interpreted with caution in preterm infants.

Postnatal surgery for myelomeningocele in neonates: neurodevelopmental outcomes.

BACKGROUND: The study aims to evaluate the neurodevelopmental outcomes of neonates with myelomeningocele (MMC) operated in the postnatal period. METHODS: This is a prospective follow-up study in a tertiary neonatal intensive care unit. Neurodevelopmental outcomes of term neonates operated for MMC and healthy term newborns were compared with the Bayley Scales of Infant and Toddler Development -Third Edition (BSID III) at 12-18 months. RESULTS: A total of 57 cases were included in the study (patient group = 27; control group = 30). Demographic data between the groups were similar. Cognitive, linguistic, and motor composite scores of the patient group were lower than those of the control group (p < 0.001). In the patient group, those who underwent ventriculoperitoneal shunt had lower cognitive, language and motor scores than those without shunt (p < 0.05). The cognitive, linguistic, and motor composite scores in the patient group who underwent surgery before 72 h were better than those who underwent surgery after 72 h. DISCUSSION: In our study, it was found that the neurodevelopmental prognosis of MMC cases requiring ventriculoperitoneal shunt in the postnatal period was significantly worse than those without shunt. It is the first study in which the neurodevelopment of patients with MMC who were operated in the postnatal period was evaluated with BSID III evaluated and delays in all areas were shown in cases with MMC compared to normal cases. Better neurodevelopmental outcomes in patients operated in the first 72 h suggest that early surgery will improve neurodevelopmental outcomes in patients with MMC.

Epidemiologic and clinical characteristics of neonates with late-onset COVID-19: 1-year data of Turkish Neonatal Society.

The literature on neonates with SARS-CoV-2 is mainly concerned with perinatal cases, and scanty data are available about environmentally infected neonates. To fill knowledge gaps on the course and prognosis of neonatal cases, we analyzed 1-year data from the Turkish Neonatal Society in this prospective cohort study of neonates with postnatal transmission. Data from 44 neonatal intensive care units (NICUs), of neonates with positive RT-PCR results at days 5-28 of life, were extracted from the online registry system and analyzed. Of 176 cases, most were term infants with normal birth weight. Fever was the most common symptom (64.2%), followed by feeding intolerance (25.6%), and cough (21.6%). The median length of hospitalization was 9 days, with approximately one quarter of infants receiving some type of ventilatory support. Myocarditis (5.7%) was the most common complication during follow-up. Among the clinical findings, cough (odds ratio [OR]: 9.52, 95% confidence interval [CI]: 4.17-21.71), tachypnea (OR: 26.5, 95% CI: 9.59-73.19), and chest retractions (OR: 27.5, 95% CI: 5.96-126.96) were associated with more severe clinical disease. Also, there were significant differences in the C-reactive protein level, prothrombin time (PT), partial thromboplastin time, international normalized ratio, and days in the NICU (p = 0.002, p = 0.012, p = 0.034, p = 0.008, and p < 0.001, respectively) between patients with mild-moderate and severe-critical presentations. A PT above 14 s was a significant predictor of severe/critical cases, with a sensitivity of 64% and specificity of 73%. CONCLUSIONS: Our data showed that late-onset COVID-19 infection in neonates who need hospitalization can be severe, showing associations with high rates of ventilatory support and myocarditis. Cough, tachypnea, and retractions on admission suggest a severe disease course. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04401540. WHAT IS KNOWN: • Neonatal cases of COVID-19 infection are mainly reported as perinatal COVID-19 cases. • Neonates with perinatal transmission have a mild course and favorable prognosis. WHAT IS NEW: • Among symptomatic neonates with late-onset COVID-19 infection, fever was the most common symptom, and almost one quarter of hospitalized cases needed some type of respiratory support. Myocarditis was the most common complication. • The presence of cough, tachypnea, retractions, and a PT above 14 s were associated with an increased risk of severe COVID-19.

Cycled Lighting Versus Continuous Near Darkness in Preterm Infants: A Randomized Controlled Trial.

OBJECTIVE: To compare the effectiveness of cycled lighting (CL) or continuous near darkness (CND) on weight in preterm infants. STUDY DESIGN: Total 147 infants with a gestational age 25-32 weeks and/or a birth weight 750-1500 g were included in the study. The infants were classified into two groups: CL and CND. Weight on postnatal day 14, weight at corrected 35 weeks, mean rectal temperature and serum growth hormone, cortisol, melatonin levels at 35 weeks' post menstrual age (PMA), weekly weight gain, full enteral feeding time, duration of mechanical ventilation, retinopathy of prematurity (ROP), length of stay in the hospital, weight and length at three and six months corrected age were compared between the groups. RESULTS: There were no differences between weights on postnatal day 14. Anthropometric parameters and mean rectal temperatures of groups also were not different at 35 weeks' PMA. There were no differences among the groups in duration of full enteral feeding time, length of stay in hospitalization, duration of mechanical ventilation, ROP and anthropometric parameters. Further, serum growth hormone, cortisol, and melatonin levels were similar between the groups at 35 weeks' PMA. CONCLUSION: CL and CND did not have any advantages over each other.

A multicenter study on epidemiological and clinical characteristics of 125 newborns born to women infected with COVID-19 by Turkish Neonatal Society.

Limited data are available on pregnant women with COVID-19 and their neonates. We aimed to evaluate the epidemiological and clinical characteristics of newborns born to women infected with COVID-19. A multicenter cohort study was conducted among newborns born to mothers with COVID-19 in 34 neonatal intensive care units (NICUs) in Turkey. Pregnant women (n = 125) who had a positive RT-PCR test and their newborns were enrolled. Cesarean section, prematurity, and low-birthweight infant rates were 71.2%, 26.4%, and 12.8%, respectively. Eight of 125 mothers (6.4%) were admitted to an intensive care unit for mechanical ventilation, among whom six died (4.8%). Majority of the newborns (86.4%) were followed in isolation rooms in the NICU. Four of 120 newborns (3.3%) had a positive RT-PCR test result. Although samples taken on the first day were negative, one neonate became positive on the second day and the other two on the fifth day. Sample from deep tracheal aspirate was positive on the first day in an intubated case.Conclusion: COVID-19 in pregnant women has important impacts on perinatal and neonatal outcomes. Maternal mortality, higher rates of preterm birth and cesarean section, suspected risk of vertical transmission, and low rate of breastfeeding show that family support should be a part of the care in the NICU.Trial registration: ClinicalTrials.gov identifier: NCT04401540 What is Known: • The common property of previous reports was the conclusions on maternal outcomes, rather than neonatal outcomes. • Published data showed similar outcomes between COVID-19 pregnant women and others. What is New: • Higher maternal mortality, higher rates of preterm birth and cesarean section, suspected risk of vertical transmission especially in a case with deep tracheal aspiration during the intubation, and the possible role of maternal disease severity on the outcomes are remarkable findings of this study. • In contrast to recommendation for breastfeeding, parents' preference to formula and expressed breast milk due to anxiety and lack of information shows that family support should be a part of the care in the NICU.

Is Nasal Septum-Tragus Length Measurement Appropriate for Endotracheal Tube Intubation Depth in Neonates? A Randomized Controlled Study.

OBJECTIVE: Endotracheal intubation is a frequent procedure performed in neonates with respiratory distress. Clinicians use different methods to estimate the intubation insertion depth, but, unfortunately, the improper insertion results are very high. In this study, we aimed to compare the two different methods (Tochen's formula = weight in kilograms + 6 cm; and nasal septum-tragus length [NTL] + 1 cm) used to determine the endotracheal tube (ETT) insertion depth. STUDY DESIGN: Infants who had intubation indications were enrolled in this study. The intubation tube was fixed using the Tochen formula (Tochen group) or the NTL + 1 cm formula (NTL group). After intubation, the chest radiograph was evaluated (above T1, proper place, and below T2). RESULTS: A total of 167 infants (22-42 weeks of gestational age) were included in the study. The proper tube placement rate in both groups was similar (32.4 vs. 30.4% for infants < 34 weeks of gestational age and 56.8 vs. 45.0% in infants > 34 weeks of gestational age). The ETT was frequently placed below T2 at a higher rate in infants with a gestational age of <34 weeks, especially in the NTL group (46% in the Tochen group and 60.7% in the NTL group). CONCLUSION: The NTL + 1 cm formula led to a higher rate of ETT placement below T2, especially in infants with a birth weight of <1,500 g. Therefore, more studies are needed to determine the optimal ETT insertion depth.

Presepsin and fetuin-A dyad for the diagnosis of proven sepsis in preterm neonates.

BACKGROUND: Diagnosis is the most strenuous step in the evaluation of neonatal sepsis. No gold standard diagnostic method is available except for blood culture. We aimed to investigate the role of positive and negative acute phase reactants, namely presepsin and fetuin-A, in the diagnosis of culture-proven late-onset sepsis. METHODS: A prospective, case-control study with the infants ≤32 weeks of age with a diagnosis of culture-proven late-onset sepsis was designed. Twenty-nine preterm infants with similar gestational and postnatal ages without sepsis constituted the control group. Serum values of presepsin, fetuin-A, C-reactive protein and interleukin-6 were evaluated at the enrollment, third and seventh days of the diagnosis in the infants with positive blood culture results. RESULTS: First-day presepsin values were significantly higher in the culture-positive infants than the control group [1583 ng/L (1023-1731) vs. 426 ng/L (287-589), p = < 0.0001]. Presepsin was found to have an 88.9% sensitivity and 88.9% specificity with a cut-off value of 823 ng/ml for culture-proven LOS in our study, and area under the receiver-operating curve was 0.939. Fetuin-A levels were similar between the study and control groups (p > 0.05). CONCLUSION: Presepsin may be an accurate marker for both diagnosis and monitoring of treatment response for culture-proven late-onset sepsis in preterm infants. However, fetuin-A does not seem to be a useful tool for the diagnosis of sepsis.

Neurodevelopmental Outcomes of Preterm Infants Treated with Oral Paracetamol Versus Ibuprofen for Patent Ductus Arteriosus.

Objective This study aims to determine the effects of paracetamol versus ibuprofen treatment given to preterm infants for the pharmacological closure of patent ductus arteriosus (PDA) on neurodevelopmental outcomes at 18 to 24 months' corrected age. Method A follow-up study was conducted to evaluate the neurodevelopmental outcomes of preterm infants (gestational age ≤ 30 weeks) enrolled in a randomized controlled trial comparing oral paracetamol versus oral ibuprofen for the closure of PDA. The developmental assessment was done by using "Bayley Scales of Infant Development, Second Edition" at 18 to 24 months' corrected age. Results A total of 80 infants completed the trial protocol. Of the 75 infants eligible for follow-up, 61 infants (30 in the paracetamol group and 31 in the ibuprofen group) were evaluated. There was no significant difference in neurodevelopmental outcomes between the two groups. Conclusion The neurodevelopmental outcomes did not differ among the preterm infants who receive either paracetamol or ibuprofen at 18 to 24 months' corrected age.

Urinary markers of acute kidney injury in newborns with perinatal asphyxia (.).

BACKGROUND: Acute kidney injury (AKI) affects up to 60% of severely asphyxiated neonates. The diagnosis of AKI can be and is further challenged by a lack of good biomarkers. We studied the role of novel markers for AKI, neutrophil gelatinase-associated lipocalin (NGAL), interleukin-8 (IL-18), Netrin-1 (NTN-1), and sodium hydrogen exchanger isoform 3 (NHE3) on development and early diagnosis of AKI in newborns with perinatal asphyxia (PA). METHODS: Forty-one newborns with a diagnosis of PA (15 with AKI and 26 without AKI) and 20 healthy matched controls were involved to the study. Urinary samples were obtained on postnatal days 1 and 4 for patients with PA and on postnatal day 1 for the control subjects. AKI was defined using a serum creatinine-based modification of the acute kidney injury network criteria. RESULTS: The levels of NGAL, NTN-1, NHE3, and IL-18 on the first postnatal day urine samples were higher in patients compared to controls (p < 0.001, p <0.001, p  <0.02, p  <0.001, respectively). In patients with AKI, the levels of NGAL and IL-18 were higher when compared to patients without AKI (p = 0.002, p  <0.001, respectively). The levels of NTN-1 and NHE3 were similar in both groups. For the samples obtained on postnatal day 4, only NGAL levels were significantly higher in patients with AKI (p = 0.004) compared to those without AKI. CONCLUSION: To our knowledge, this is the largest study, which evaluated the utility of urinary biomarkers in the diagnosis of AKI in newborns with PA. First day, urine NGAL and IL-18 levels have an important diagnostic power in such patients.

Oral paracetamol versus oral ibuprofen in the management of patent ductus arteriosus in preterm infants: a randomized controlled trial.

OBJECTIVE: To compare the efficacy and safety of oral paracetamol and oral ibuprofen for the pharmacological closure of patent ductus arteriosus (PDA) in preterm infants. STUDY DESIGN: This prospective, randomized, controlled study enrolled 90 preterm infants with gestational age ≤ 30 weeks, birthweight ≤ 1250 g, and postnatal age 48 to 96 hours who had echocardiographically confirmed significant PDA. Each enrolled patient received either oral paracetamol (15 mg/kg every 6 hours for 3 days) or oral ibuprofen (initial dose of 10 mg/kg, followed by 5 mg/kg at 24 and 48 hours). RESULTS: Spontaneous closure rate for the entire study group was 54%. After the first course of treatment, the PDA closed in 31 (77.5%) of the patients assigned to the oral ibuprofen group vs 29 (72.5%) of those enrolled in the oral paracetamol group (P = .6). The reopening rate was higher in the paracetamol group than in the ibuprofen group, but the reopening rates were not statistically different (24.1% [7 of 29] vs 16.1% [5 of 31]; P = .43). The cumulative closure rates after the second course of drugs were high in both groups. Only 2 patient (2.5%) in the paracetamol group and 3 patients (5%) in the ibuprofen group required surgical ligation. CONCLUSION: This randomized, controlled clinical study compared oral paracetamol with ibuprofen in preterm infants and demonstrated that paracetamol may be a medical alternative in the management of PDA.

Is folic acid supplementation really necessary in preterm infants ≤ 32 weeks of gestation?

OBJECTIVES: The aim of this study was to define whether there was folate deficiency in hospitalized preterm infants, and, second, to define the effect of feeding modalities on serum folate levels. METHODS: Infants born ≤ 32 weeks of gestation were included in the study. Blood samples for the determination of serum folate levels were obtained on days 14 and 28 postnatally, as well as 36 weeks postconceptionally (or just before discharge if patients are discharged <36 weeks)--samples A, B, and C, respectively. Infants were divided into 3 groups based on mode of feeding; human breast milk (HBM), fortified HBM (fHBM), or preterm formula (PF). RESULTS: A total of 162 preterm infants were enrolled: 17 (10.5%) of whom received HBM alone, 94 (58%) received fHBM, and 51 (31.5%) were fed with PF. None of the preterm infants developed folate deficiency during the study period. Preterm infants in the fHBM and PF groups had significant higher serum folate levels in samples C when compared with those receiving HBM alone (P < 0.001 for both). Multivariate analysis to evaluate the effects of maternal supplementation, smoking habit, gestational age, birth weight, and cumulative folic acid intake in samples A, B, and C suggested that maternal smoking and maternal folic acid supplementation had significant effects on serum folate levels in sample A and B. CONCLUSIONS: Preterm infants receiving parenteral nutrition with high folic acid content have no risk of folate deficiency during the 2 months of age; however, preterm infants fed orally from birth with HBM or PF with a low folic acid content could be at risk for folate deficiency, especially when mothers are smokers and/or do not receive folic acid supplementation during pregnancy.

Beneficial effects of Etanercept on experimental necrotizing enterocolitis.

PURPOSE: Tissue damage in necrotizing enterocolitis (NEC) of infants occurs as a result of an uncontrolled inflammatory response. The aim of this study was to investigate any potential anti-inflammatory effects that Etanercept may have on the inflammatory response in an experimental NEC model in newborn rats. METHODS: Newborn pups were randomized into three groups immediately after birth (Control, NEC + Placebo and NEC + Etanercept). Pups in the NEC + Placebo and NEC + Etanercept groups were subjected to an NEC-inducing protocol (hypercarbia, hypothermia and hyperoxia) twice a day for 3 days. Pups in the NEC + Etanercept group were given an intraperitoneal injection of Etanercept. Rats were harvested for biochemical and histopathological examinations. RESULTS: The histopathological injury score of rats in the NEC + Placebo group was significantly higher compared to the NEC + Etanercept and Control groups (p < 0.05 for both comparisons). Tissue levels of tumor necrosis factor-α, interleukin-1ß, and malondialdehyde were higher in the placebo group compared to the Etanercept group. CONCLUSION: Our results suggest that Etanercept attenuates intestinal tissue damage in NEC by reducing inflammation and blocking the production of free-oxygen radicals, while also reducing tissue levels of tumor necrosis factor-α and interleukin-1ß.

Successful management of twin anemia/polycythemia sequence by syngeneic partial exchange transfusion.

Twin anemia/polycythemia sequence (TAPS) is characterized by large intertwin hemoglobin (Hb) differences without signs of twin oligopolyhydramnios. The spontaneous form complicates approximately 3-5% of monochorionic twin pregnancies. TAPS placentas are characterized by the presence of only very few and small unidirectional arteriovenous anastomoses, which allow a slow transfusion of blood from the donor to the recipient, gradually leading to highly discordant Hb levels. Neonatal morbidity in TAPS appears to be mainly limited to hematological problems at birth. Donor twins may be severely anemic and require blood transfusions, whereas recipient twins may be severely polycythemic and require partial exchange transfusion (PET). We herein report monochorionic twins with TAPS: the anemic twin was transfused with the blood concomitantly obtained from the polycythemic co-twin during PET. To our knowledge this is the first therapeutic approach using a recipient twin's whole blood as a donor source instead of a foreign blood donor. In this case, we have approached this recently (un)known form of chronic fetofetal transfusion from a different aspect. In our opinion, this will lead to new postnatal therapeutic approaches for optimal TAPS management.

Epidemiology and Outcomes of Neonatal Meningitis: Results of the Turkish Neo-Meningitis Nationwide Study.

OBJECTIVE: To investigate the incidence and etiology of neonatal meningitis and to assess the associated risk factors, complications and outcomes in a nationwide multicenter retrospective descriptive study. METHOD: Twenty-seven centers from 7 geographical regions participated in the study. Newborns with a positive cerebrospinal fluid culture and/or cerebrospinal fluid polymerase chain reaction were included in the study. Demographic characteristics, clinical, laboratory and neuroimaging findings and mortality characteristics were analyzed. RESULTS: A total of 634 confirmed cases of neonatal meningitis were included in the final analysis. The incidence was 2.51 per 1000 intensive care unit hospitalizations and mortality was observed in 149 (23.5%). Gram-positive bacteria were the predominant pathogens (54.5%), with coagulase-negative Staphylococci accounting for 45.3% of the cases, followed by Gram-negative organisms (37.3%). Viral and fungal organisms were isolated in 3.2% and 1.7% of the infants, respectively. Gram-negative culture growth was more common in infants who died (51% vs. 34.6%; P < 0.001). In the multivariable model, the odds of mortality was higher in those with respiratory distress requiring invasive ventilatory support [odds ratio (OR): 10.3; 95% confidence interval (CI): 4.9-21.7; P < 0.01], hypotension requiring inotropes (OR: 4.4; 95% CI: 2.7-7.1; P < 0.001), low birth weight status (OR: 2.5; 95% CI: 1.4-4.6; P = 0.002), lack of exposure to antenatal steroids (OR: 2.4; 95% CI: 1.3-4.4; P = 0.005) and the presence of concomitant sepsis (OR: 1.9; 95% CI: 1.1-3.2; P = 0.017). CONCLUSIONS: In this nationwide study, neonatal meningitis was found to be associated with high mortality. Coagulase-negative Staphylococci was the most common causative microorganism followed by Gram-negative bacteria. Severe clinical presentation with invasive mechanical ventilation and inotrope requirement, as well as concomitant sepsis, low birth weight status and lack of exposure to antenatal steroids, were found to be independent risk factors for mortality.

Protective effects of colchicine in an experimental model of necrotizing enterocolitis in neonatal rats.

BACKGROUND: The pathophysiology of necrotizing enterocolitis (NEC) includes the massive production of endogenous cytokines with exaggerated activation of inflammatory pathways. Colchicine has been used as an anti-inflammatory agent. The aim of this study was to investigate the possible beneficial effects of colchicine in a neonatal rat model of NEC. MATERIALS AND METHODS: We randomly divided rat pups into three groups: a control group, a saline-treated NEC group, and a colchicine-treated NEC group. We induced NEC by hyperosmolar enteral formula feeding and exposure to hypoxia/reoxygenation after cold stress. Intestinal samples were harvested for biochemical and histopathologic analyses. RESULTS: The grade of intestinal injury of pups in the saline-treated NEC group was significantly higher than in the control and colchicine-treated groups (P < 0.001 and 0.003, respectively). The median level of intestinal malondialdehyde was significantly higher in the saline-treated NEC group compared with the control group (P = 0.006) or the colchicine-treated NEC group (P = 0.015). We observed significantly higher activity levels of intestinal superoxide dismutase and glutathione peroxidase in the colchicine-treated NEC group compared with the saline-treated NEC group (P = 0.033 and 0.030, respectively). The tissue levels of tumor necrosis factor-α and interleukin-1ß were significantly higher in the saline-treated NEC group compared with the colchicine-treated NEC group (P < 0.001 and 0.003, respectively). CONCLUSIONS: We observed that in this model of NEC, colchicine had favorable effects on intestinal histologic and biochemical changes.

The association of a cervical length of <25 mm in high-risk pregnancies on neonatal morbidity and mortality in preterm infants.

PURPOSE: To evaluate and compare the effects of a short cervix (<25 mm) on neonatal morbidity and mortality as opposed to a normal cervical length (≥25 mm). The predictive value of a short cervix on neonatal outcome is also investigated. METHODS: Preterm infants who were admitted to the neonatal intensive care unit and whose mothers had undergone a pre-delivery evaluation for cervical length (CL) and cervical cultures were included in the study. Infants were stratified into two groups based on CL measurements (Group 1, CL < 25 mm; Group 2, CL ≥ 25 mm). RESULTS: A total of 203 infants were included in the final analysis. Group 1 consisted of 105 neonates while Group 2 had 98 newborns. Cervical culture positivity rate was 46.7 % (n = 49) in Group 1 compared to 19.4 % (n = 19) in Group 2 (p = 0.0001). Frequencies of early onset neonatal sepsis (EOS) in Group 1 and Group 2 were 31.5 and 18.4 %, respectively (p = 0.032), whereas respective frequencies of proven sepsis in the two groups were 18.1 and 8.2 % (p = 0.037). A CL < 25 mm was found to increase the risk of cervical culture positivity, EOS and proven EOS by odds ratios of 3.63, 2.03 and 2.48, respectively. CONCLUSIONS: This is the first clinical study to demonstrate a significant link between CL and each of cervical culture positivity, EOS and neonatal morbidity and mortality. Preterm infants born to high-risk mothers with short CL should be monitored closely for the risk of EOS.