Reply to Chambers, P. Comment on "Huțanu et al. Low Serum Vitamin D in COVID-19 Patients Is Not Related to Inflammatory Markers and Patients' Outcomes-A Single-Center Experience and a Brief Review of the Literature. Nutrients 2022, 14, 1998".

We thank Patrick Chambers for his interest [...].

Low Serum Vitamin D in COVID-19 Patients Is Not Related to Inflammatory Markers and Patients' Outcomes-A Single-Center Experience and a Brief Review of the Literature.

The aim of the study was to evaluate the vitamin D status in hospitalized COVID-19 patients and the correlation with C reactive protein (CRP), ferritin, fibrinogen, and peripheral blood leukocytes, as well as inflammatory derived indices. A prospective study was performed on 203 COVID-19 hospitalized patients, classified by disease severity. Blood was collected after admission, and inflammatory biomarkers and vitamin D status were assessed using routine laboratory procedures. No significant correlation was found between vitamin D serum levels and disease severity stratified by different age groups. However, the highest vitamin D levels were found in patients with mild disease: median 29.39 (IQR 12.12-44.02) ng/mL, while for moderate and severe forms the serum levels were significantly lower: median 15.10 (IQR 9.56-24.11) ng/mL for moderate, and 18.86 (IQR 12.50-27.88) ng/mL for severe; p = 0.009. Patients with no comorbidities showed a significantly higher level of vitamin D median 24.72 (IQR 16.05-31.52) ng/mL compared to subjects with at least one comorbidity: median 16.02 (IQR 9.81-25.22) ng/mL, p = 0.004. We did not find an association between vitamin D levels and inflammatory biomarkers except for significantly lower vitamin D levels in moderate and severe COVID-19 compared to mild disease forms.

Critical Care Management of Decompensated Right Heart Failure in Pulmonary Arterial Hypertension Patients - An Ongoing Approach.

Despite substantial advancements in diagnosis and specific medical therapy in pulmonary arterial hypertension patients' management, this condition continues to represent a major cause of mortality worldwide. In pulmonary arterial hypertension, the continuous increase of pulmonary vascular resistance and rapid development of right heart failure determine a poor prognosis. Against targeted therapy, patients inexorable deteriorate over time. Pulmonary arterial hypertension patients with acute right heart failure who need intensive care unit admission present a complexity of the disease pathophysiology. Intensive care management challenges are multifaceted. Awareness of algorithms of right-sided heart failure monitoring in intensive care units, targeted pulmonary hypertension therapies, and recognition of precipitating factors, hemodynamic instability and progressive multisystem organ failure requires a multidisciplinary pulmonary hypertension team. This paper summarizes the management strategies of acute right-sided heart failure in pulmonary arterial hypertension adult cases based on recently available data.

Arthritis associated with Mycoplasma pneumoniae in a pediatric patient: A case report.

INTRODUCTION: Mycoplasma pneumoniae (MP) infection in infants is usually overlooked and it might result in important complications if left untreated. MP-induced arthritis is probably the least common extrapulmonary manifestation and frequently leads to delays in the diagnosis. PATIENT CONCERNS: We report the case of a 2-year-old female child admitted in our clinic for prolonged fever (onset 2 weeks before the admission), for which the general practitioner established the diagnosis of acute pharyngitis and recommended antibiotics. But the fever persisted and the patient was referred to a pediatrician. DIAGNOSIS: The laboratory tests revealed leukocytosis with neutrophilia, elevated C-reactive protein and liver cytolysis. The blood and urine cultures, as well as the serological hepatitis B and C, toxoplasmosis, Epstein Barr virus, Rubella, Herpes virus, and cytomegalovirus were negative. The chest X-ray established the diagnosis of pneumonia. The fever persisted for approximately 2 weeks after admission. On the 2nd week of admission, the patient began to experience gait difficulties complaining of pain in the right hip and ankle. The cardiology and pneumology consults revealed no pathological findings. The evolution was favorable after the initiation of Levofloxacin and MP infection was detected as we suspected. Moreover, the ultrasound of the hip revealed a mild joint effusion, while the ankle joint appeared to be normal at ultrasound. Thus, we established the diagnosis of hip and ankle arthritis based on the clinical and ultrasound findings. INTERVENTIONS: Levofloxacin by vein was continued for 5 days, replaced afterwards with clarithromycin orally for 2 weeks. OUTCOMES: The gait difficulties persisted for approximately 5 months from the initial diagnosis, and improved once the titer of immunoglobulin M anti-MP antibodies lowered considerably. After more than 8 months, the patient was completely asymptomatic and the immunoglobulin M anti-MP was close to the normal range. CONCLUSION: The awareness of MP-induced arthritis in children represents the cornerstone in preventing diagnostic delays and initiating the proper treatment.

Evaluation of TNF-α genetic polymorphisms as predictors for sepsis susceptibility and progression.

BACKGROUND: The goal of the study was to evaluate a potential role for tumor necrosis factor alpha (TNF-α) genetic variability as biomarker in sepsis. In particular, we aimed to determine if single nucleotide polymorphisms (SNPs) of TNF-α gene are associated with sepsis in terms of risk, severity and outcome. METHODS: We performed a prospective study on 163 adult critically ill septic patients (septic shock 65, sepsis 98, further divided in 40 survivors and 123 deceased) and 232 healthy controls. Genotyping of TNF-α SNPs (-308G/A, -238G/A, -376G/A and +489G/A) was performed for all patients and controls and plasma cytokine levels were measured during the first 24 h after sepsis onset. RESULTS: TNF-α +489G/A A-allele carriage was associated with significantly lower risk of developing sepsis and sepsis shock (AA+AG vs GG: OR = 0.53; p = 0.004; 95% CI = 0.34-0.82 and OR = 0.39; p = 0.003; 95% CI = 0.21-0.74, respectively) but not with sepsis-related outcomes. There was no significant association between any of the other TNF-α promoter SNPs, or their haplotype frequencies and sepsis or septic shock risk. Circulating TNF-α levels were higher in septic shock; they were not correlated with SNP genotype distribution; GG homozygosity for each polymorphism was correlated with higher TNF-α levels in septic shock. CONCLUSIONS: TNF-α +489G/A SNP A-allele carriage may confer protection against sepsis and septic shock development but apparently does not influence sepsis-related mortality. Promoter TNF-α SNPs did not affect transcription and were not associated with distinct sepsis, septic shock risk or outcomes.

Precision Medicine and its Role in the Treatment of Sepsis: A Personalised View.

In recent years, a new form of medicine has become increasingly significant, namely, personalised medicine (PM). PM is a form of care in which treatment is tailored for an individual patient. PM is about using multiple data sets to create a digital human mapping. A person's biological traits are determined by the interactions of hundreds of genes and gene networks, as well as external factors such as diet and exercise. Combining and then investigating these multiple databases with powerful statistical tools, allows a new understanding of how genetic intricacy drives health and disease and so leads to a closer personalised medical approach that targets each individual's unique genetic make-up. Sepsis is a systemic inflammatory response to infection, ranging from systemic inflammatory response syndrome (SIRS) to septic shock and multiple organ dysfunction syndromes (MODS). Sepsis is the most common cause of death in intensive care patients. Treatments in an ICU may need to be adapted to the continuous and rapid changes of the disease, making it challenging to identify a single target. PM is thus seen as the future of sepsis treatment in the ICU. The fact that individual patients respond differently to treatment should be regarded as a starting point in the approach to providing treatment. The disease itself comes secondary to this concept.

The role of interleukin-6 as an early predictor of sepsis in a murine sepsis model.

AIM: Evaluating the role of interleukin-6 (IL-6) as an early predictor of sepsis in a murine model. MATERIALS AND METHODS: The study divided 26 Wistar rats into two experimental groups in which sepsis was induced through the intraperitoneal injection of different Escherichia coli cultures [Group 1: Extended-spectrum beta-lactamase (ESBL)-producing culture and Group 2: Standardized ATCC35218 culture] and a control group. IL-6 levels were determined at 5 and 24 hours post-inoculation and immunohistochemistry (IHC) was performed on tissue samples from the sacrificed animals. RESULTS: Mean plasma IL-6 levels in Group 1 peaked at 5 hours [37.4 pg∕mL; standard deviation (SD) = 2.4 pg∕mL] and decreased at 24 hours (34 pg∕mL; SD=3.2 pg∕mL) after inoculation. IL-6 levels in Group 1 were elevated compared to Group 2, at 5 hours (33.7 pg∕mL; SD=3.3 pg∕mL; p=0.019) and non-significantly so at 24 hours (32.5 pg∕mL; SD=2.4 pg∕mL; p=0.233). The results did not show an increase over control levels at either 5 hours (37.6 pg∕mL; SD=3.4 pg∕mL) or 24 hours (40.8 pg∕mL; SD=2.9 pg∕mL) after inoculation. The IHC shows a varying degree of IL-6 expression across all organ types studied. No statistically significant correlations were found between the tissue level quantification of IL-6 and serum values at 24 hours in either group. CONCLUSIONS: For an early stage of infection/inflammation, serum levels of IL-6 are not correlated with tissue-level inflammation disproving a potential role of IL-6 as a very precocious diagnostic and predictor test. Accumulation of IL-6 in lung, kidney and spleen tissue can be observed from the beginning of inflammation.

Diagnostic Difficulties in a Severely Ill HIV Patient with Multiple Superinfections - A Case Report.

INTRODUCTION: As chronic HIV infection is prone to co-infections more than any other infectious condition, many severely immune-depressed patients require advanced diagnostic investigations and complex treatment. CASE REPORT: The case of a 30-year-old severely immune-depressed patient with AIDS, who developed neurological impairment and was diagnosed with encephalitis is presented. Multiple diagnostic approaches had to be used in order to identify the etiologic agents responsible for the clinical, immunological and biological evolution. Despite using advanced laboratory investigations and complex treatment, the patient developed multiple organ dysfunction syndromes that led to a fatal outcome. CONCLUSIONS: Establishing etiologic relations and treatment priorities in patients with severe immunodeficiency and co-infections can prove difficult, underlining the need of rapid syndromic testing.

Severe Austrian Syndrome in an Immunocompromised Adult Patient - A Case Report.

BACKGROUND: Known also as Osler's triad, Austrian syndrome is a complex pathology which consists of pneumonia, meningitis and endocarditis, all caused by the haematogenous dissemination of Streptococcus pneumoniae. The multivalvular lesions are responsible for a severe and potential lethal outcome. CASE REPORT: The case of a 51-year-old female patient, with a past medical history of splenectomy, is presented. She developed bronchopneumonia, acute meningitis and infective endocarditis as a result of Streptococcus pneumoniae infection and subsequently developed multiple organ dysfunction syndromes which led to a fatal outcome. Bacteriological tests did not reveal the etiological agent. The histopathological examination showed a severe multivalvular endocarditis, while a PCR based molecular analysis from formalin fixed valvular tissue identified Streptococcus pneumoniae as the etiologic agent. CONCLUSIONS: The presented case shows a rare syndrome with a high risk of morbidity and mortality. Following the broad-spectrum treatment and intensive therapeutic support, the patient made unfavourable progress which raised differential diagnosis problems. In this case, the post-mortem diagnosis demonstrated multiple valvular lesions occurred as a result of endocarditis.

Communication skills in pediatrics - the relationship between pediatrician and child.

Interpersonal and communication skills are 2 essential qualities of every physician. These are separate and distinct parts of the professional character of every physician. In pediatrics these abilities present even a higher impact.We performed a survey-type prospective study based on questionnaires on 100 subjects, equally divided into 4 groups: 25 children, 25 pediatricians, 25 care-givers (parents, tutors, and relatives), and 25 health care staff, in a Tertiary Pediatric Clinic from Romania, between January 2017 and April 2017.We included 100 participants in our study, equally divided into 4 groups: pediatric patients, pediatricians, care-givers, and health care staff. The 1st group comprised 25 children diagnosed with different chronic conditions, presenting the age between 5 and 14 years. The male gender predominated among the children (57%). The lowest general average score for "Communication" section was encountered among pediatricians group, 3.8, while the other 3 groups presented the same average score for this section, that is, 4.6. The children and the health care staff offered the same average score for "Transparency," that is, 4.6, while the pediatricians offered a score of 4.5, and the care-givers of 4.7. The lowest average score for the item "Hospital environment" was given by the doctors, that is, 3.3, followed by care-givers with a score of 3.6, health care staff 3.7, and children with an average score of 3.8. All the 4 groups included in the study offered a general average of 4.9 out of 5 for the "Intercultural issues" section. The lowest average score for "Time management" section was offered by both children and pediatricians, that is, 4.1, while care-givers and health care staff had a slightly better perception regarding this item, offering 4.2 and 4.3, respectively.The opinion among the 4 groups included in the study was generally similar regarding the 5 items assessed by our questionnaires. Therefore, the main aspects that need to be improved in the health care system in downward order are the following: hospital environment, time management, communication, transparency, and intercultural issues.

Echocardiographic characteristics of pulmonary arterial hypertension in children with horizontally transmitted HIV.

BACKGROUND: The prevalence of primitive pulmonary arterial hypertension (PAH) in patients with human immunodeficiency virus infection (HIV) is estimated at approximately 0.5%, significantly higher than in the general population. OBJECTIVES: This study aimed to assess the echocardiographic modifications in HIV-associated pulmonary arterial hypertension (PAH). MATERIAL AND METHODS: A group of 117 patients, aged under 16, with horizontally transmitted HIV staged according to the U.S. Center for Disease Control and Prevention criteria, were included in this prospective study, with echocardiographic abnormalities in 79 children. The study group consisted of 27 HIV-infected patients with PAH, while the control group consisted of 38 patients with normal ultrasound features. The diagnostic criterion for PAH was the presence of a mean pulmonary artery pressure above 25 mm Hg, determined at 2 consecutive measurements having at least 6 months distance between them. All subjects underwent a complex echocardiographic assessment, including assessment of left and right ventricular hypertrophy and evaluation of left ventricular function, associated with determination of the immunological stage. RESULTS: We recorded the presence of PAH in 27 patients (23.08%), in whom an average value of 31.48 mm Hg was recorded for pulmonary artery pressure. All patients had mild forms of PAH. Age, gender and immunological stage showed no significant differences in the PAH group compared to patients in the control group. Right ventricular hypertrophy was encountered in 95.23% and left ventricular hypertrophy in 88.88% of the patients with PAH. Left ventricular dysfunction, a complication of pulmonary hypertension, was relatively rare (11.11%). CONCLUSIONS: In children with HIV infection, PAH is present in a relatively mild form and does not correlate with the clinical and immunological stage of HIV infection, evolving as a seemingly primitive condition.

The Relevance of Coding Gene Polymorphysms of Cytokines and Cellular Receptors in Sepsis.

Sepsis is an injurious systemic host response to infection, which can often lead to septic shock and death. Recently, the immune-pathogenesis and genomics of sepsis have become a research topic focusing on the establishment of diagnostic and prognostic biomarkers. As yet, none have been identified as having the necessary specificity to be used independently of other factors in this respect. However the accumulation of current evidence regarding genetic variations, especially the single nucleotide polymorphisms (SNPs) of cytokines and other innate immunity determinants, partially explains the susceptibility and individual differences of patients with regard to the evolution of sepsis. This article outlines the role of genetic variation of some serum proteins which have the potential to be used as biomarker values in evaluating sepsis susceptibility and the progression of the condition.

Lung Abscess Remains a Life-Threatening Condition in Pediatrics - A Case Report.

Pulmonary abscess or lung abscess is a lung infection which destroys the lung parenchyma leading to cavitations and central necrosis in localised areas formed by thick-walled purulent material. It can be primary or secondary. Lung abscesses can occur at any age, but it seems that paediatric pulmonary abscess morbidity is lower than in adults. We present the case of a one year and 5-month-old male child admitted to our clinic for fever, loss of appetite and an overall altered general status. Laboratory tests revealed elevated inflammatory biomarkers, leukocytosis with neutrophilia, anaemia, thrombocytosis, low serum iron concentration and increased lactate dehydrogenase level. Despite wide-spectrum antibiotic therapy, the patient's progress remained poor after seven days of treatment and a CT scan established the diagnosis of a large lung abscess. Despite changing the antibiotic therapy, surgical intervention was eventually needed. There was a slow but steady improvment and eventually, the patient was discharged after approximately five weeks.

Caspase 3 expression and plasma level of Fas ligand as apoptosis biomarkers in inflammatory endotoxemic lung injury.

OBJECTIVE: The objective of this study is to evaluate if the immunohistochemical expression of a pulmonary apoptosis marker and plasma level of Fas ligand (FasL) correlates with the dose- and time-dependent severity of lung injury, induced by the administration of lipo-polysaccharide (LPS) in an endotoxemic rat model. MATERIALS AND METHODS: Our study included 30 male Wistar rats, randomly divided into three groups: one control group (n=6) and two experimental groups (n=12÷group), in whom we induced endotoxemia by intraperitoneal injection of progressively increasing doses of LPS (5, 10 mg÷kg). We measured FasL plasma levels of the rats at different time points and analyzed the relationships with markers of lung injury. To investigate the level of caspase 3-protein expression, the immunohistochemistry of the lung tissue was assessed. RESULTS: The median percentage of caspase 3-stained cells for the 5 mg÷kg LPS dose was 0.36%, for the 10 mg÷kg LPS dose was 0.4% and for the control group was 0.03% (p<0.0001). The elevated expression levels of caspase 3 were consistent with the altered lung morphologies observed (rs=0.88). LPS administration in rats resulted in a significant dose-dependent increase in the levels of plasma FasL (p<0.0001). These levels correlated with markers of lung injury: degree of hypoxemia (rs=-0.42), histological measured lung injury score (rs=0.72), the density of the caspase 3 staining cells in the immunohistochemistry assessment of apoptosis (rs=0.81) and with the plasma RAGE (receptor for advanced glycated end-products) values (rs=0.70). CONCLUSIONS: Apoptosis is increased in edotoxemia induced lung injury and is likely to contribute to alveolar injury.

Fatal endocarditis with methicilin-sensible Staphylococcus aureus and major complications: rhabdomyolysis, pericarditis, and intracerebral hematoma: A case report and review of the literature.

BACKGROUND: Over the last decades Staphylococcus aureus (SA) has become the dominant etiology of native valve infective endocarditis, with the community-acquired methicillin-sensible Staphylococcus aureus (CA-MSSA) strains being the prevailing type. CASE: We report here a case of extremely severe CA-MSSA aortic valve acute endocarditis associated with persistent Staphylococcus aureus bacteremia (SAB) in a previously healthy man and include a literature review.The patient developed severe and rare complications (purpura, purulent pericarditis, intracerebral hematoma, and rhabdomyolysis) through systemic embolism; they required drainage of pericardial empyema and cerebral hematoma, the latter eventually caused a fatal outcome. The strains recovered from sequential blood culture sets and pericardial fluid were MSSA negative for genes encoding for staphylococcal toxic shock syndrome toxin (TSST)-1 and Panton-Valentine leukocidin. C, G, and I enterotoxin genes were detected. CONCLUSIONS: This case with unusually severe evolution underlines the limited ability of vancomycin to control some MSSA infections, possibly due to potential involvement of SA virulence factors, hence the importance of clinical vigilance for community SAB cases.

Staphylococcal Scalded Skin Syndrome in Child. A Case Report and a Review from Literature.

Staphylococcal scalded skin syndrome (SSSS) is the medical term used to define a skin condition induced by the exfoliative toxins produced by Staphylococcus aureus. The disorder is also known as Ritter disease, bullous impetigo, neonatal pemphigus, or staphylococcal scarlet fever. The disease especially affects infants and small children, but has also been described in adults. Prompt therapy with proper antibiotics and supportive treatment has led to a decrease in the mortality rate. The current case report describes the clinical progress of a patient with generalized erythema and fever, followed by the appearance of bullous lesions with tendency to rupture under the smallest pressure, and with extended areas of denudation. The patient aged four years and six months was admitted to our clinic to establish the aetiology and treatment of a generalized bullous exanthema, followed by a skin denudation associated with fever and impaired general status. Based on clinical and paraclinical examinations a diagnosis of Staphylococcal scalded skin syndrome was established which responded favourably to antibiotic treatment, hydro-electrolytic re-equilibration, and adequate local hygiene. Staphylococcal infection can represent a problem of significant pathological importance sometimes requiring a multidisciplinary approach involving paediatricians, dermatologists, infectious diseases specialists, and plastic surgeons.

Ischemic preconditioning and inflammatory response syndrome after reperfusion injury: an experimental model in diabetic rats.

Quantification of local ischemia and inflammatory response syndrome correlated with histological changes associated with ischemia-reperfusion injury (IRI) after revascularization techniques. We included 12 adult male Wistar rats, aged eight weeks that were randomly divided into two groups. The first group acted as the control and at the second group, we induced diabetes by intraperitoneal streptozotocin administration (60 mg/kg). After eight weeks, the rats were subject to ischemic preconditioning for 10 minutes at three regular intervals. Twenty-four hours post-preconditioning, both groups were subject to ischemia for 20 minutes, followed by 30 minutes of reperfusion. Oxygen extraction was higher in Group 1, the arterio-venous CO2 gradient was higher in the control group, but not significant. The lactate production was higher in Group 1. The second group had a higher Na+ and also a significant difference in K+ values. Receptor for Advanced Glycation End (RAGE) values were higher in the second group but with no significant difference (RAGE1=0.32 ng/mL versus RAGE2=0.40 ng/mL). The muscle samples from the control group displayed significant rhabdomyolysis, damage to the nucleus, while the preconditioned group showed almost normal morphological characteristics. The lungs and kidneys were most damaged in the control group, with damage expressed as thickened alveolar septa, neutrophil infiltrates, eosinophilic precipitates in the proximal convolute tubule. Ischemic preconditioning significantly attenuates the ischemic reperfusion injury.

Time- and dose-dependent severity of lung injury in a rat model of sepsis.

Different animal models of experimental lung injury have been used to investigate mechanisms of lung injury. Lipopolysaccharide (LPS) administration is the most often used approach to model the consequences of bacterial sepsis. We created an endotoxemia rat model, simulating sepsis-related lung injury, in order to quantify the time and dose dependent severity lesions induced by the administration of lipopolysaccharide. Our study included 42 male Wistar rats, randomly divided into four groups: one control group (n=6) and three experimental groups (n=12/group) in whom we induced sepsis by intraperitoneal injection of progressively increasing doses of LPS (3, 5, 10 mg/kg). At six hours, the animals included in the groups with higher doses of LPS developed thrombocytopenia, elevated lactate levels, and liver and renal injury in a dose and time dependent manner. The severity of hypoxemia at six hours correlated with the increasing doses of LPS, with a slight improvement at 24 hours. Lung injury scores became more severe with increased dose and time of exposure to LPS without reaching the level of hyaline membranes formation. We also demonstrated translocation of a protein from the airspaces into plasma (RAGE - receptor for advanced glycation end products). Induction of sepsis using LPS is a known experimental model, but LPS treatment in rats does not cause the severe endothelial and epithelial injury that occurs in humans with acute respiratory distress syndrome (ARDS). In our study, the clinical, laboratory and histopathological findings confirmed sepsis and the damage of the alveolar-capillary membrane in a dose-dependent manner.

Ultrasound and histopathological features of myocardial involvement in HIV infection in children.

AIM: HIV infection in children is an important clinical and pathologic entity, which embraces many forms of presentation and can involve multiple organs and systems. This study aimed at identifying the main forms of cardiovascular involvement in HIV-infected children with horizontally transmitted disease and describing them with the aid of ultrasound and histopathological examinations. RESULTS: We recorded cardiovascular anomalies in 79 (67.52%) patients out of the 117 comprised in the study population, and noted the following prevalence distribution: systolic dysfunction in 49 (41.88%) patients, left ventricular hypertrophy (LVH) in 30 (25.6%) patients, right ventricular hypertrophy (RVH) in 15 (12.82%) patients, and dilated cardiomyopathy (DCM) in 22 (18.8%) patients. We also carried out post-mortem histopathological examinations in five patients, and observed the main modification incurred by the disease. CONCLUSIONS: Cardiac involvement during HIV infection differs significantly in different mechanisms of virus transmission, and the horizontal transmission of HIV yields a lower prevalence of this type of pathology. The general diagnostic picture can be significantly improved by adding histopathological examination to the ultrasonographic method of investigation.