The challenges in the monitoring of infectious diseases after the earthquake in Türkiye in 2023.

After the devastating earthquake in Türkiye and Syria in February, 2023, the long-term failure to meet the need for shelter, unfavourable living conditions in tent settlements, poor access to clean drinking water, water suitable for personal hygiene, and sanitary facilities, as well as interruptions in provision of primary health-care services, have emerged as the most important risk factors contributing to the spread of infectious diseases. 3 months after the earthquake, most of these problems persist in Türkiye. Data on the control of infectious diseases are scarce according to the reports prepared by medical specialist associations based on observations of health-care providers working in the region and statements made by the local health authorities. According to these unsystematised data, and considering the conditions in the region, faecal-oral transmissible gastrointestinal infections, as well as respiratory and vector-borne infections, are the main challenges. Vaccine-preventable diseases, such as measles, varicella, meningitis, and polio can be spread in temporary shelters due to interrupted vaccine services and crowded living conditions. In addition to controlling risk factors for infectious diseases, sharing data on the status and control of infectious diseases in the region with the community, health-care providers, and relevant expert groups should be a priority to improve the understanding of the effects of interventions and prepare for possible infectious disease outbreaks.

Long-term effects of COVID-19 on lungs and the clinical relevance: a 6-month prospective cohort study.

Background: We aimed to explore the prevalence of prolonged symptoms, pulmonary impairments and residual disease on chest tomography (CT) in COVID-19 patients at 6 months after acute illness. Methods: In this prospective, single-center study, hospitalized patients with radiologically and laboratory-confirmed COVID-19 were included. Results: A high proportion of the 116 patients reported persistent symptoms (n = 54; 46.6%). On follow-up CT, 33 patients (28.4%) demonstrated residual disease. Multivariate analyses revealed that only neutrophil-to-lymphocyte ratio was an independent predictor for residual disease. Conclusion: Hospitalized patients with mild/moderate COVID-19 still had persistent symptoms and were prone to develop long-term pulmonary sequelae on chest CT. However, it did not have a significant effect on long-term pulmonary functions.

Criteria for Hyperinflammation Developing in COVID-19: Analysis of 2 Cohorts From Different Periods of the Pandemic.

OBJECTIVE: Hyperinflammation (HI) that develops in week 2 of COVID-19 contributes to a worse outcome. Because week 2 laboratory findings can be relatively mild, the available criteria for classification of hemophagocytic lymphohistiocytosis or macrophage activation syndrome are not helpful. METHODS: Our study included a discovery cohort of patients from Turkey with symptomatic COVID-19 who were followed up while hospitalized during the initial wave and a replication cohort of hospitalized patients from a later period, all of whom required oxygen support and received glucocorticoids. Diagnosis of HI was made by an expert panel; most patients with COVID-19-associated HI (HIC) received tocilizumab or anakinra. Clinical and laboratory data from start day of treatment with tocilizumab or anakinra in HIC patients were compared with the data from day 5-6 in patients without HIC. Values maximizing the sensitivity and specificity of each parameter were calculated to determine criteria items. RESULTS: The discovery cohort included 685 patients, and the replication cohort included 156 patients, with 150 and 61 patients receiving treatment for HI, respectively. Mortality rate in HI patients in the discovery cohort (23.3%) was higher than the rate in patients without HI (3.7%) and the rate in patients in the overall replication cohort (10.3%). The 12-item criteria that we developed for HIC showed that a score of 35 provided 85.3% sensitivity and 81.7% specificity for identification of HIC. In the replication cohort, the same criteria resulted in 90.0% sensitivity for HIC; however, lower specificity values were observed because of the inclusion of milder cases of HIC responding only to glucocorticoids. CONCLUSION: The use of the 12-item criteria for HIC can better define patients with HIC with reasonable sensitivity and specificity and enables an earlier treatment start.

COVID-19: An Update on Epidemiology, Prevention and Treatment, September-2023.

After a downward trend for more than 12 months, the incidence of COVID-19 has increased in the last months. Although COVID-19 is not as frequent as in the first years of the pandemic, case numbers are still very high, and it causes a significant number of deaths. COVID-19 is not seen with a predictable frequency, at least two times more deadly than the flu, continues as an epidemic, and has not reached the endemic level yet. Currently, the Omicron strains EG.5 and XBB.1.16 are dominant worldwide. Although BA.2.86 and FLip variants, including FL.1.5.1 are not widespread at the moment, both were shown to be highly immune-evasive and require close monitoring. Prevention of COVID-19 relies on vaccinations, surveillance, proper ventilation of enclosed spaces, isolation of patients, and mask usage. Currently, monovalent COVID-19 vaccines, including XBB.1.5 Omicron SARS-CoV-2, are recommended for both primary and booster vaccinations against COVID-19. Monovalent vaccines, including only original SARS-CoV-2 strain, and bivalent vaccines, including original virus plus BA4/5 variant, are no longer recommended against COVID-19. Booster vaccination with XBB.1.5 containing vaccine should be prioritized for patients at high risk for severe COVID-19. Bacillus Calmette-Guérin (BCG) vaccination does not seem to be effective in preventing COVID-19. At the current phase of the pandemic, nirmatrelvir/ritonavir, remdesivir, molnupiravir, sotrovimab (for patients from XBB.1.5 variant dominant settings), and convalescent plasma can be considered for the treatment of high-risk early-stage outpatients with COVID-19, while hospitalized patients with more severe disease can be treated with dexamethasone, anti cytokines including tocilizumab, sarilumab, baricitinib, and tofacitinib and antithrombotic agents including enoxaparin. Remdesivir oral analogues and ensitrelvir fumarate are promising agents for treating acute COVID-19, which are in phase trials now; however, ivermectin, fluvoxamine, and metformin were shown to be ineffective.

In vitro activities of antibiotic combinations against mature biofilms of ventilator-associated pneumonia isolates.

Background: The authors aimed to determine the efficacy of frequently used antibiotics, alone or in combination, against biofilms of ventilator-associated pneumonia isolates. Materials & methods: The authors determined the MICs, minimum biofilm inhibitory concentrations and minimum biofilm eradication concentrations of meropenem, ciprofloxacin and colistin as well as their combinations against planktonic forms and biofilms of Pseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii clinical isolates. Results: Generally, the minimum biofilm inhibitory concentrations and minimum biofilm eradication concentrations of the antibiotics were 1000-fold higher than their MICs, and synergy was provided by different concentrations of meropenem-colistin and meropenem-ciprofloxacin combinations with checkerboard and time-kill curve methods. Conclusion: The combination of meropenem and ciprofloxacin seems to be a good candidate for the treatment of biofilm-associated infections; none of the concentrations obtained as a result of the synergy test were clinically significant.

Dipyridamole does not have any additive effect on the prevention of COVID-19 coagulopathy.

OBJECTIVE: Severe acute respiratory syndrome (SARS) coronavirus 2 (SaRS-Cov-2) associated respiratory disease (COVID-19), announced as a pandemic, is a multisystem syndrome. SARS-CoV-2 directly infects and damages vascular endothelial cells, which leads to microvascular dysfunction and promotes a procoagulant state. Dipyridamole (DP) acts as a reversible phosphodiesterase inhibitor and is used mainly as an antiplatelet agent. It is hypothetised that it has possible activities in COVID-19. DESIGN AND METHODOLOGY: We report our retrospective, real-world results of DP added to low-molecular weight heparin (LMWH) in the treatment of 462 clinically diagnosed and hospitalized COVID-19 patients. We compared anticoagulation with and without DP addition with no administration of anticoagulation in the same time frame. The primary outcome was proven or highly suspected coagulopathy within 30 days of hospitalization. RESULTS: Definitive coagulopathy has been diagnosed in 3 (3.5%) of 85 LMWH administered patients and 7 (2.13%) of 328 DP + LMWH received patients (P=0.456). Five cases with definitive coagulopathy were not initiated any anticoagulation at the time of the event. The multivariate analysis showed that DP addition to the anticoagulant approach did not have any impact on the risk of demonstrated coagulopathy and highly-suspected coagulopathy. CONCLUSION: We think that our clinical experience is valuable in showing the real-life results of DP + LMWH treatment in COVID-19. This approach did not affect the coagulopathy rate. Our data did also not document an additive effect of DP in the COVID-19 outcome. Prospective controlled trials would give more convincing results regarding the role of DP in COVID-19 endothelial dysfunction and clinical outcome.

Intrathecal Colistin Induced Chemical Meningitis in a Case of Multi-Drug Resistant Acinetobacter baumannii Meningitis.

The possibility of encountering multi-drug resistant Gram-negative bacteria is higher in nosocomial meningitis. These bacteria are clinically important because of their higher mortality rate, and colistin is almost the only treatment option in resistant strains. However, intrathecal administration of colistin can result in chemical meningitis. We reported a case with chemical meningitis during the intravenous sulbactam plus colistin and intrathecal colistin therapy for multi-drug resistant Acinetobacter baumannii meningitis. Cerebrospinal fluid findings of the patient improved after discontinuation of intrathecal colistin therapy. This reversible complication may occur during intrathecal therapy. Discontinuation of intrathecal therapy or reducing the antibiotic dose will be the most appropriate approach to manage such cases.

[A Case of Chronic Q Fever Endocarditis Mimicking Lymphoproliferative Disorders]. / Lenfoproliferatif Hastaliklarla Karisan Bir Kronik Q Atesi Endokarditi Olgusu.

Q fever is a zoonosis caused by Coxiella burnetii. In this report, a case of chronic Q fever endocarditis with pancytopenia and hypergammaglobulinemia mimicking a lymphoproliferative disease was presented. A 39-years-old male living in Çatalca and whose family is engaged in animal husbandry admitted with the complaints of weakness and fatigue. The patient had aortic valve replacement 29 years ago and had aortic valve re-replacement, and ascending aorta grafting because of endocarditis three years ago. It was revealed that the second operation of the patient was due to possible infective endocarditis, but no definitive agent could be identified. He was evaluated for massive hepatosplenomegaly, pancytopenia, hypergammaglobulinemia, presence of M-spike and elevated ß-2 microglobulin levels and was referred to our hematology clinic with a preliminary diagnosis of lymphoproliferative disease. Lymphoplasmacytic lymphoma was excluded with the result of bone marrow biopsy and he was referred to our clinic for the investigation of possible infectious etiologies. We detected hepatosplenomegaly and finger clubbing. His blood analyses were normal except for the following: leukocyte count 3800/µl, platelet count 148000/µl, gamma globulin 5.9 gr/dl, rheumatoid factor (RF) and antinuclear antibody (ANA) positivity. Chronic Q fever endocarditis was suspected and C.burnetii Phase I IgG test was found positive in 1/132071 titers. Although transesophageal echocardiography showed no lesion of endocarditis, positron emission tomography/computed tomography revealed increased fluorodeoxyglucose uptake around the prosthetic heart valve and graft. The patient was diagnosed as having Q fever endocarditis and graft infection. He refused hospitalization and was started on hydroxychloroquine and doxycycline treatment. The patient stopped taking these antibiotics by himself seven days after the diagnosis. He was admitted with a headache to another hospital and operated for an intracranial hemorrhage and died shortly after. Apart from unfamiliarity, wide range of clinical presentations of disease could also lead to delayed diagnosis. Among patients with chronic Q fever, continuous bacteremia and antigenic stimulus causes inflammatory syndrome with hepatosplenomegaly, hypergammaglobulinemia and, presence of autoantibodies which leads to misdiagnoses of rheumatologic, autoimmune or hematologic diseases Chronic Q fever should be investigated in patients with known valvulopathy and chronic hepatomegaly or splenomegaly, pancytopenia, hypergammaglobulinemia, and unexplained autoantibody positivity.

An update of anti-viral treatment of COVID-19

Background/aim: Currently there is not an effective antiviral treatment for COVID-19, but a large number of drugs have been evaluated since the beginning of the pandemic, and many of them have been used for the treatment of COVID-19 despite the preliminary or conflicting results of the clinical trials. We aimed to review and summarize all of the current knowledge on the antivirals for COVID-19 Results: There are 2 main drug groups for SARS-CoV-2: agents that target proteins or RNA of the virus or interfere with proteins or biological processes in the host that support the virus. The main drug groups include inhibitors of viral entry into the human cell (convalescent plasma, monoclonal antibodies, nanobodies, mini proteins, human soluble ACE-2, camostat, dutasteride, proxalutamide, bromhexin, hydroxychloroquine, umifenovir nitazoxanid, niclosamide, lactoferrin), inhibitors of viral proteases (lopinavir/ritonavir, PF-07321332, PF-07304814, GC376), inhibitors of viral RNA (remdesivir, favipiravir, molnupiravir, AT-527, merimepodib, PTC299), inhibitors of host proteins supporting virus (plitidepsin, fluvoxamine, ivermectin), and agents supporting host natural immunity (Interferons). Conclusion: When taking into account the results of all the available laboratory and clinical trials on the subject, monoclonal antibodies seem to be the most effective treatment for COVID-19 at the moment, and high-titer convalescent plasma also could be effective when administered during the early phase of the disease. As lopinavir/ritonavir, hydroxychloroquine, merimepodib, and umifenovir were found to be ineffective in RCTs, they should not be used. Additional studies are needed to define the role of remdesivir, favipiravir, interferons, ivermectin, dutasteride, proxulutamide, fluvoxamine, bromhexine, nitazoxanide, and niclosamid in the treatment of COVID-19. Finally, the results of phase trials are waited to learn whether or not the newer agents such as molnupiravir, PF-07321332, PF-07304814, plitidepsin and AT-527 are effective in the treatment of COVID-19.

Efficacy and safety of an inactivated whole-virion SARS-CoV-2 vaccine (CoronaVac): interim results of a double-blind, randomised, placebo-controlled, phase 3 trial in Turkey.

BACKGROUND: CoronaVac, an inactivated whole-virion SARS-CoV-2 vaccine, has been shown to be well tolerated with a good safety profile in individuals aged 18 years and older in phase 1/2 trials, and provided a good humoral response against SARS-CoV-2. We present the interim efficacy and safety results of a phase 3 clinical trial of CoronaVac in Turkey. METHODS: This was a double-blind, randomised, placebo-controlled phase 3 trial. Volunteers aged 18-59 years with no history of COVID-19 and with negative PCR and antibody test results for SARS-CoV-2 were enrolled at 24 centres in Turkey. Exclusion criteria included (but were not limited to) immunosuppressive therapy (including steroids) within the past 6 months, bleeding disorders, asplenia, and receipt of any blood products or immunoglobulins within the past 3 months. The K1 cohort consisted of health-care workers (randomised in a 1:1 ratio), and individuals other than health-care workers were also recruited into the K2 cohort (randomised in a 2:1 ratio) using an interactive web response system. The study vaccine was 3 µg inactivated SARS-CoV-2 virion adsorbed to aluminium hydroxide in a 0·5 mL aqueous suspension. Participants received either vaccine or placebo (consisting of all vaccine components except inactivated virus) intramuscularly on days 0 and 14. The primary efficacy outcome was the prevention of PCR-confirmed symptomatic COVID-19 at least 14 days after the second dose in the per protocol population. Safety analyses were done in the intention-to-treat population. This study is registered with ClinicalTrials.gov (NCT04582344) and is active but no longer recruiting. FINDINGS: Among 11 303 volunteers screened between Sept 14, 2020, and Jan 5, 2021, 10 218 were randomly allocated. After exclusion of four participants from the vaccine group because of protocol deviations, the intention-to-treat group consisted of 10 214 participants (6646 [65·1%] in the vaccine group and 3568 [34·9%] in the placebo group) and the per protocol group consisted of 10 029 participants (6559 [65·4%] and 3470 [34·6%]) who received two doses of vaccine or placebo. During a median follow-up period of 43 days (IQR 36-48), nine cases of PCR-confirmed symptomatic COVID-19 were reported in the vaccine group (31·7 cases [14·6-59·3] per 1000 person-years) and 32 cases were reported in the placebo group (192·3 cases [135·7-261·1] per 1000 person-years) 14 days or more after the second dose, yielding a vaccine efficacy of 83·5% (95% CI 65·4-92·1; p<0·0001). The frequencies of any adverse events were 1259 (18·9%) in the vaccine group and 603 (16·9%) in the placebo group (p=0·0108) with no fatalities or grade 4 adverse events. The most common systemic adverse event was fatigue (546 [8·2%] participants in the vaccine group and 248 [7·0%] the placebo group, p=0·0228). Injection-site pain was the most frequent local adverse event (157 [2·4%] in the vaccine group and 40 [1·1%] in the placebo group, p<0·0001). INTERPRETATION: CoronaVac has high efficacy against PCR-confirmed symptomatic COVID-19 with a good safety and tolerability profile. FUNDING: Turkish Health Institutes Association.

National Early Warning Score 2 and laboratory predictors correlate with clinical deterioration in hospitalized patients with COVID-19.

Aim: We aimed to determine the prognostic values of the National Early Warning Score 2 (NEWS2) and laboratory parameters during the first week of COVID-19. Materials & methods: All adult patients who were hospitalized for confirmed COVID-19 between 11 March and 11 May 2020 were retrospectively included. Results: Overall, 611 patients were included. Our results showed that NEWS2, procalcitonin, neutrophil/lymphocyte ratio and albumin at D0, D3, D5 and D7 were the best predictors for clinical deterioration defined as a composite of ICU admission during hospitalization or in-hospital death. Procalcitonin had the highest odds ratio for clinical deterioration on all days. Conclusion: This study provides a list of several laboratory parameters correlated with NEWS2 and potential predictors for clinical deterioration in patients with COVID-19.

Lay abstract The COVID-19 pandemic is a grueling problem worldwide. There is a lack of knowledge about the predictive value of National Early Warning Score 2 (NEWS2) for severe COVID-19 illness. We analyzed the prognostic value of NEWS2 and laboratory parameters during the clinical course of COVID-19. This study provides a list of several laboratory parameters correlated with NEWS2 and potential predictors for intensive care unit admission during hospitalization or in-hospital death.

Initial complete blood count score and predicting disease progression in COVID-19 patients.

INTRODUCTION: Coronavirus has caused a pandemic since it was first detected in Wuhan in December 2019. The mortality rate is high in moderate and severe cases. Our study aimed to screen the CBC parameters as a useful predictive factor for COVID-19 resulting in critical illness. METHODS: A total of 285 patients with positive PCR results were analyzed. The median age was 55 (24-90), and 64.2% of patients were male. Sixty-eight percent of cases were hospitalized with moderate, 32% with severe disease at initial admission. RESULTS: We found that lymphocyte count <620/mcl, neutrophil-to-lymphocyte ratio (NLR) >6, and platelet to lymphocyte ratio (PLR) >350 were predictive of the outcome. We scored our cohort 0-3 for these three parameters. Patients with a score of 2-3 were more likely to have progressive disease, anti-cytokine treatment, intensive care admission, intubation, and death, compared to patients with a score of 0-1. Additionally, they tended to be hospitalized for longer (median 11.5 days, mean 15.6), compared to those with a score 0 or 1 (median 9 days, mean 11.3). Twenty-eight of 38 cases with scores of 2-3 were discharged (73.6%), whereas the rate was 89% for patients with a score of 0-1 (P=0.009). CONCLUSION: Based on the absolute lymphocyte count (<620/mcl, NLR >6, PLR >350), our three-parameter score was able to predict disease progression, and the likelihood of anti-cytokine treatment, intubation, and death. We think that COVID-19 patients presenting with moderate to severe pneumonia, and having scores of 2 or 3 on our scale, should be closely monitored and robustly supported.

The effect of tocilizumab, anakinra and prednisolone on antibody response to SARS-CoV-2 in patients with COVID-19: A prospective cohort study with multivariate analysis of factors affecting the antibody response.

OBJECTIVES: Disease severity, previous medications and immunosuppressive agents could affect the antibody response against SARS-CoV-2. This study aimed to analyze variables affecting the humoral response to SARS-CoV-2. METHODS: This prospective cohort study included adult patients who recovered from COVID-19 and were admitted to a COVID-19 follow-up unit. Eight patient groups were defined in accordance with the results of thoracic computed tomography (CT), SARS-CoV-2 PCR test, and tocilizumab or anakinra use during active disease. Anti-S IgG antibodies were determined by ELISA in serum samples. Anti-S positive and negative cases were compared. RESULTS: A total of 518 patients were included in the study. SARS-CoV-2 IgG antibodies were positive in 82.8% of patients. SARS-CoV-2 PCR positivity, extent of lung involvement on CT, and time to antibody testing were independently associated with antibody positivity. Tocilizumab, anakinra or prednisolone use was not a factor affecting the antibody response. The rate of antibody response and sample/CO values among antibody-positive patients showed a linear relationship with the extent of lung involvement on CT. CONCLUSIONS: The use of tocilizumab, anakinra and prednisolone for COVID-19 did not affect the antibody response against SARS-CoV-2. The main driver of antibody response among patients with COVID-19 was the extent of pulmonary involvement on CT.

Antiviral treatment of COVID-19

Currently, there is not any specific effective antiviral treatment for COVID-19. Although most of the COVID-19 patients have mild or moderate courses, up to 5%­10% can have severe, potentially life threatening course, there is an urgent need for effective drugs. Optimized supportive care remains the mainstay of therapy. There have been more than 300 clinical trials going on, various antiviral and immunomodulating agents are in various stages of evaluation for COVID-19 in those trials and some of them will be published in the next couple of months. Despite the urgent need to find an effective antiviral treatment for COVID-19 through randomized controlled studies, certain agents are being used all over the world based on either in-vitro or extrapolated evidence or observational studies. The most frequently used agents both in Turkey and all over the world including chloroquine, hydroxychloroquine, lopinavir/ritonavir, favipiravir and remdesivir will be reviewed here .Nitazoxanide and ivermectin were also included in this review as they have recently been reported to have an activity against SARS-CoV-2 in vitro and are licensed for the treatment of some other human infections.

Consensus Report on Diagnosis, Treatment and Prevention of Infective Endocarditis by Turkish Society of Cardiovascular Surgery (TSCVS), Turkish Society of Clinical Microbiology and Infectious Diseases (KLIMIK), Turkish Society of Cardiology (TSC), Turkish Society of Nuclear Medicine (TSNM), Turkish Society of Radiology (TSR), Turkish Dental Association (TDA) and Federation of Turkish Pathology Societies (TURKPATH) Cardiovascular System Study Group.

Infective endocarditis (IE) is rare, but associated with significant morbidity and mortality rates. Estimates of the incidence of IE in Turkey are compromised by the absence of population-based prospective studies. Due to the frequent presence of predisposing cardiac conditions and higher rates of nosocomial bacteremia in highrisk groups, the incidence of IE is expected to be higher in Turkey. Additionally, while IE generally affects older people in developed countries, it still affects young people in Turkey. In order to reduce the mortality and morbidity, it is critical to diagnose the IE to determine the causative agent and to start treatment rapidly. However, most of the patients cannot be diagnosed in their first visits, about half of them can be diagnosed after three months, and the disease often goes unnoticed. In patients diagnosed with IE, the rate of identification of causative organisms is significantly lower in Turkey than in developed countries. Furthermore, most of the centers do not perform some essential microbiological diagnostic tests as a routine practice. Some antimicrobials that are recommended as the first-line of treatment for IE, particularly antistaphylococcal penicillins, are not available in Turkey. These problems necessitate reviewing the epidemiological, laboratory, and clinical characteristics of IE in our country, as well as the current information about its diagnosis, treatment, and prevention together with local data. Physicians can follow patients with IE in many specialties. Diagnosis and treatment processes of IE should be standardized at every stage so that management of IE, a setting in which many physicians are involved, can always be in line with current recommendations. Study Group for Infective Endocarditis and Other Cardiovascular Infections of the Turkish Society of Clinical Microbiology and Infectious Diseases has called for collaboration of the relevant specialist organizations to establish a consensus report on the diagnosis, treatment, and prevention of IE in the light of current information and local data in Turkey.

Q fever endocarditis: is it always subacute or chronic?

Q fever is a zoonotic disease caused by Coxiella burnetii, an obligate intracellular bacterium, which cannot be grown using routine blood culture methods. Although C. burnetii is reported to be the causative agent in approximately 50% of blood culture-negative infective endocarditis cases in developed countries, the incidence in Turkey is yet to be defined. The clinical course of Q fever endocarditis is generally subacute and chronic; the disease may be present for years with only subtle symptoms and no vegetation visible on echocardiography while the bacteria gradually destroy the heart valves. This is the case of the successful treatment of a young man with Q fever endocarditis that had an acute clinical course. In 1 month, he developed New York Heart Association class IV heart failure and a large, 3-cm vegetation was observed on an echocardiogram.