Factors associated with COVID-19 among hospitalized patients with severe acute respiratory infections in Serbia, 2022-2023: A test negative case-control study.

Severe acute respiratory infections (SARI) are estimated to be the cause of death in about 19% of all children younger than 5 years globally. The outbreak of coronaviral disease (COVID-19) caused by SARS-CoV-2, increased considerably the burden of SARI worldwide. We used data from a vaccine effectiveness study to identify the factors associated with SARS CoV-2 infection among hospitalized SARI patients. We recruited SARI patients at 3 hospitals in Serbia from 7 April 2022-1 May 2023. We collected demographic and clinical data from patients using a structured questionnaire, and all SARI patients were tested for SARS-CoV-2 by RT-PCR. We conducted an unmatched test negative case-control study. SARS-CoV-2 infected SARI patients were considered cases, while SARS CoV-2 negative SARI patients were controls. We conducted bivariate and multivariable logistic regression analysis in order to identify variables associated with SARS-CoV-2 infection. We included 110 SARI patients: 74 were cases and 36 controls. We identified 5 factors associated with SARS-CoV-2 positivity, age (OR = 1.04; 95% CI = 1.01-1.07), having received primary COVID-19 vaccine series (OR = 0.28; 95% CI = 0.09-0.88), current smoking (OR = 8.64; 95% CI = 2.43-30.72), previous SARS CoV-2 infection (OR = 3.48; 95% CI = 1.50-8.11) and number of days before seeking medical help (OR = 0.81; 95% CI = 0.64-1.02). In Serbia during a period of Omicron circulation, we found that older age, unvaccinated, hospitalized SARI patients, previously infected with SARS CoV-2 virus and those who smoked, were more likely to be SARS-CoV-2-positive; these patient populations should be prioritized for COVID vaccination.

Decoding the historical tale: COVID-19 impact on haematological malignancy patients-EPICOVIDEHA insights from 2020 to 2022.

Background: The COVID-19 pandemic heightened risks for individuals with hematological malignancies due to compromised immune systems, leading to more severe outcomes and increased mortality. While interventions like vaccines, targeted antivirals, and monoclonal antibodies have been effective for the general population, their benefits for these patients may not be as pronounced. Methods: The EPICOVIDEHA registry (National Clinical Trials Identifier, NCT04733729) gathers COVID-19 data from hematological malignancy patients since the pandemic's start worldwide. It spans various global locations, allowing comprehensive analysis over the first three years (2020-2022). Findings: The EPICOVIDEHA registry collected data from January 2020 to December 2022, involving 8767 COVID-19 cases in hematological malignancy patients from 152 centers across 41 countries, with 42% being female. Over this period, there was a significant reduction in critical infections and an overall decrease in mortality from 29% to 4%. However, hospitalization, particularly in the ICU, remained associated with higher mortality rates. Factors contributing to increased mortality included age, multiple comorbidities, active malignancy at COVID-19 onset, pulmonary symptoms, and hospitalization. On the positive side, vaccination with one to two doses or three or more doses, as well as encountering COVID-19 in 2022, were associated with improved survival. Interpretation: Patients with hematological malignancies still face elevated risks, despite reductions in critical infections and overall mortality rates over time. Hospitalization, especially in ICUs, remains a significant concern. The study underscores the importance of vaccination and the timing of COVID-19 exposure in 2022 for enhanced survival in this patient group. Ongoing monitoring and targeted interventions are essential to support this vulnerable population, emphasizing the critical role of timely diagnosis and prompt treatment in preventing severe COVID-19 cases. Funding: Not applicable.

The mortality of COVID-19 in CML patients from 2020 until 2022: results from the EPICOVIDEHA survey.

Since the beginning of the COVID-19 pandemic, there has been an overall improvement in patient mortality. However, haematological malignancy patients continue to experience significant impacts from COVID-19, including high rates of hospitalization, intensive care unit (ICU) admissions, and mortality. In comparison to other haematological malignancy patients, individuals with chronic myeloid leukemia (CML) generally have better prognosis. This study, conducted using a large haematological malignancy patient database (EPICOVIDEHA), demonstrated that the majority of CML patients experienced mild infections. The decline in severe and critical infections over the years can largely be attributed to the widespread administration of vaccinations and the positive response they elicited. Notably, the mortality rate among CML patients was low and exhibited a downward trend in subsequent years. Importantly, our analysis provided confirmation of the effectiveness of vaccinations in CML patients.

Age, successive waves, immunization, and mortality in elderly COVID-19 hematological patients: EPICOVIDEHA findings.

OBJECTIVES: Elderly patients with hematologic malignancies face the highest risk of severe COVID-19 outcomes. The infection's impact on different age groups remains unstudied in detail. METHODS: We analyzed elderly patients (age groups: 65-70, 71-75, 76-80, and >80 years old) with hematologic malignancies included in the EPICOVIDEHA registry between January 2020 and July 2022. Univariable and multivariable Cox regression models were conducted to identify factors influencing death in COVID-19 patients with hematological malignancy. RESULTS: The study included data from 3,603 elderly patients (aged 65 or older) with hematological malignancy, with a majority being male (58.1%) and a significant proportion having comorbidities. The patients were divided into four age groups, and the analysis assessed COVID-19 outcomes, vaccination status, and other variables in relation to age and pandemic waves. The 90-day survival rate for patients with COVID-19 was 71.2%, with significant differences between groups. The pandemic waves had varying impacts, with the first wave affecting patients over 80 years old, the second being more severe in 65-70, and the third being the least severe in all age groups. Factors contributing to 90-day mortality included age, comorbidities, lymphopenia, active malignancy, acute leukemia, less than three vaccine doses, severe COVID-19, and using only corticosteroids as treatment. CONCLUSION: These data underscore the heterogeneity of elderly hematological patients, highlight the different impacts of COVID-19 waves and the pivotal importance of vaccination, and may help in planning future healthcare efforts.

Molnupiravir compared to nirmatrelvir/ritonavir for COVID-19 in high-risk patients with haematological malignancy in Europe. A matched-paired analysis from the EPICOVIDEHA registry.

INTRODUCTION: Molnupiravir and nirmatrelvir/ritonavir are antivirals used to prevent progression to severe SARS-CoV-2 infections and decrease hospitalisation and mortality rates. Nirmatrelvir/ritonavir was authorised in Europe in December 2021, whereas molnupiravir is not yet licensed in Europe as of February 2022. Molnupiravir may be an alternative to nirmatrelvir/ritonavir because it is associated with fewer drug-drug interactions and contraindications. A caveat for molnupiravir is the mode of action induces viral mutations. Mortality rate reduction with molnupiravir was less pronounced than that with nirmatrelvir/ritonavir in patients without haematological malignancy. Little is known about the comparative efficacy of the two drugs in patients with haematological malignancy at high-risk of severe COVID-19. Thus, molnupiravir and nirmatrelvir/ritonavir were compared in a cohort of patients with haematological malignancies. METHODS: Clinical data from patients treated with molnupiravir or nirmatrelvir/ritonavir monotherapy for COVID-19 were retrieved from the EPICOVIDEHA registry. Patients treated with molnupiravir were matched by sex, age (±10 years), and severity of baseline haematological malignancy to controls treated with nirmatrelvir/ritonavir. RESULTS: A total of 116 patients receiving molnupiravir for the clinical management of COVID-19 were matched to an equal number of controls receiving nirmatrelvir/ritonavir. In each of the groups, 68 (59%) patients were male; with a median age of 64 years (interquartile range [IQR] 53-74) for molnupiravir recipients and 64 years (IQR 54-73) for nirmatrelvir/ritonavir recipients; 56.9% (n=66) of the patients had controlled baseline haematological malignancy, 12.9% (n=15) had stable disease, and 30.2% (n=35) had active disease at COVID-19 onset in each group. During COVID-19 infection, one third of patients from each group were admitted to hospital. Although a similar proportion of patients in the two groups were vaccinated (molnupiravir n=77, 66% vs. nirmatrelvir/ritonavir n=87, 75%), more of those treated with nirmatrelvir/ritonavir had received four vaccine doses (n=27, 23%) compared with those treated with molnupiravir (n=5, 4%) (P<0.001). No differences were detected in COVID-19 severity (P=0.39) or hospitalisation (P=1.0). No statistically significant differences were identified in overall mortality rate (P=0.78) or survival probability (d30 P=0.19, d60 P=0.67, d90 P=0.68, last day of follow up P=0.68). Deaths were either attributed to COVID-19, or the infection was judged by the treating physician to have contributed to death. CONCLUSIONS: Hospitalisation and mortality rates with molnupiravir were comparable to those with nirmatrelvir/ritonavir in high-risk patients with haematological malignancies and COVID-19. Molnupiravir is a plausible alternative to nirmatrelvir/ritonavir for COVID-19 treatment in patients with haematological malignancy.

Invasive fungal disease in COVID-19 patients: a single-center prospective observational study.

Background: Invasive fungal diseases (IFDs) are caused by fungal infections that manifest as serious secondary infections in patients with COVID-19. The increased morbidity and mortality rates are most frequently observed in patients with COVID-19-associated pulmonary aspergillosis (CAPA) and COVID-19-associated candidiasis (CAC). CAPA is the most frequently encountered infection with an incidence rate of 0.7-7.7%, while CAC is a less common and less studied fungal infection in COVID-19 patients. Materials and methods: The present article is a prospective observational single-center study that was conducted between 1 September 2021 and 24 December 2021, involving 6,335 patients who were admitted to COVID Hospital "Batajnica," University Clinical Center of Serbia, Belgrade. Results: Of the 6,335 patients hospitalized during the four-month period of the study, 120 patients (1.86%) who had a proven diagnosis of IFD were included in the study. These patients were divided into two groups: CAPA patients (n = 63) and CAC patients (n = 56); however, one of the 120 patients was diagnosed with Cryptoccocus neoformans infection. The mean age of the study population was 65.7 ± 13.9 years, and 78 (65.5%) of them were men. The patients were identified to have the following non-malignant comorbidities: arterial hypertension in 62 (52.1%) patients, diabetes mellitus in 34 (28.65), pre-existing lung damage similar to that observed in COPD and asthma in 20 (16.8%), and chronic renal insufficiency in 13 (10.9%) patients. The hematological malignancies were found to be the most prevalent malignancies and were identified in 20 (16.8%) patients, particularly in CAPA patients [11 (17.5%); p < 0.041]. Fiberoptic bronchoscopy with bronchoalveolar lavage fluid (BALF) and microscopic examination confirmed the presence of fungal infections in 17 (14.3%) patients. Serology testing was also performed in the majority of cases. Antibodies against Aspergillus spp. and Candida spp. were predominantly found in CAPA patients (p < 0.001). The patients were also tested for the presence of (1-3)-ß-D glucan (p < 0.019), galactomannan, and mannan in the specimens. Blood cultures were found to be positive in 45 (37.8%) patients, mostly in CAC patients. Mechanical ventilation was applied in 41 (34.5%) patients, while a non-invasive technique, such as continuous positive airway pressure (CPAP) or high-flow nasal cannula (HFNC), was used in 20 (16.8%) patients. The following antifungals were administered: echinocandins in 42 (35.3%), voriconazole in 30 (25.2%), and fluconazole in 27 (22.7%) patients. Most of the patients received systemic corticosteroids (mainly methylprednisolone), while 11 (9.16%) received favipiravir, 32 (26.67%) remdesivir, 8 (6.67%) casirivimab/imdevimab, and 5 (4.16%) sotrovimab. The outcome was lethal in 76 (63.9%) patients, predominantly CAC patients (p < 0.001). Conclusion: Invasive fungal disease is a severe complication associated with COVID-19 and accounts for increased mortality in these patients. Early identification and appropriate treatment may provide a favorable outcome.

Simultaneous Onset of Haematological Malignancy and COVID: An Epicovideha Survey.

Background: The outcome of patients with simultaneous diagnosis of haematological malignancies (HM) and COVID-19 is unknown and there are no specific treatment guidelines. Methods: We describe the clinical features and outcome of a cohort of 450 patients with simultaneous diagnosis of HM and COVID-19 registered in the EPICOVIDEHA registry between March 2020 to February 2022. Results: Acute leukaemia and lymphoma were the most frequent HM (35.8% and 35.1%, respectively). Overall, 343 (76.2%) patients received treatment for HM, which was delayed for longer than one month since diagnosis in 57 (16.6%). An overall response rate was observed in 140 (40.8%) patients after the first line of treatment. After a median follow-up of 35 days, overall mortality was 177/450 (39.3%); 30-day mortality was significantly higher in patients not receiving HM treatment (42.1%) than in those receiving treatment (27.4%, p = 0.004), either before and/or after COVID-19, or compared to patients receiving HM treatment at least after COVID-19 (15.2%, p < 0.001). Age, severe/critical COVID-19, ≥2 comorbidities, and lack of HM treatment were independent risk factors for mortality, whereas a lymphocyte count >500/mcl at COVID-19 onset was protective. Conclusions: HM treatment should be delivered as soon as possible for patients with simultaneous diagnosis of COVID-19 and HM requiring immediate therapy.

An exceptional case report of disseminated cryptococcosis in a hitherto immunocompetent patient.

Cryptococcosis is an opportunistic fungal infection causes significant disease predominantly in immunocompromised patients. Here we present an excepcional case of disseminated cryptococcosis with pulmonary and cerebral involvement in an immunocompetent patient with no apparent predisposing factors at the time of hospital admission. We described a case of an apparently immunocompetent 66-years old man admitted to hospital with a one-month history of cough, fever and vertigo. During hospitalization, thorax imaging was suggestive of lung metastasis, therefore, he went through several investigations. During hospitalization, he developed neurological symptoms and subsequently underwent a lumbar puncture. Cerebrospinal fluid (CSF) culture was positive for Cryptococcus spp. isolated on Sabouraud's dextrose agar and bird seed agar. In addition, the direct microscopy examination was positive for the India ink test, as well as with the latex agglutination test for cryptococcal polysaccharide antigen (CrAg) in CSF, while serum CrAg was negative. Despite the absence of classic immunocompromising features, he was treated with amphotericin B and fluconazole due to suspected disseminated cryptococcal infection. Later, he was diagnosed with prostatic adenocarcinoma. Upon successful completion of treatment for disseminated cryptococcosis, the patient underwent radical prostate ablation surgery as a treatment forprostatic adenocarcinoma. This exceptional case emphasizes the high degree of suspicion of atypical infections, and in these cases, it is particularly important to consider fungal infections in hitherto healthy patients with no apparent predisposing factors. Although Cryptococcus spp. is predominantly reported in patients with hematological malignancies, cryptococcosis investigation should also be considered as part of the initial workup of patients with a new diagnosis of a solid tumour prior to chemotherapy or radiotherapy.

Relevance of TNF-α, IL-6 and IRAK1 gene expression for assessing disease severity and therapy effects in tuberculosis patients.

INTRODUCTION: Tuberculosis (TBC) is a contagious chronic respiratory disease which despite the known cause, Mycobacterium tuberculosis (Mtb), and many decades of successful therapy, remains one of the leading global health problems. Immune responses against Mtb infection involve both of types of immunity, but cellular immunity, in which certain cytokines and Th1 cells play a key role, is crucial. A better understanding of the functions of the cytokine network involved in the state and progression of TBC could identify specific molecular markers for monitoring of disease activity as well as therapy outcomes in TBC patients. METHODOLOGY: We investigated expression of TNF-α, IL-6 and IRAK1 genes using an RT-qPCR technique in peripheral blood mononuclear cells of 33 TBC patients and 10 healthy individuals. RESULTS: Comparison between TBC patients and healthy individuals revealed statistically significant differences for all analyzed genes. The levels of expression of TNF-α and IL-6 mRNA were higher, while the level of IRAK1 mRNA was lower in the TBC group compared to controls. Moreover, a strong positive correlation was observed between TNF-α and IL-6 gene expression. When clinical parameters were analyzed, increased levels of TNF-α mRNA were detected in patients with a longer duration of therapy (>2 months) compared to those with a shorter therapy duration (< 2 months), and in patients without anemia. CONCLUSIONS: Our results indicate that the inflammatory genes we examined play a crucial role in the pathogenesis of tuberculosis, and that the expression of the TNF-α gene could be a marker for monitoring the clinical effect of the ant-tuberculosis drugs during therapy.

Rare histological subtype of pulmonary artery intimal sarcoma diagnosed by multidisciplinary approach.

Pulmonary artery intimal sarcoma (PAS) is a rare mesenchymal tumor mostly diagnosed in middle-aged women. In a 63-year-old female, the radiological findings showed cavitation in the left upper lobe of the lung and infiltrative tumor mass around the left pulmonary artery. PAS consisted of small, round tumor cells with about 80% of mitotic activity and with myxoid background and specific immunoprofile and diagnosed as undifferentiated sarcoma with round cell features type. The final diagnosis of PAS was established according to the pathohistological, chest computed tomography scan, and surgery finding.

Endotracheal stent increased survival length in patients with invasive thymic adenocarcinoma.

We reported the first case of inoperative thymic adenocarcinoma successfully palliative treated by the double-stent procedure. In a patient who expressed stridor, computed tomography was done and necrotic mediastinal mass, which protrudes into a trachea, was demonstrated. Fiberoptic bronchoscopy showed tracheal infiltration and 70% stenosis; therefore, surgical resection was inapplicable. Recanalization with repeated argon plasma coagulation and debridement of necrotic mass was performed, followed by placement of the endotracheal stent, radiotherapy, and chemotherapy. After 1 year, the patient developed gastric aspiration and tracheoesophageal fistula; therefore, the esophageal stent was placed. The outcome was lethal, but the placement of endotracheal stent significantly increased a length of survival for the patient with invasive thymic adenocarcinoma.

First reported case of fulminant TB with progression of infection from lungs to the genitourinary region.

Although tuberculosis (TB) is a curable disease, it continues to be one of the leading infections associated with death in the world. Extra-pulmonary TB (EPTB) occurs in approximately 10% of the total cases, presenting with lymph nodes, pleura, bone and genitourinary tract as the most common locations. Genitourinary tuberculosis, the second most common EPTB, is very difficult to diagnose unless there is a high index of suspicion. Isolated TB orchitis or prostatitis without clinical evidence of renal involvement is a rare entity among genitourinary tuberculosis. We presented the first reported case of TB prostatitis and orchitis associated with pulmonary TB and the presence of an acute massive caseous pneumonia in an immunocompetent man. Despite the anti-TB therapy, the patient presented a rapid progression of disease and deterioration of general conditions taking to death, which occurred four days after TB treatment had started. Disseminated TB is a relatively uncommon cause of acute massive caseous pneumonia; however, there should always be suspicion of the disease, since it is a potentially treatable cause. This rare case supports the assertion that TB should be considered as an important differential diagnosis of genitourinary tumors irrespective of evidence of active TB elsewhere in the body.

First reported case of fulminant TB with progression of infection from lungs to the genitourinary region

ABSTRACT Although tuberculosis (TB) is a curable disease, it continues to be one of the leading infections associated with death in the world. Extra-pulmonary TB (EPTB) occurs in approximately 10% of the total cases, presenting with lymph nodes, pleura, bone and genitourinary tract as the most common locations. Genitourinary tuberculosis, the second most common EPTB, is very difficult to diagnose unless there is a high index of suspicion. Isolated TB orchitis or prostatitis without clinical evidence of renal involvement is a rare entity among genitourinary tuberculosis. We presented the first reported case of TB prostatitis and orchitis associated with pulmonary TB and the presence of an acute massive caseous pneumonia in an immunocompetent man. Despite the anti-TB therapy, the patient presented a rapid progression of disease and deterioration of general conditions taking to death, which occurred four days after TB treatment had started. Disseminated TB is a relatively uncommon cause of acute massive caseous pneumonia; however, there should always be suspicion of the disease, since it is a potentially treatable cause. This rare case supports the assertion that TB should be considered as an important differential diagnosis of genitourinary tumors irrespective of evidence of active TB elsewhere in the body.

Pulmonary sequestration mimicring lun cancer: A case report.

Introduction: Pulmonary sequestration is a rare congenital anomaly and most intralobar sequestrations were located in lower lobes. Case report: We reported an unusual 28-yearold female patient with intralobar pulmonary sequestration on the left lower lobe, successfully treated with lobectomy. Computed tomography (CT) of the chest with intravenous contrast revealed multiple clustered cystic lesions in the left lower lobe with aberrant artery from descedenting aorta. Additional aortography showed an aberrant artery (3 mm in diameter) arising from the abdominal aorta and flowing into the lesion. Conclusion: Standard therapy regimen for pulmonary sequestration includes surgery. CT scan of thorax with intravenous contrast and aortography represent the gold standard for its diagnosis. Tumor-like shadows seen on the chest radiography or CT scans should not be always suspected on malignant lesions.

Conservative treatment of bronchobiliary fistula evaluated with magnetic resonance imaging.

INTRODUCTION: Bronchobiliary fistula (BBF) is a pathological communication between the bronchial system and the biliary tree that presents with bilioptysis. Many conditions can cause its development. There is still no optimal therapy for BBF. Conservative treatment is rarely indicated, as was published before in a few cases. CASE REPORT: We presented a 71-year-old Caucasian Serbin woman with BBF secondary to previous laparotomy due to multiple echinococcus liver cysts. The diagnosis was established by the presence of bilirubin and bile acids in sputum and magnetic resonance cholangiopancreatography (MRCP). A repeat MRCP performed after conservative procedure, did not reveal fistulous communication. CONCLUSION: We suggest that in small and less severe fistulas between the biliary and the bronchial tract, conservative treatment may be used successfully, and invasive treatment methods are not needed in all patients.