Mucormycosis, New Causative Agents, and New Susceptible Populations: Review of Cases in a Tertiary Care Hospital in Iran (2007-2021).

Background: Mucormycosis is an aggressive opportunistic fungal infection that afflicts patients with severe underlying immunosuppression, uncontrolled hyperglycemia and/or ketoacidosis, iron overload, and occasionally healthy patients who are inoculated with fungal spores through traumatic injuries. The epidemiology of mucormycosis has changed after the COVID-19 pandemic, with mucormycosis becoming the most common and the fatal coinfection. Methods: In a retrospective, cross-sectional study, 82 hospitalized patients with a definite diagnosis of mucormycosis were reported from 2007 to 2021 in a referral, tertiary care center in Tehran, Iran. Results: The number of post-COVID cases increased 4.6 times per year, with 41.5% of patients admitted during the two years of the pandemic. Mucormycosis was more common in women (57.3%), and the most common underlying diseases were diabetes (43.7%), both COVID-19 and diabetes (23.2%), cancer (11%), rheumatic diseases (7.3%), COVID-19 without other underlying diseases (6.1%), and transplantation (4.9%). Rhino-orbito-cerebral Mucormycosis (54.9%) followed by Sino-orbital infection (23.2%) was the most common presentation. There was a significant relationship between the use of immunosuppressive agents and the development of Mucormycosis (P<0.005) The average mortality was 41.5%, but this ratio decreased to 35% during the pandemic era. Conclusion: The COVID-19 pandemic caused a 4.6-fold increase in the number of mucormycosis patients, and there was a significant relationship between hyperglycemia, corticosteroid use, and mucormycosis. The death rate during the COVID-19 pandemic has decreased by 6.5%, and during the COVID period, the interval between the arrival of a patient with mucormycosis and the start of the correct treatment was significantly decreased.

The effect of donepezil hydrochloride on post-COVID memory impairment: A randomized controlled trial.

BACKGROUND: Post-Coronavirus Disease (COVID-19) condition, known as "post-COVID syndrome," is associated with a range of complications persisting even after recovery. Among these complications, cognitive dysfunction, including memory impairment, has been relatively common observed, impacting executive function and quality of life. To date, no approved treatment exists for this specific complication. Therefore, the present clinical trial aimed to investigate the impact of Donepezil Hydrochloride on post-COVID memory impairment. METHODS: A randomized, controlled trial (Approval ID: IRCT20210816052203N1) was conducted, enrolling 25 patients with post-COVID memory impairment. Participants with a history of hospitalization were randomly assigned to either the drug group (n = 10) or the control group (n = 15). Memory indices were assessed at baseline, one month, and three months later using the Wechsler Memory Scale-Revised test. SPSS software and appropriate statistical tests were employed for data analysis. RESULTS: The statistical analysis revealed no significant difference in WMS-R subtest and index scores between the drug and control groups at the 4-week and 12-week follow-up periods. However, within the drug group, there was a notable increase in the visual reproduction I and verbal paired associates II subtests during the specified time intervals. CONCLUSION: While donepezil 5 mg did not exhibit a significant overall increase in memory scales compared to the control group over time, our findings suggest that this medication may exert a positive effect on specific memory subtests. Further research and exploration are warranted to better understand the potential benefits of donepezil in managing post-COVID-related memory impairment. TRIAL REGISTRATION: The study was approved by the Research Ethics Committee of Aja University of Medical Sciences (Approval ID: IR.AJAUMS.REC.1400.125) and registered in the Iranian Registry of Clinical Trials (IRCT) (Approval ID: IRCT20210816052203N1).

Prospective analysis of febrile neutropenia patients with bacteraemia: the results of an international ID-IRI study.

OBJECTIVES: Bacteraemia during the course of neutropenia is often fatal. We aimed to identify factors predicting mortality to have an insight into better clinical management. METHODS: The study has a prospective, observational design using pooled data from febrile neutropenia patients with bacteraemia in 41 centres in 16 countries. Polymicrobial bacteraemias were excluded. It was performed through the Infectious Diseases-International Research Initiative platform between 17 March 2021 and June 2021. Univariate analysis followed by a multivariate binary logistic regression model was used to determine independent predictors of 30-d in-hospital mortality (sensitivity, 81.2%; specificity, 65%). RESULTS: A total of 431 patients were enrolled, and 85 (19.7%) died. Haematological malignancies were detected in 361 (83.7%) patients. Escherichia coli (n = 117, 27.1%), Klebsiellae (n = 95, 22% %), Pseudomonadaceae (n = 63, 14.6%), Coagulase-negative Staphylococci (n = 57, 13.2%), Staphylococcus aureus (n = 30, 7%), and Enterococci (n = 21, 4.9%) were the common pathogens. Meropenem and piperacillin-tazobactam susceptibility, among the isolated pathogens, were only 66.1% and 53.6%, respectively. Pulse rate (odds ratio [OR], 1.018; 95% confidence interval [CI], 1.002-1.034), quick SOFA score (OR, 2.857; 95% CI, 2.120-3.851), inappropriate antimicrobial treatment (OR, 1.774; 95% CI, 1.011-3.851), Gram-negative bacteraemia (OR, 2.894; 95% CI, 1.437-5.825), bacteraemia of non-urinary origin (OR, 11.262; 95% CI, 1.368-92.720), and advancing age (OR, 1.017; 95% CI, 1.001-1.034) were independent predictors of mortality. Bacteraemia in our neutropenic patient population had distinctive characteristics. The severity of infection and the way to control it with appropriate antimicrobials, and local epidemiological data, came forward. CONCLUSIONS: Local antibiotic susceptibility profiles should be integrated into therapeutic recommendations, and infection control and prevention measures should be prioritised in this era of rapidly increasing antibiotic resistance.

Clinicopathological profile of peritoneal tuberculosis and a new scoring model for predicting mortality: an international ID-IRI study.

Existing literature about peritoneal tuberculosis (TBP) is relatively insufficient. The majority of reports are from a single center and do not assess predictive factors for mortality. In this international study, we investigated the clinicopathological characteristics of a large series of patients with TBP and determined the key features associated with mortality. TBP patients detected between 2010 and 2022 in 38 medical centers in 13 countries were included in this retrospective cohort. Participating physicians filled out an online questionnaire to report study data. In this study, 208 patients with TBP were included. Mean age of TBP cases was 41.4 ± 17.5 years. One hundred six patients (50.9%) were females. Nineteen patients (9.1%) had HIV infection, 45 (21.6%) had diabetes mellitus, 30 (14.4%) had chronic renal failure, 12 (5.7%) had cirrhosis, 7 (3.3%) had malignancy, and 21 (10.1%) had a history of immunosuppressive medication use. A total of 34 (16.3%) patients died and death was attributable to TBP in all cases. A pioneer mortality predicting model was established and HIV positivity, cirrhosis, abdominal pain, weakness, nausea and vomiting, ascites, isolation of Mycobacterium tuberculosis in peritoneal biopsy samples, TB relapse, advanced age, high serum creatinine and ALT levels, and decreased duration of isoniazid use were significantly related with mortality (p < 0.05). This is the first international study on TBP and is the largest case series to date. We suggest that using the mortality predicting model will allow early identification of high-risk patients likely to die of TBP.

Side effects after COVID-19 vaccination: a comparison between the most common available vaccines in Iran.

Background and Objectives: Since the coronavirus disease 2019 (COVID-19) pandemic began, several vaccines have been manufactured to subside it. This study aimed to determine the prevalence of side effects after injecting common COVID-19 vaccines available in Iran. Materials and Methods: This cross-sectional study was accomplished on Shahid Beheshti University of Medical Sciences (Tehran, Iran) employees during January and September 2022. Eligible participants were selected based on the simple random method and interviewed about side effects after injecting COVID-19 vaccine. Results: The mean age of 656 participants was 38.03 ± 9.53 years, and 453 (69.1%) were female. The prevalence of post-vaccination side effects was higher after receiving the first dose (53.2%) than the second (35.9%) and third (49.4%) doses. Across all three vaccine doses, the overall proportion of side effects was higher following AstraZeneca than the others. The most common side effect after the first dose of the vaccine was myalgia (41.9%), followed by fever (36.6%), chills (31.6%), local reactions (27.0%), headache (25.5%), and sweating (21.6%). People experienced mainly myalgia (23.3%) and fever (20.3%) after injecting the second dose of the vaccine. Additionally, the participants had myalgia (37.2%), fever (30.8%), chills (29.2%), local reactions (26.0%), and headache (24.4%) after the third dose of the vaccine. Conclusion: AstraZeneca had a higher proportion of post-vaccination adverse effects than Sputnik V, Pastocovac, and Sinopharm. The most common side effects were flu-like syndrome and local reactions at the injection site. Furthermore, people rarely experienced life-threatening side effects. Thus, the available COVID-19 vaccines in Iran are safe.

Classical fever of unknown origin in 21 countries with different economic development: an international ID-IRI study.

Fever of unknown origin (FUO) is a serious challenge for physicians. The aim of the present study was to consider epidemiology and dynamics of FUO in countries with different economic development. The data of FUO patients hospitalized/followed between 1st July 2016 and 1st July 2021 were collected retrospectively and submitted from referral centers in 21 countries through ID-IRI clinical research platform. The countries were categorized into developing (low-income (LI) and lower middle-income (LMI) economies) and developed countries (upper middle-income (UMI) and high-income (HI) economies). This research included 788 patients. FUO diagnoses were as follows: infections (51.6%; n = 407), neoplasms (11.4%, n = 90), collagen vascular disorders (9.3%, n = 73), undiagnosed (20.1%, n = 158), miscellaneous diseases (7.7%, n = 60). The most common infections were tuberculosis (n = 45, 5.7%), brucellosis (n = 39, 4.9%), rickettsiosis (n = 23, 2.9%), HIV infection (n = 20, 2.5%), and typhoid fever (n = 13, 1.6%). Cardiovascular infections (n = 56, 7.1%) were the most common infectious syndromes. Only collagen vascular disorders were reported significantly more from developed countries (RR = 2.00, 95% CI: 1.19-3.38). FUO had similar characteristics in LI/LMI and UMI/HI countries including the portion of undiagnosed cases (OR, 95% CI; 0.87 (0.65-1.15)), death attributed to FUO (RR = 0.87, 95% CI: 0.65-1.15, p-value = 0.3355), and the mean duration until diagnosis (p = 0.9663). Various aspects of FUO cannot be determined by the economic development solely. Other development indices can be considered in future analyses. Physicians in different countries should be equally prepared for FUO patients.

Delayed Diagnosis of Chronic Necrotizing Granulomatous Skin Lesions due to TAP2 Deficiency.

Major histocompatibility complex class I (MHC-I) deficiency, also known as bare lymphocyte syndrome type 1 (BLS-1), is a rare autosomal recessively inherited immunodeficiency disorder with remarkable clinical and biological heterogeneity. Transporter associated with antigen processing (TAP) is a member of the ATP-binding cassette superfamily of transporters and consists of two subunits, TAP1 or TAP2. Any defect resulting from a mutation or deletion of these two subunits may adversely affect the peptide translocation in the endoplasmic reticulum, which is an important process for properly assembling MHC-I molecules. To date, only 12 TAP2-deficient patients were reported in the literature. Herein, we described two Iranian cases with 2 and 3 decades of delayed diagnosis of chronic necrotizing granulomatous skin lesions due to TAP2 deficiency without pulmonary involvement. Segregation analysis in family members identified 3 additional homozygous asymptomatic carriers. In both asymptomatic and symptomatic carriers, HLA-I expression was only 4-15% of the one observed in healthy controls. We performed the first deep immunophenotyping in TAP2-deficient patients. While total CD8 T cell counts were normal as previously reported, the patients showed strongly impaired naïve CD8 T cell counts. Mucosal-associated invariant T (MAIT) cells and invariant natural killer T (iNKT) cell counts were increased.

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19.

Background: We previously reported inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity in 1-5% of unvaccinated patients with life-threatening COVID-19, and auto-antibodies against type I IFN in another 15-20% of cases. Methods: We report here a genome-wide rare variant burden association analysis in 3,269 unvaccinated patients with life-threatening COVID-19 (1,301 previously reported and 1,968 new patients), and 1,373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. A quarter of the patients tested had antibodies against type I IFN (234 of 928) and were excluded from the analysis. Results: No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7 , with an OR of 27.68 (95%CI:1.5-528.7, P= 1.1×10 -4 ), in analyses restricted to biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70 [95%CI:1.3-8.2], P= 2.1×10 -4 ). Adding the recently reported TYK2 COVID-19 locus strengthened this enrichment, particularly under a recessive model (OR=19.65 [95%CI:2.1-2635.4]; P= 3.4×10 -3 ). When these 14 loci and TLR7 were considered, all individuals hemizygous ( n =20) or homozygous ( n =5) for pLOF or bLOF variants were patients (OR=39.19 [95%CI:5.2-5037.0], P =4.7×10 -7 ), who also showed an enrichment in heterozygous variants (OR=2.36 [95%CI:1.0-5.9], P =0.02). Finally, the patients with pLOF or bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years; P= 1.68×10 -5 ). Conclusions: Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old.

Garcin syndrome in a case of acquired immunodeficiency syndrome.

In this study, we report a parapharyngeal diffuse large B-cell lymphoma in a human immunodeficiency virus (HIV) infected patient which had caused the patient to suffer from Garcin syndrome.

Antibiotic use during the first 6 months of COVID-19 pandemic in Iran: A large-scale multi-centre study.

WHAT IS KNOWN AND OBJECTIVE: Although antibiotics are ineffective against viral infections, epidemiological studies have revealed that the COVID-19 pandemic resulted in the overuse of antibiotics and disruption of antimicrobial stewardship programmes. We investigated the pattern of antibiotic use during the first 6 months of the COVID-19 pandemic in Iran. METHODS: A multi-centre retrospective study was designed to investigate the use of 16 broad-spectrum antibiotics in 12 medical centres. The rate of antibiotic use was calculated and reported based on the Defined Daily Dose (DDD) per 100 hospital bed-days. The bacterial co-infection rate was also reported. RESULTS AND DISCUSSION: Totally, 43,791 hospitalized COVID-19 patients were recruited in this study. It was found that 121.6 DDD of antibiotics were used per 100 hospital bed-days, which estimated that each patient received approximately 1.21 DDDs of antibiotics every day. However, the bacterial co-infections were detected only in 14.4% of the cases. A direct correlation was observed between the rate of antibiotic use and mortality (r[142] = 0.237, p = 0.004). The rate of antibiotic consumption was not significantly different between the ICU and non-ICU settings (p = 0.15). WHAT IS NEW AND CONCLUSION: In this study, widespread antibiotic use was detected in the absence of the confirmed bacterial coinfection in COVID-19 patients. This over-consumption of broad-spectrum antibiotics may be associated with increased mortality in hospitalized COVID-19 patients, which can be an alarming finding.

Evaluation of the epidemiologic, clinical, radiologic, and treatment methods of patients with subacute and chronic meningitis.

BACKGROUND: Meningitis is known as a meningeal inflammation accompanied by pleocytosis in the cerebrospinal fluid (CSF), and can be classified into acute, subacute, and chronic meningitis based on symptoms duration of ≤ 5 days, ≥ 5 days and ≥ 4 weeks, respectively. Subacute and chronic meningitis are caused mainly by indolent infectious agents and noninfectious causes such as autoimmune, and neoplastic. In this study, we investigated the characteristics, diagnosis, and treatment of subacute and chronic meningitis. METHODS: We extracted the medical records of patients with chronic and subacute meningitis who were referred to three tertiary centers from Jun 2011 to Jun 2021. Initially, 2050 cases of meningitis were screened, and then 79 patients were included in the study. RESULTS: Headache (87.3%), nausea and vomiting (74.7%), fever (56.4%), and visual impairments (55.7%) were the most prevalent symptoms. The most common signs were nuchal rigidity (45.3%), altered mental status (26.9%), and papillary edema (37.5%). Brain computed tomography (CT) was normal in 68.6% of the patients while 22.9% of the cases had hydrocephalus. Brain magnetic resonance imaging (MRI) was normal in 60.0% of the patients. The most common abnormal MRI findings were leptomeningeal enhancement (16.0%) and hydrocephalus (16.0%). We had a 44.3% definite diagnosis with bacterial (n:25, 31.6%) and neoplastic (n:8, 10.1%) being the most prevalent etiologies. Mycobacterium tuberculosis (60%) and Brucella spp. (12%) were the most prevalent bacterial pathogens. CONCLUSIONS: The most common etiologies include infectious, neoplastic, and immunologic. Due to insidious presentation and uncommon etiologies, establishing a proper diagnosis, and providing timely targeted treatment for patients with subacute and chronic meningitis remains a challenge for clinicians.

Self-reported antibiotic stewardship and infection control measures from 57 intensive care units: An international ID-IRI survey.

We explored the self-reported antibiotic stewardship (AS), and infection prevention and control (IPC) activities in intensive care units (ICUs) of different income settings. A cross-sectional study was conducted using an online questionnaire to collect data about IPC and AS measures in participating ICUs. The study participants were Infectious Diseases-International Research Initiative (IDI-IR) members, committed as per their institutional agreement form. We analyzed responses from 57 ICUs in 24 countries (Lower-middle income (LMI), n = 13; Upper-middle income (UMI), n = 33; High-income (HI), n = 11). This represented (~5%) of centers represented in the ID-IRI. Surveillance programs were implemented in (76.9%-90.9%) of ICUs with fewer contact precaution measures in LMI ones (p = 0.02); (LMI:69.2%, UMI:97%, HI:100%). Participation in regional antimicrobial resistance programs was more significantly applied in HI (p = 0.02) (LMI:38.4%,UMI:81.8%,HI:72.2%). AS programs are implemented in 77.2% of institutions with AS champions in 66.7%. Infectious diseases physicians and microbiologists are members of many AS teams (59%&50%) respectively. Unqualified healthcare professionals(42.1%), and deficient incentives(28.1%) are the main barriers to implementing AS. We underscore the existing differences in IPC and AS programs' implementation, team composition, and faced barriers. Continuous collaboration and sharing best practices on APM is needed. The role of regional and international organizations should be encouraged. Global support for capacity building of healthcare practitioners is warranted.

A Case of Fingolimod-associated Cryptococcal Meningitis.

BACKGROUND: Leukopenia, a rare adverse effect of Fingolimod therapy, paves the way for opportunistic infections. In this study, we reported rare fingolimod associated cryptococcal meningitis. CASE PRESENTATION: A 39-year-old woman with RRMS was referred to the emergency department. The patient's major complaints were headache, fever, weakness, and progressive loss of consciousness within the last two days prior to the referral. The patient had a history of hospitalization due to RRMS [two times]. In the second hospitalization, interferon Beta-1a was replaced with Fingolimod. Using polymerase chain reaction, Cryptococcus neoformans was detected in CSF. Liposomal amphotericin B and fluconazole [800 mg per day] were started. Six weeks later, the patient was discharged without any major complaints. CONCLUSION: Albeit fingolimod associated cryptococcal meningitis is a rare event, Fingolimod therapy in patients with MS should be performed cautiously. Regular follow-ups may give rise to a timely diagnosis of probable fingolimod associated cryptococcal meningitis. Fingolimod therapy can lead to lymphocytopenia and various infections. We, therefore, suggest that intermittent blood lymphocyte counts as well as monitoring of clinical manifestations among MS patients treated with Fingolimod to avoid additional neurological and physical disabilities in these patients.

Investigation of pharmacokinetic and clinical outcomes of various meropenem regimens in patients with ventilator-associated pneumonia and augmented renal clearance.

INTRODUCTION: Augmented renal clearance (ARC) defined as creatinine clearance (Clcr) above 130 mL/min/1.73m2 may lead to suboptimal antibacterial treatment. The aim of this study was to determine a strategy for meropenem administration to achieve both pharmacodynamic-pharmacokinetic (PK-PD) target (50%fT > MIC) and better clinical outcomes in patients with VAP and ARC. MATERIALS AND METHODS: In this randomized clinical trial, patients with VAP and high risk for ARC were recruited. An 8-h urine collection was performed on the 1st, 3rd, and 5th days of study to measure Clcr. Included patients were divided into three groups: (1) 1 g meropenem, 3-h infusion, (2) 2 g meropenem, 3-h infusion, (3) 1 g meropenem, 6-h infusion. On the 2nd, 3rd, and 5th days of treatment, peak and trough blood samples were collected to undergo HPLC assay. MICs were assessed using microdilution method. Patients were also clinically monitored for 14 days. RESULTS: Forty-five patients were included. Group 3 showed significanty higher rate of patients achieving fT > MIC > 50% (100% for group 3 versus 40% for group 2 and 13% for group 1; p = 0.0001). Mean fT > MIC% was significantly higher in group 3 (78.77 ± 5.87 for group 3 versus 49.6 ± 7.38 for group 2 and 43.2 ± 7.98 for group 1; p = 0.0001). Statistical analysis showed no significant differences among groups regarding clinical improvement. CONCLUSION: According to the findings of this trial, prolonged meropenem infusion is an appropriate strategy compared to dose elevation among ARC patients.

Benefit of Hemoadsorption Therapy in Patients Suffering Sepsis-Associated Acute Kidney Injury: A Case Series.

INTRODUCTION: Sepsis is defined as life-threatening organ dysfunction in result of the host's dysregulated response to infection and septic shock. Sepsis-associated kidney injury is usually defined as concurrent presence of acute kidney injury (AKI) and sepsis without other significant causative factors. METHOD: The current retrospective study was conducted to elucidate beneficial and side effects of CytoSorb®. A total of 17 patients were primarily treated with continuous renal replacement therapy in combination with CytoSorb. The demand for norepinephrine, mean arterial pressure, lactate, and procalcitonin (PCT) levels, as well as ICU length of stay, was measured. RESULT: The blood lactate levels decreased by 32.30% when comparing mean levels before and after treatment. All patients who survived (n = 14) had reduction in vasopressor demand to 68.96% of their initial dose before the start of treatment. Hospital survival was greater in patients who initially had higher vasopressor demand compared to their nonsurviving counterparts, but in whom vasopressor dosages were reduced significantly during their treatments. Mortality as predicted by APACHE II score in the overall patient population was 79.9%, whereas, the observed ICU mortality was 31%. The baseline PCT levels on patients received 1, 2, and 3 CytoSorbs were 27.08 ± 5.81 ng/mL, 13.28 ± 2.62 ng/mL, and 21.03 ± 6.56 ng/mL, respectively. Observed PCT levels at 24 h after the last treatment on patients received 1, 2, and 3 CytoSorb were 31.55 ± 15.70 ng/mL, 5.61 ± 1.77 ng/mL, and 8.11 ± 3.62 ng/mL, respectively. CONCLUSION: In conclusion, it seems that applying the CytoSorb in combination with CRRT in ICU septic patients with AKI, is related to a significant decrease in mortality, if the integrity and continuity of the treatment be kept, as much as possible. This study presented an effectively positive outcome with cytokine adsorber treatment as an adjuvant along with standard treatment in a high-risk mortality case of septic shock with organ failure.

Association between serum inflammatory parameters and the disease severity in COVID-19 patients.

OBJECTIVE: Most patients infected with the novel coronavirus (SARS-CoV-2), as the causative agent of COVID-19 disease, show mild symptoms, but some of them develop severe illness. The purpose of this study was to analyze the blood markers of COVID-19 patients and to investigate the correlation between serum inflammatory cytokines and the disease severity. METHODS: In this prospective cross-sectional study, 50 patients with COVID-19 and 20 patients without COVID-19 were enrolled. According to ICU admission criteria, patients were divided into two groups of non-severe and severe. Differences in the serum levels of C-reactive protein (CRP), IL-6, and TNF-α, as well as erythrocyte sedimentation rate (ESR), lymphocytes (LYM) count, and neutrophils (NEU) count between the two groups were determined and analyzed. RESULTS: Out of the 50 patients with COVID-19, 14 were diagnosed as severe cases. There was no significant difference between the two groups of COVID-19 patients in terms of gender and age. Blood tests of COVID-19 patients showed a significant decrease and increase in NEU and LYM counts, respectively. There were significant differences in the serum levels of IL-6, TNF-α, and CRP between the severe and non-severe groups, which were higher in the severe group. Also, there was a significant correlation between the disease severity and CRP with ESR (r = 0.79), CRP with IL-6 (r = 0.74), LYM with NEU (r = -0.97), and ESR with TNF-α (r = 0.7). CONCLUSION: The findings of this study, as the first study in Iran, suggest that the levels of IL-6, TNF-α, ESR, and CRP could be used to predict the severity of COVID-19 disease.

X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19.

Autosomal inborn errors of type I IFN immunity and autoantibodies against these cytokines underlie at least 10% of critical COVID-19 pneumonia cases. We report very rare, biochemically deleterious X-linked TLR7 variants in 16 unrelated male individuals aged 7 to 71 years (mean: 36.7 years) from a cohort of 1,202 male patients aged 0.5 to 99 years (mean: 52.9 years) with unexplained critical COVID-19 pneumonia. None of the 331 asymptomatically or mildly infected male individuals aged 1.3 to 102 years (mean: 38.7 years) tested carry such TLR7 variants (p = 3.5 × 10-5). The phenotypes of five hemizygous relatives of index cases infected with SARS-CoV-2 include asymptomatic or mild infection (n=2, 5 and 38 years), or moderate (n=1, 5 years), severe (n=1, 27 years), or critical (n=1, 29 years) pneumonia. Two boys (aged 7 and 12 years) from a cohort of 262 male patients with severe COVID-19 pneumonia (mean: 51.0 years) are hemizygous for a deleterious TLR7 variant. The cumulative allele frequency for deleterious TLR7 variants in the male general population is < 6.5x10-4 We also show that blood B cell lines and myeloid cell subsets from the patients do not respond to TLR7 stimulation, a phenotype rescued by wild-type TLR7 The patients' blood plasmacytoid dendritic cells (pDCs) produce low levels of type I IFNs in response to SARS-CoV-2. Overall, X-linked recessive TLR7 deficiency is a highly penetrant genetic etiology of critical COVID-19 pneumonia, in about 1.8% of male patients below the age of 60 years. Human TLR7 and pDCs are essential for protective type I IFN immunity against SARS-CoV-2 in the respiratory tract.