COVID-19 community care in Israel-a nationwide cohort study from a large health maintenance organization.

BACKGROUND: Among the many medical challenges presented by the COVID-19 pandemic, management of the majority of patients in community outpatient settings is crucial. The aim of this study was to describe the characteristics and outcomes among confirmed COVID-19 cases who were managed at three settings: two outpatient settings and one inpatient. METHODS: A retrospective database cohort study was conducted in a large Israeli Health Maintenance Organization. All COVID-19 cases diagnosed between 28 February 2020 and 20 July 2020 were included. Cases in the community settings were managed through a nationwide remote monitoring center, using preliminary telehealth triage and 24/7 virtual care. Outcome parameters included hospital admission, disease severity, need for respiratory support and mortality. RESULTS: About 5448 cases, aged range 0-97 years, were enrolled; 88.7% were initially managed as outpatient either at home or in designated hotels, 3.1 and 2.1% of them, respectively, later required hospitalization. The main reason for hospitalization was dyspnea; 12 were diagnosed with severe disease; 56 patients (1.3%) died, five (0.1%) of whom were initially allocated to the outpatient settings. CONCLUSIONS: Care for appropriately selected COVID-19 patients in the community provides a safe and effective option. This can contribute to reducing the hospitalization burden, with no evidence of increased morbidity or mortality.

Doxycycline desensitization in chronic Q fever-A critical tool for the clinician.

We present the case of a 45 year old woman with acute Q fever pneumonia who progressed to the chronic phase of the disease despite azithromycin therapy. A trial of doxycycline was halted because of severe allergy and she was put on clarithromycin and later moxifloxacin. Failure of both drugs required desensitization to doxycycline with escalating doses. After two-year treatment with doxycycline-hydroxychloroquine combination, complete recovery was declared. Our case highlights the option of doxycycline desensitization when an acute allergic reaction poses an obstacle to optimal treatment.

A novel host-protein assay outperforms routine parameters for distinguishing between bacterial and viral lower respiratory tract infections.

Bacterial and viral lower respiratory tract infections (LRTIs) are often clinically indistinguishable, leading to antibiotic overuse. We compared the diagnostic accuracy of a new assay that combines 3 host-biomarkers (TRAIL, IP-10, CRP) with parameters in routine use to distinguish bacterial from viral LRTIs. Study cohort included 184 potentially eligible pediatric and adult patients. Reference standard diagnosis was based on adjudication by an expert panel following comprehensive clinical and laboratory investigation (including respiratory PCRs). Experts were blinded to assay results and assay performers were blinded to reference standard outcomes. Evaluated cohort included 88 bacterial and 36 viral patients (23 did not fulfill inclusion criteria; 37 had indeterminate reference standard outcome). Assay distinguished bacterial from viral LRTI patients with sensitivity of 0.93±0.06 and specificity of 0.91±0.09, outperforming routine parameters, including WBC, CRP and chest x-ray signs. These findings support the assay's potential to help clinicians avoid missing bacterial LRTIs or overusing antibiotics.

Clinical and Microbiological Outcomes of Asymptomatic Bacteriuria in Elderly Stroke Patients.

BACKGROUND: The optimal approach to the evaluation of asymptomatic bacteruria in stroke patients is uncertain. OBJECTIVES: To compare elderly patients after an acute stroke with and without asymptomatic bacteriuria for the development of symptomatic urinary tract infections (UTI). METHODS: We prospectively monitored patients over 65 years of age admitted to our rehabilitation hospital after an acute stroke, with and without asymptomatic bacteriuria, for the development of symptomatic UTIs. The prevalence of bacteriuria was determined by urine cultures obtained 2 and 4 weeks after admission. Patients with and without persistent bacteriuria were compared to identify variables associated with bacteriuria. RESULTS: Fifty-five patients were included in the study. The prevalence of asymptomatic bacteriuria at baseline was 20%. Of all 55 stroke patients, 13 (23.6%) developed a symptomatic UTI during the 30 day follow-up. Patients with stroke and asymptomatic bacteriuria at baseline had an increased risk of developing a symptomatic UTI (54.5% with asymptomatic bacteriuria vs. 15.9% without, P = 0.011). To exclude the effects of several confounders, we performed multivariate Cox regression analysis, which showed that bacteruria remained a significant covariate for symptomatic UTI (hazard ratio 2.86, 95% confidence interval 0.71-10.46, P = 0.051). When subjects who experienced symptomatic urinary infection were included, the prevalence of bacteriuria in the study cohort declined to about 45.5% by 30 days. CONCLUSIONS: Elderly patients with stroke and asymptomatic bacteriuria have an increased risk of developing a symptomatic UTI compared to those without asymptomatic bacteriuria during a 30 day post-stroke follow-up.

Interferon-gamma-release assay prevents unnecessary tuberculosis therapy.

BACKGROUND: The mass influx of immigrants from tuberculosis-endemic countries into Israel was followed by a considerable increase in the incidence of tuberculosis (TB). All contacts of active TB patients are obliged to be screened by tuberculin skin tests (TST) and, if found positive, prophylactic treatment is considered. OBJECTIVES: To assess the utility of interferon-gamma (IFNγ)-release assay with a prolonged follow-up in preventing unnecessary anti-TB therapy in individuals with suspected false positive results. METHODS: Between 2008 and 2012 the QuantiFERON TB gold-in-tube test (QFT-G) was performed in 278 sequential individuals who were mostly TST-positive and/or were in contact with an active TB patient. In all, whole blood was examined by the IFNγ-release assay. We correlated the TST diameter with the QFT-G assay and followed those patients with a negative assay. RESULTS: The QFT-G test was positive in only 72 (42%) of all 171 TST-positive individuals. There was no correlation between the diameter of TST and QFT-G positivity. Follow-up over 5 years was available in 128 (62%) of all QFT-G-negative individuals. All remained well and none developed active TB. CONCLUSIONS: A negative QFT-G test may obviate the need for anti-TB therapy in more than half of those with a positive TST.

A novel host-proteome signature for distinguishing between acute bacterial and viral infections.

Bacterial and viral infections are often clinically indistinguishable, leading to inappropriate patient management and antibiotic misuse. Bacterial-induced host proteins such as procalcitonin, C-reactive protein (CRP), and Interleukin-6, are routinely used to support diagnosis of infection. However, their performance is negatively affected by inter-patient variability, including time from symptom onset, clinical syndrome, and pathogens. Our aim was to identify novel viral-induced host proteins that can complement bacterial-induced proteins to increase diagnostic accuracy. Initially, we conducted a bioinformatic screen to identify putative circulating host immune response proteins. The resulting 600 candidates were then quantitatively screened for diagnostic potential using blood samples from 1002 prospectively recruited patients with suspected acute infectious disease and controls with no apparent infection. For each patient, three independent physicians assigned a diagnosis based on comprehensive clinical and laboratory investigation including PCR for 21 pathogens yielding 319 bacterial, 334 viral, 112 control and 98 indeterminate diagnoses; 139 patients were excluded based on predetermined criteria. The best performing host-protein was TNF-related apoptosis-inducing ligand (TRAIL) (area under the curve [AUC] of 0.89; 95% confidence interval [CI], 0.86 to 0.91), which was consistently up-regulated in viral infected patients. We further developed a multi-protein signature using logistic-regression on half of the patients and validated it on the remaining half. The signature with the highest precision included both viral- and bacterial-induced proteins: TRAIL, Interferon gamma-induced protein-10, and CRP (AUC of 0.94; 95% CI, 0.92 to 0.96). The signature was superior to any of the individual proteins (P<0.001), as well as routinely used clinical parameters and their combinations (P<0.001). It remained robust across different physiological systems, times from symptom onset, and pathogens (AUCs 0.87-1.0). The accurate differential diagnosis provided by this novel combination of viral- and bacterial-induced proteins has the potential to improve management of patients with acute infections and reduce antibiotic misuse.

[IMMUNIZATIONS IN IMMUNOCOMPROMISED HOSTS--PRINCIPLES AND UPDATED RECOMMENDATIONS].

The last decades have seen a marked increase in the number of immunocompromised patients. These patients are at higher risk for severe outcomes from infections, many of which are vaccine-preventable diseases. However, such complex cases raise several important issues of concern: 1. The administration of live vaccines to an immunocompromised patient may lead to adverse events and exacerbate the underlying condition? 2. Vaccines should preferably be administered prior to the planned immunosuppressive therapies. 3. Vaccination with inactivated vaccines may not ensure complete immune responses and may lead to lower and shorter protection rates depending on the extent of immunosuppression. 4. Should household contacts of immunocompromised patients receive vaccines? Which vaccines can be safely administered to household members? 5. Do clinicians have sufficient or updated information concerning the safety, efficacy and contraindications to vaccination of such at-risk patients? 6. Which vaccines can be safely administered to immunocompromised travelers to tropical destinations? The answers to those questions are multifaceted, and data on safety, immunogenicity, and efficacy of vaccines for immunocompromised populations are limited. This article summarizes the current recommendations for immunizations in immunocompromised patients, indications and potential adverse effects.

Initial effects of the National PCV7 Childhood Immunization Program on adult invasive pneumococcal disease in Israel.

BACKGROUND: PCV7 was introduced as universal childhood vaccination in Israel in July 2009 and PCV13 in November 2010. Here we report data on adult invasive pneumococcal disease (IPD), two years post PCV7 implementation and before an expected effect of PCV13. METHODS: An ongoing nationwide active-surveillance (all 27 laboratories performing blood cultures in Israel), providing all blood & CSF S. pneumoniae isolates from persons >18 y was initiated in July 2009. Capture-recapture method assured reporting of >95% cases. All isolates were serotyped in one central laboratory. IPD outcome and medical history were recorded in 90%. Second year post PCV implementation is compared to the first year. RESULTS: During July 2009 to June 2011, 970 IPD cases were reported (annual incidence [/100,000] of 9.17 and 10.16 in the two consecutive years, respectively). Respective case fatality rates (CFRs) were 20% and 19.1%. Incidence of IPD and CFR increased with age and number of comorbidities. Incidence rate was significantly greater during the second winter, 7.79/100,000 vs. 6.14/100,000 in first winter, p = 0.004, with a non-significant decrease during summer months (3.02 to 2.48/100,000). The proportion of IPD cases due to PCV7-serotypes decreased from 27.5% to 13.1% (first to second year) (p<0.001). Yet, non-PCV13-strains increased from 32.7% to 40.2% (p = 0.017). The increase in non-PCV13-strains was highly significant in immunocompromised patients and to a lesser degree in non-immunocompromised at risk or in older patients (>64 y). Among younger/healthier patients serotype 5 was the major increasing serotype. Penicillin and ceftriaxone resistance decreased significantly in the second year. CONCLUSIONS: While overall annual incidence of IPD did not change, the indirect effect of PCV7 vaccination was evident by the significant decrease in PCV7 serotypes across all age groups. Increase in non-VT13 strains was significant in immunocompromised patients. A longer follow-up is required to appreciate the full effect of infant vaccination on annual IPD.

Leukemoid reaction: spectrum and prognosis of 173 adult patients.

BACKGROUND: The prognosis of patients with leukemoid reaction (LR) depends mainly on their underlying illness. Our aim was to investigate the etiologies and prognosis of a mixed group of patients with LR. METHODS: We identified 173 patients who had ≥30.0 × 10(9) leukocytes/µL without hematologic malignancies. Causes of LR and factors contributing to death were analyzed. RESULTS: Patients with LR constituted 0.59% of all admitted adults. The median age was 75 years, but 20 patients were aged <40 years. There was no difference in LR prevalence by gender (female/male = 88/85). Average white blood cell (WBC) count was 37.7 × 10(9)/µL. Fourteen patients (8.0%) had a WBC count of >50.0 × 10(9)/µL. The median duration of LR was 1 day, but 39 patients had prolonged LR (>1 day). Infection was the most common cause of LR (n = 83, 47.9%; 95% confidence interval, 40.7-55.4), followed by ischemia/stress (27.7%), inflammation (6.9%), and obstetric diagnoses (6.9%). Higher WBC counts were significantly associated with positive blood cultures (P = .017) or a positive Clostridium difficile toxin (P = .001). Antibiotics were prescribed for 140 patients (80.9%). Sixty-six patients (38.1%) died during hospitalization. Those with prolonged LR had an in-hospital mortality rate of 61.5%. Factors found to be highly correlated with death were age (odds ratio [OR] = 1.051, P < .001), any infectious diagnosis (OR = 2.574, P = .014), and sepsis (OR = 3.752, P = .001). CONCLUSIONS: LR carries a grave prognosis, especially among the elderly and those with sepsis. LR was found to have multiple etiologies including infections, stress, inflammation, and obstetric diagnoses.

Pregnancy course and outcome in women traveling to developing countries.

BACKGROUND: The issue of travel to developing countries during pregnancy has not been sufficiently studied. The aim of this study is to investigate the rate, course, and outcome of pregnancies in women who traveled to developing countries while pregnant, or became pregnant during such travel. METHODS: Women visiting two major travel clinics in Israel for consultation within the years 2004 to 2009, who were pregnant or declared an intention of becoming pregnant during travel were contacted. This was followed by a telephone interview by an obstetrician with those women who were actually pregnant. Background characteristics, morbidity during travel, and pregnancy course and outcome were collected. RESULTS: Overall 52,430 travelers' records had been screened. Of these, we identified 49 women who were pregnant during their trip, but 3 declined participation. Of the remaining 46 women, 33 were pregnant at departure, and 13 conceived during travel. The incidence of pregnancy during travel was thus 0.93/1000 travelers. Thirty-three women traveled to East Asia, 8 to South and Central America, 5 to Africa. More than two thirds of women received pretravel vaccinations. Adherence to the World Health Organization recommendations regarding food and drink was high (87%) and travelers' diarrhea occurred in only 11% of women. Five of 22 women traveling to malarious areas had taken antimalarial prophylaxis. Six women required medical therapy during travel. Pregnancy outcome was not different from the normal population except for an unusually low rate of preterm delivery. CONCLUSIONS: In this cohort, travel to developing countries was not associated with adverse pregnancy outcome. Larger studies are needed to support these findings.

Impact of a computerized integrated antibiotic authorization system.

BACKGROUND: Overuse and abuse of antibiotics is a major cause of microbial resistance. Within the hospital setting such overuse necessitates real-time supervision by infectious diseases (ID) specialists. OBJECTIVES: To evaluate the impact of a recently introduced computerized antibiotic authorization system on the pharmacy budget. METHODS: The study was performed in a 400 bed university hospital. With the new system, antibiotic requests are entered electronically by the ward physician and reviewed within minutes to hours by ID specialists. The feedbacks are seen in the wards and pharmacy. Successive years, one before and the other after introduction of the system, were compared. RESULTS: During the first year with the new system 7167 antibiotic requests were entered; 20% of them were rejected, mainly for improper indication (43% of the rejections). During that year the antibiotic expenditure was reduced by 17%, compared to the previous year (approximately equal to 200,000 US$), and was against the trend of the last 5 years. Of the 35 antibiotics under the control of the ID team, the use of 7 was probably curtailed by the supervision. Pareto analysis revealed that four drugs constituted > 50% of the pharmacy's expenses. The mortality rate (per 1000 hospitalization days) during those 2 years fell from 4.0 to 3.8. CONCLUSIONS: Computerized antibiotic control by ID specialists is a feasible cost-saving new modality that may help reduce unnecessary antibiotic prescriptions.

Antibiotic exposure as a risk factor for fluconazole-resistant Candida bloodstream infection.

Recent exposure to azoles is an important risk factor for infection with fluconazole-resistant Candida spp., but little is known about the role of antibacterial drug exposure in the emergence of drug-resistant Candida. We did a prospective nationwide surveillance study of candidemia in Israel and analyzed the propensity score-adjusted association between antifungal and antibacterial drug exposure and bloodstream infection with C. glabrata and fluconazole-resistant Candida isolates. Four hundred forty-four episodes of candidemia (450 Candida isolates, 69 [15%] C. glabrata isolates, and 38 [8.5%] fluconazole-resistant isolates) from 18 medical centers in Israel were included. C. glabrata bloodstream infection was strongly associated with recent metronidazole exposure (odds ratio [OR], 3.2; P < 0.001). Infection with a fluconazole-resistant isolate was associated with exposure to carbapenems, trimethoprim-sulfamethoxazole, clindamycin, and colistin (odds ratio, 2.8; P = 0.01). The inclusion of antibacterial drug exposure in a multivariable model significantly enhanced the model's predictive accuracy for fluconazole-resistant Candida bloodstream infection. Our findings may be relevant to the selection of empirical antifungal treatment and broaden the scope of antibiotic-associated collateral damage.

When uncommon uncovers: mucosal tuberculosis in a medical tourist from Burundi.

Tuberculosis confined to the mucus membranes is a rare presentation in the era of effective chemotherapy. We describe a case of mucosal tuberculosis in a "medical tourist" from Burundi that went undiagnosed for 6 years. Starting as conjunctivitis, the disease has spread to involve the nose and larynx as well. The clinical, pathophysiological, and epidemiological aspects are discussed.

Pseudomonas aeruginosa bacteremia upon hospital admission: risk factors for mortality and influence of inadequate empirical antimicrobial therapy.

Pseudomonas aeruginosa is an uncommon cause of bacteremia upon hospital admission (UHA) and the chosen empirical antimicrobial therapy may not cover it appropriately. In a multicenter prospective study conducted in Israel, we evaluated risk factors for in-hospital mortality in patients with P. aeruginosa bacteremia UHA and determined the influence of delay in adequate empirical antimicrobial therapy on patients' outcome. Seventy-six adult patients with P. aeruginosa bacteremia within 72 h of hospital admission were included. Demographic, clinical, and treatment data were collected. Microbiological adequacy of empirical therapy was determined. Severe sepsis or septic shock at admission (OR, 21.9; P < 0.001), respiratory or unknown sources of bacteremia (OR, 11.5; P = 0.003), recent hospitalization (OR, 6.2; P = 0.032), and poor functional status (OR, 5.8; P = 0.029) were identified as independent predictors of mortality. Inadequate empirical antimicrobial therapy was marginally associated with increased mortality only among patients who presented with severe sepsis or septic shock (P = 0.051).

Perichondritis of the auricle: analysis of 114 cases.

BACKGROUND: Perichondritis of the auricle is a serious disease that may lead to residual deformity. OBJECTIVES: To assess our experience with perichondritis in a large group of patients hospitalized with this entity. METHODS: We retrospectively studied 114 patients who were admitted with perichondritis during 1987-2004, including their demographic details, medical history, current illness, etiology, pathogens and treatments. RESULTS: The patients' mean age was 41.8 +/- 20.7 years. In more than half of the patients the etiology could not be determined. Forty-seven patients (41%) were treated prior to hospitalization for an average of 2.5 +/- 1.9 days. Eight patients (7%) required surgical intervention. Pseudomonas aeruginosa was found to be the predominant organism (69% of available isolates) and was associated with a more advanced clinical presentation and longer hospitalization (P = 0.008). CONCLUSIONS: Perichondritis develops in many cases after apparent minor trauma. Since P. aeruginosa is probably the predominant pathogen, initial treatment should include anti-pseudomonal antibiotics.

National multicenter study of predictors and outcomes of bacteremia upon hospital admission caused by Enterobacteriaceae producing extended-spectrum beta-lactamases.

Extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae are pathogens that may lead to a spectrum of clinical syndromes. We aimed to identify predictors and outcomes of ESBL bacteremia upon hospital admission (UHA) in a nationwide prospective study. Thus, a multicenter prospective study was conducted in 10 Israeli hospitals. Adult patients with bacteremia due to Enterobacteriaceae diagnosed within 72 h of hospitalization were included. Patients with ESBL producers (cases) were compared to those with non-ESBL producers (controls), and a 1:1 ratio was attempted in each center. A case-control study to identify predictors and a cohort study to identify outcomes were conducted. Bivariate and multivariate logistic regressions were used for analyses. Overall, 447 patients with bacteremia due to Enterobacteriaceae were recruited: 205 cases and 242 controls. Independent predictors of ESBL were increased age, multiple comorbid conditions, poor functional status, recent contact with health care settings, invasive procedures, and prior receipt of antimicrobial therapy. In addition, patients presenting with septic shock and/or multiorgan failure were more likely to have ESBL infections. Patients with ESBL producers suffered more frequently from a delay in appropriate antimicrobial therapy (odds ratio [OR], 4.7; P, <0.001) and had a higher mortality rate (OR, 3.5; P, <0.001). After controlling for confounding variables, both ESBL production (OR, 2.3; P, 9.1) and a delay in adequate therapy (OR, 0.05; P, 0.001) were significant predictors for mortality and other adverse outcomes. We conclude that among patients with bacteremia due to Enterobacteriaceae UHA, those with ESBL producers tend to be older and chronically ill and to have a delay in effective therapy and severe adverse outcomes. Efforts should be directed to improving the detection of patients with ESBL bacteremia UHA and to providing immediate appropriate therapy.

Fusarium keratitis acquired during travel to Namibia.

Fungal infections in travelers are rare. Fusariosis has recently become an important infection of immunocompromised patients. Herein, we describe the case of an immunocompetent traveler who contracted Fusarium keratitis while in Africa.