Superinfections in COVID-19 patients receiving extracorporeal membrane oxygenation support.

BACKGROUND: The risk of superinfections and associations with mortality among patients with corona virus disease 2019 (COVID-19) receiving veno-venous extracorporeal membrane oxygenation (VV-ECMO) is poorly elucidated. METHOD: We identified all patients with COVID-19 treated with VV-ECMO >24 h at Rigshospitalet, Denmark from March 2020 to December 2021. Data were obtained by review of medical files. Associations between superinfections and mortality were assessed by logistic regression analyses adjusted for sex and age. RESULTS: Fifty patients, median age 53 years (interquartile range [IQR] 45-59), 66% male, were included. Median time on VV-ECMO was 14.5 days (IQR 6.3-23.5), 42% were discharged from hospital alive. Bacteremia, ventilator associated pneumonia (VAP), invasive candidiasis, pulmonary aspergillosis, herpes simplex virus, and cytomegalovirus (CMV) were detected in 38%, 42%, 12%, 12%, 14%, and 20% of patients, respectively. No patients with pulmonary aspergillosis survived. CMV was associated with increased risk of death, odds ratio 12.6 (95% confidence interval 1.9-257, p = .05), whereas we found no associations between other superinfections and risk of death. CONCLUSION: Bacteremia and VAP are common but does not seem to affect mortality, whereas pulmonary aspergillosis and CMV are associated with poor prognosis among COVID-19 patients treated with VV-ECMO.

Corticosteroids and superinfections in COVID-19 patients on invasive mechanical ventilation.

OBJECTIVES: To determine the incidence and characteristics of superinfections in mechanically ventilated COVID-19 patients, and the impact of dexamethasone as standard therapy. METHODS: This multicentre, observational, retrospective study included patients ≥ 18 years admitted from March 1st 2020 to January 31st 2021 with COVID-19 infection who received mechanical ventilation. Patient characteristics, clinical characteristics, therapy and survival were examined. RESULTS: 155/156 patients (115 men, mean age 62 years, range 26-84 years) were included. 67 patients (43%) had 90 superinfections, pneumonia dominated (78%). Superinfections were associated with receiving dexamethasone (66% vs 32%, p<0.0001), autoimmune disease (18% vs 5.7%, p<0.016) and with longer ICU stays (26 vs 17 days, p<0,001). Invasive fungal infections were reported exclusively in dexamethasone-treated patients [8/67 (12%) vs 0/88 (0%), p<0.0001]. Unadjusted 90-day survival did not differ between patients with or without superinfections (64% vs 73%, p=0.25), but was lower in patients receiving dexamethasone versus not (58% vs 78%, p=0.007). In multiple regression analysis, superinfection was associated with dexamethasone use [OR 3.7 (1.80-7.61), p<0.001], pre-existing autoimmune disease [OR 3.82 (1.13-12.9), p=0.031] and length of ICU stay [OR 1.05 p<0.001]. CONCLUSIONS: In critically ill COVID-19 patients, dexamethasone as standard of care was strongly and independently associated with superinfections.

Prediction of ventilator-associated pneumonia outcomes according to the early microbiological response: a retrospective observational study.

BACKGROUND: Ventilator-associated pneumonia (VAP) is a leading infectious cause of morbidity in critically ill patients, yet current guidelines offer no indications for follow-up cultures. We aimed to evaluate the role of follow-up cultures and microbiological response 3 days after diagnosing VAP as predictors of short- and long-term outcomes. METHODS: We performed a retrospective analysis of a cohort prospectively collected from 2004 to 2017. VAP was diagnosed based on clinical, radiographical and microbiological criteria. For microbiological identification, a tracheobronchial aspirate was performed at diagnosis and repeated after 72 h. We defined three groups when comparing the two tracheobronchial aspirate results: persistence, superinfection and eradication of causative pathogens. RESULTS: 157 patients were enrolled in the study, among whom microbiological persistence, superinfection or eradication was present in 67 (48%), 25 (16%) and 65 (41%), respectively, after 72 h. Those with superinfection had the highest mortalities in the intensive care unit (p=0.015) and at 90 days (p=0.036), while also having the fewest ventilator-free days (p=0.019). Multivariable analysis revealed shock at VAP diagnosis (OR 3.43, 95% CI 1.25-9.40), Staphylococcus aureus isolation at VAP diagnosis (OR 2.87, 95% CI 1.06-7.75) and hypothermia at VAP diagnosis (OR 0.67, 95% CI 0.48-0.95, per +1°C) to be associated with superinfection. CONCLUSIONS: Our retrospective analysis suggests that VAP short- and long-term outcomes may be associated with superinfection in follow-up cultures. Follow-up cultures may help guide antibiotic therapy and its duration. Further prospective studies are necessary to verify our findings.

Both Coinfection and Superinfection Drive Complex Anaplasma marginale Strain Structure in a Natural Transmission Setting.

Vector-borne pathogens commonly establish multistrain infections, also called complex infections. How complex infections are established, either before or after the development of an adaptive immune response, termed coinfection or superinfection, respectively, has broad implications for the maintenance of genetic diversity, pathogen phenotype, epidemiology, and disease control strategies. Anaplasma marginale, a genetically diverse, obligate, intracellular, tick-borne bacterial pathogen of cattle, commonly establishes complex infections, particularly in regions with high transmission rates. Both coinfection and superinfection can be established experimentally; however, it is unknown how complex infections develop in a natural transmission setting. To address this question, we introduced naive animals into a herd in southern Ghana with a high infection prevalence and high transmission pressure and tracked the strain acquisition of A. marginale through time using multilocus sequence typing. As expected, the genetic diversity among strains was high, and 97% of animals in the herd harbored multiple strains. All the introduced naive animals became infected, and three to four strains were typically detected in an individual animal prior to seroconversion, while one to two new strains were detected in an individual animal following seroconversion. On average, the number of strains acquired via superinfection was 16% lower than the number acquired via coinfection. Thus, while complex infections develop via both coinfection and superinfection, coinfection predominates in this setting. These findings have broad implications for the development of control strategies in high-transmission settings.

Invasive pulmonary aspergillosis in critically ill patients with severe COVID-19 pneumonia: Results from the prospective AspCOVID-19 study.

BACKGROUND: Superinfections, including invasive pulmonary aspergillosis (IPA), are well-known complications of critically ill patients with severe viral pneumonia. Aim of this study was to evaluate the incidence, risk factors and outcome of IPA in critically ill patients with severe COVID-19 pneumonia. METHODS: We prospectively screened 32 critically ill patients with severe COVID-19 pneumonia for a time period of 28 days using a standardized study protocol for oberservation of developement of COVID-19 associated invasive pulmonary aspergillosis (CAPA). We collected laboratory, microbiological, virological and clinical parameters at defined timepoints in combination with galactomannan-antigen-detection from nondirected bronchial lavage (NBL). We used logistic regression analyses to assess if COVID-19 was independently associated with IPA and compared it with matched controls. FINDINGS: CAPA was diagnosed at a median of 4 days after ICU admission in 11/32 (34%) of critically ill patients with severe COVID-19 pneumonia as compared to 8% in the control cohort. In the COVID-19 cohort, mean age, APACHE II score and ICU mortality were higher in patients with CAPA than in patients without CAPA (36% versus 9.5%; p<0.001). ICU stay (21 versus 17 days; p = 0.340) and days of mechanical ventilation (20 versus 15 days; p = 0.570) were not different between both groups. In regression analysis COVID-19 and APACHE II score were independently associated with IPA. INTERPRETATION: CAPA is highly prevalent and associated with a high mortality rate. COVID-19 is independently associated with invasive pulmonary aspergillosis. A standardized screening and diagnostic approach as presented in our study can help to identify affected patients at an early stage.

Surgical Resections of Superinfected Pneumatoceles in a COVID-19 Patient.

Emerging studies on radiologic findings in patients with coronavirus disease 2019 (COVID-19) report a high incidence of bilateral lung involvement, with ground-glass opacities imaging being the most common pattern on computed tomography. Cystic lesions, such as pneumatoceles, are rare, although they may occur in 10% of cases. Cyst formation may be explained by a focal pulmonary trauma caused by mechanical ventilation or infection-related damage to the alveolar walls leading to pneumatoceles. The superinfection of pneumatoceles is a potential life-threatening condition for which no standardized therapeutic algorithm has been accepted. We report a case of a COVID-19 patient successfully treated by lung resections for infected pneumatoceles.

Brèves.

TITLE: Brèves. ABSTRACT: L'unité d'enseignement « Immunopathologie ¼ qui propose les brèves de ce numéro est suivie par des étudiants des sept parcours recherche du Master Biologie Santé de l'Université de Montpellier. On y étudie les bases physiopathologiques des maladies immunologiques, les cibles thérapeutiques et les mécanismes d'échappement des microorganismes et des tumeurs. Ce Master rassemble des étudiants issus du domaine des sciences et technologies et de celui de la santé. Les articles présentés ont été choisis par les étudiants selon leur domaine de prédilection.

Outcomes of donor-derived superinfection screening in HIV-positive to HIV-positive kidney and liver transplantation: a multicentre, prospective, observational study.

BACKGROUND: One of the primary risks of HIV-positive to HIV-positive organ transplantation is loss of virological control because of donor-derived HIV superinfection, which occurs when an HIV-positive individual becomes infected with a new distinct HIV strain. In this study, as part of the larger HIV Organ Policy Equity pilot study, HIV-positive to HIV-positive kidney and liver transplant recipients in the USA were examined for evidence of sustained donor-derived HIV superinfection. METHODS: In this multicentre, prospective, observational study, HIV-positive to HIV-positive kidney and liver transplant recipients were followed in three hospitals in the USA. Candidates with well controlled HIV infection on ART, no active opportunistic infections, and minimum CD4 T-cell counts (>100 cells per µL for liver and >200 cells per µL for kidney per federal guidelines) were eligible to receive a kidney or liver from deceased HIV-positive donors without active infections or neoplasm. Peripheral blood mononuclear cells were collected from donor-recipient pairs at the time of transplantation, and from recipients at several timepoints up to 3 years after transplantation. Donor samples were assessed for HIV RNA viral load, CD4 cell count, and antiretroviral drug-resistant mutations. Donor and recipient HIV proviral DNA, and viral RNA from the viraemic timepoint were sequenced using a site-directed next-generation sequencing assay for the reverse transcriptase and gp41 genes. Neighbour-joining phylogenetic trees and direct sequence comparison were used to detect the presence of HIV superinfection. This study is registered with ClinicalTrials.gov, NCT02602262. FINDINGS: 14 HIV-positive to HIV-positive kidney and eight liver transplant recipients were followed from March, 2016, to July, 2019. 17 recipients had adequate viral sequences allowing for HIV superinfection assessment. Eight donors were suppressed (viral load <400 copies per mL), and none had multiclass drug-resistant mutations detected. None of the recipients examined had evidence of HIV superinfection. One recipient had a viraemic episode (viral load of 2 080 000 copies per mL) 3 years after transplantation as a result of non-adherence to ART. Only recipient viral sequences were detected during the viraemic episode, suggesting that the donor virus, if present, was not reactivated despite temporary withdrawal of ART. INTERPRETATION: These findings suggest that loss of HIV suppression due to donor-derived HIV superinfection might not be a significant clinical concern in carefully monitored ART suppressed HIV-positive organ recipients. FUNDING: US National Institute of Allergy and Infectious Diseases and National Cancer Institute.

The influenza replication blocking inhibitor LASAG does not sensitize human epithelial cells for bacterial infections.

Severe influenza virus (IV) infections still represent a major challenge to public health. To combat IV infections, vaccines and antiviral compounds are available. However, vaccine efficacies vary with very limited to no protection against newly emerging zoonotic IV introductions. In addition, the development of resistant virus variants against currently available antivirals can be rapidly detected, in consequence demanding the design of novel antiviral strategies. Virus supportive cellular signaling cascades, such as the NF-κB pathway, have been identified to be promising antiviral targets against IV in in vitro and in vivo studies and clinical trials. While administration of NF-κB pathway inhibiting agents, such as LASAG results in decreased IV replication, it remained unclear whether blocking of NF-κB might sensitize cells to secondary bacterial infections, which often come along with viral infections. Thus, we examined IV and Staphylococcus aureus growth during LASAG treatment. Interestingly, our data reveal that the presence of LASAG during superinfection still leads to reduced IV titers. Furthermore, the inhibition of the NF-κB pathway resulted in decreased intracellular Staphylococcus aureus loads within epithelial cells, indicating a dependency on the pathway for bacterial uptake. Unfortunately, so far it is not entirely clear if this phenomenon might be a drawback in bacterial clearance during infection.

Pyoderma Gangrenosum and Superimposed Infection: A Case Report.

Pyoderma gangrenosum (PG) is a rare, ulcerating, inflammatory disease that is often misdiagnosed as a skin and soft tissue infection. If PG is identified, it is treated with topical or systemic immunosuppressants to reduce inflammation and induce remission. However, the use of immunosuppressants has been linked to a higher risk of superimposed infections. The authors report the case of a 24-year-old female patient with bilateral lower extremity PG with a superimposed infection of Pseudomonas aeruginosa and Bacteroides fragilis after intralesional corticosteroid therapy.

Bacterial Superinfection of Amoebic Liver Abscess.

A 78-year-old male, originally from China, was brought to the hospital for weakness, urinary incontinence, confusion, and poor oral intake. He was started on empiric antibiotics, which were narrowed when blood cultures produced gram-negative bacteremia speciating to Klebsiella pneumoniae, sensitive to ceftriaxone. Computed tomography scan of the abdomen and pelvis demonstrated a large cystic region with air-fluid level in the left lobe of the liver. Suspecting this to be the source of the patient's bacteremia, the lesion was percutaneously drained and the fluid cultured, which also revealed ceftriaxone-sensitive Klebsiella pneumoniae. While a stool ova and parasite examination on the patient was negative, further workup was positive for Entamoeba histolytica antibody in the serum, detected via enzyme-linked immunosorbent assay and indicative of either current or past infection. This suggested possible prolonged subclinical infection with bacterial superinfection, especially given that Klebsiella pneumoniae is one of the most common organisms cultured from these abscesses. In patients with liver abscesses who immigrated from developing and/or endemic regions or have a relevant recent travel history, an underlying amoebic etiology of an abscess should be considered.

Interferon Lambda Inhibits Bacterial Uptake during Influenza Superinfection.

Influenza kills 30,000 to 40,000 people each year in the United States and causes 10 times as many hospitalizations. A common complication of influenza is bacterial superinfection, which exacerbates morbidity and mortality from the viral illness. Recently, methicillin-resistant Staphylococcus aureus (MRSA) has emerged as the dominant pathogen found in bacterial superinfection, with Streptococcus pneumoniae a close second. However, clinicians have few tools to treat bacterial superinfection. Current therapy for influenza/bacterial superinfection consists of treating the underlying influenza infection and adding various antibiotics, which are increasingly rendered ineffective by rising bacterial multidrug resistance. Several groups have recently proposed the use of the antiviral cytokine interferon lambda (IFN-λ) as a therapeutic for influenza, as administration of pegylated IFN-λ improves lung function and survival during influenza by reducing the overabundance of neutrophils in the lung. However, our data suggest that therapeutic IFN-λ impairs bacterial clearance during influenza superinfection. Specifically, mice treated with an adenoviral vector to overexpress IFN-λ during influenza infection exhibited increased bacterial burdens upon superinfection with either MRSA or S. pneumoniae Surprisingly, adhesion molecule expression, antimicrobial peptide production, and reactive oxygen species activity were not altered by IFN-λ treatment. However, neutrophil uptake of MRSA and S. pneumoniae was significantly reduced upon IFN-λ treatment during influenza superinfection in vivo Together, these data support the theory that IFN-λ decreases neutrophil motility and function in the influenza-infected lung, which increases the bacterial burden during superinfection. Thus, we believe that caution should be exercised in the possible future use of IFN-λ as therapy for influenza.

Photodynamic Therapy With Methylene Blue for Skin Ulcers Infected With Pseudomonas aeruginosa and Fusarium spp. / Terapia fotodinámica con azul de metileno en úlceras cutáneas infectadas con Pseudomonas aeruginosa y Fusarium spp.

Photodynamic therapy (PDT) is a therapeutic modality with significant antimicrobial activity. We present 2 cases of chronic lower limb ulcers in which fungal and bacterial superinfection complicated management. PDT with methylene blue as the photosensitizer led to clinical and microbiological cure with no significant adverse effects. PDT with methylene blue is a valid option for the management of superinfected chronic ulcers, reducing the use of antibiotics and the induction of resistance.

The association between benzodiazepines and influenza-like illness-related pneumonia and mortality: a survival analysis using UK Primary Care data.

PURPOSE: Bacterial superinfections, including pneumonia, are frequent complications of influenza-like illness (ILI). Clinical and laboratory evidence suggests that benzodiazepines and Z-drugs may influence susceptibility to infections and mortality. We investigated whether benzodiazepines and zopiclone modify the occurrence of ILI-related pneumonia and mortality. METHODS: We obtained data on 804 051 ILI patients from a comprehensive primary care database, the Clinical Practice Research Datalink. The follow-up period started from the diagnosis of ILI for 30 days. Pneumonia and deaths occurring within the 30-day follow-up period were considered as potentially 'ILI related'. Exposure to benzodiazepines and zopiclone was determined in the period preceding a diagnosis of ILI with current use defined as a prescription for benzodiazepines in the month prior to ILI diagnosis. Cox regression was used for the analyses. Adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) are presented. RESULTS: Influenza-like illness-related pneumonia and mortality were noted in 1117 and 707 ILI patients, respectively. Current exposure to benzodiazepines was associated with increased occurrence of both ILI-related pneumonia and mortality (ILI-related pneumonia adjusted HR 4.24, 95%CI [2.27, 7.95]; ILI-related mortality adjusted HR 20.69, 95%CI [15.54, 27.54]). A similar increase in ILI-related mortality but not pneumonia was observed with current zopiclone use (ILI-related mortality adjusted HR 10.86, 95%CI [6.93, 17.02]; ILI-related pneumonia adjusted HR 1.97, 95%CI [0.63, 6.12]). CONCLUSION: Benzodiazepines may increase the likelihood of pneumonia and mortality related to ILI. A cautionary approach to prescribing benzodiazepine is suggested in people known to be at increased risk of pneumonia or mortality. Copyright © 2016 John Wiley & Sons, Ltd.

[Severe crusted scabies: A "historic" case involving the death of a 52-year-old patient]. / Gale hyperkératosique sévère : atteinte « historique ¼ et décès d'une patiente de 52ans.

BACKGROUND: Crusted scabies, also known as Norwegian scabies, is a rare and extremely debilitating form of Sarcoptes scabiei var. hominis infestation that generally occurs in immunosuppressed patients. Herein, we report a "historic" and fatal case. PATIENTS AND METHODS: A 52-year-old woman was admitted to the emergency department presenting crusted dermatitis together with extreme deterioration of her general condition. Her general practitioner had initiated dermo-corticosteroid therapy for suspected atopic dermatitis two months earlier, and she had been confined to bed for the previous 10 days. Her son presented pruritus that became worse at night. On examination the patient was moaning, dehydrated and confused and her entire skin was hyperkeratotic, with very thick, yellowish, cracked crusts covering 40 % of her body. Tests indicated severe water and electrolytic disorders as well as Staphylococcus aureus bacteremia. A tape test established the diagnosis of crusted scabies. The severity was grade III on the Davis clinical grading scale. The patient showed signs of multi-organ failure and was transferred to intensive care, but she died during the night. DISCUSSION: This case is remarkable for its historic severity. In France, scabies infestation is a re-emerging disease and has been a public health priority since 2012. The rare hyperkeratotic form is not fully understood and frequently diagnosed late, in some cases with a fatal outcome.

Kaposi varicelliform eruption in patients with autoimmune bullous dermatoses.

BACKGROUND: Viral superinfection of skin affected by preceding dermatosis has been studied extensively in eczema and reported anecdotally in pemphigus. Little is known about its involvement and complications in patients with other immunobullous diseases. METHODS: To investigate clinical features and complications of viral superinfection in patients with immunobullous diseases, we performed a retrospective chart review. RESULTS: We identified 12 patients with immunobullous diseases (linear immunoglobulin A bullous dermatosis, n = 2; pemphigoid, n = 3; pemphigus, n = 7) and superinfection by herpes simplex virus 1 (n = 9) or 2 (n = 3). Complications included inpatient hospitalization for intensive management of skin lesions during viral flare (n = 6), herpes keratitis (n = 1), and death due to sepsis (n = 1). Five patients previously had a skin swab negative for herpes simplex virus polymerase chain reaction before a positive test. Nine patients were taking systemic corticosteroids or corticosteroid-sparing agents at herpetic infection; two with linear immunoglobulin A bullous dermatosis and one with a new diagnosis of pemphigus vulgaris had not. CONCLUSIONS: Viral superinfection is a potentially serious complication in patients with immunobullous diseases. Clinicians should have a high index of suspicion for this phenomenon, even when patients are not otherwise immunosuppressed or when previous viral skin assays have been negative.