[Infection prevention in secondary immunodeficiencies]. / Preventie van infecties bij verworven afweerstoornis.

Over one million people in The Netherlands are estimated having an immunodeficiency, of which the majority has an acquired immunodeficiency due to immunosuppressive medication. These patients are at risk for a more severe course of common infections, and also for opportunistic infections and viral reactivations. The following topics are discussed: types of immunodeficiency and how to estimate its severity; commonly seen infections in immunocompromised patients; recommended screening before start of immunosuppressive medication; pitfalls in clinical clues and diagnostics, and safety and immunogenicity of vaccination in these patients. Conclusively, recognition of an immunodeficiency and awareness of the risks and preventive measures are required. This article attempts to provide a pragmatic classification on the infection risk per type of immunosuppressive medication for clinical practice.

Clinical Impact of Polymerase Chain Reaction-Based Aspergillus and Azole Resistance Detection in Invasive Aspergillosis: A Prospective Multicenter Study.

BACKGROUND: Invasive aspergillosis (IA) by a triazole-resistant Aspergillus fumigatus is associated with high mortality. Real-time resistance detection will result in earlier initiation of appropriate therapy. METHODS: In a prospective study, we evaluated the clinical value of the AsperGenius polymerase chain reaction (PCR) assay in hematology patients from 12 centers. This PCR assay detects the most frequent cyp51A mutations in A. fumigatus conferring azole resistance. Patients were included when a computed tomography scan showed a pulmonary infiltrate and bronchoalveolar fluid (BALf) sampling was performed. The primary end point was antifungal treatment failure in patients with azole-resistant IA. RESULTS: Of 323 patients enrolled, complete mycological and radiological information was available for 276 (94%), and probable IA was diagnosed in 99/276 (36%). Sufficient BALf for PCR testing was available for 293/323 (91%). Aspergillus DNA was detected in 116/293 (40%) and A. fumigatus DNA in 89/293 (30%). The resistance PCR was conclusive in 58/89 (65%) and resistance detected in 8/58 (14%). Two had a mixed azole-susceptible/azole-resistant infection. In the 6 remaining patients, treatment failure was observed in 1. Galactomannan positivity was associated with mortality (P = .004) while an isolated positive Aspergillus PCR was not (P = .83). CONCLUSIONS: Real-time PCR-based resistance testing may help to limit the clinical impact of triazole resistance. In contrast, the clinical impact of an isolated positive Aspergillus PCR on BALf seems limited. The interpretation of the EORTC/MSGERC PCR criterion for BALf may need further specification (eg, minimum cycle threshold value and/or PCR positive on >1 BALf sample).

Dutch Healthcare Professionals' Opinion on the Allocation of Responsibilities concerning Prescribing and Administering Medically Indicated Vaccines to Immunocompromised Patients.

BACKGROUND: Specific vaccines are indicated for immunocompromised patients (ICPs) due to their vulnerability to infections. Recommendation of these vaccines by healthcare professionals (HCPs) is a crucial facilitator for vaccine uptake. Unfortunately, the responsibilities to recommend and administer these vaccines are not clearly allocated among HCPs involved in the care of adult ICPs. We aimed to evaluate HCPs' opinions on directorship and their role in facilitating the uptake of medically indicated vaccines as a basis to improve vaccination practices. METHODS: A cross-sectional survey was performed among in-hospital medical specialists (MSs), general practitioners (GPs), and public health specialists (PHSs) in the Netherlands to assess their opinion on directorship and the implementation of vaccination care. Additionally, perceived barriers, facilitators, and possible solutions to improve vaccine uptake were investigated. RESULTS: In total, 306 HCPs completed the survey. HCPs almost unanimously (98%) reported that according to them, the primary treating physician is responsible for recommending medically indicated vaccines. Administering these vaccines was seen as a more shared responsibility. The most important barriers experienced by HCPs in recommending and administering were reimbursement problems, a lack of a national vaccination registration system, insufficient collaboration among HCPs, and logistical problems. MSs, GPs and PHSs all mentioned the same three solutions as important strategies to improve vaccination practices, i.e., reimbursement of vaccines, reliable and easily accessible registration of received vaccines, and arrangements for collaboration among the different HCPs that are involved in care. CONCLUSION: The improvement in vaccination practices in ICPs should focus on better collaboration among MSs, GPs, and PHSs, who should know each other's expertise; clear agreement on responsibility; reimbursement for vaccines; and the availability of clear registration of vaccination history.

Correction: Immunogenicity and reactogenicity of SARS-CoV-2 vaccines in people living with HIV in the Netherlands: A nationwide prospective cohort study.

[This corrects the article DOI: 10.1371/journal.pmed.1003979.].

Immunogenicity of an Additional mRNA-1273 SARS-CoV-2 Vaccination in People With HIV With Hyporesponse After Primary Vaccination.

BACKGROUND: The COVIH study is a prospective coronavirus disease 2019 (COVID-19) vaccination study in 1154 people with HIV (PWH), of whom 14% showed reduced antibody levels after primary vaccination. We evaluated whether an additional vaccination boosts immune responses in these hyporesponders. METHODS: The primary end point was the increase in antibodies 28 days after additional mRNA-1273 vaccination. Secondary end points included neutralizing antibodies, S-specific T-cell and B-cell responses, and reactogenicity. RESULTS: Of the 66 participants, 40 previously received 2 doses ChAdOx1-S, 22 received 2 doses BNT162b2, and 4 received a single dose Ad26.COV2.S. The median age was 63 years (interquartile range [IQR], 60-66), 86% were male, and median CD4+ T-cell count was 650/µL (IQR, 423-941). The mean S1-specific antibody level increased from 35 binding antibody units (BAU)/mL (95% confidence interval [CI], 24-46) to 4317 BAU/mL (95% CI, 3275-5360) (P < .0001). Of all participants, 97% showed an adequate response and the 45 antibody-negative participants all seroconverted. A significant increase in the proportion of PWH with ancestral S-specific CD4+ T cells (P = .04) and S-specific B cells (P = .02) was observed. CONCLUSIONS: An additional mRNA-1273 vaccination induced a robust serological response in 97% of PWH with a hyporesponse after primary vaccination. Clinical Trials Registration. EUCTR2021-001054-57-N.

Immunogenicity and reactogenicity of SARS-CoV-2 vaccines in people living with HIV in the Netherlands: A nationwide prospective cohort study.

BACKGROUND: Vaccines can be less immunogenic in people living with HIV (PLWH), but for SARS-CoV-2 vaccinations this is unknown. In this study we set out to investigate, for the vaccines currently approved in the Netherlands, the immunogenicity and reactogenicity of SARS-CoV-2 vaccinations in PLWH. METHODS AND FINDINGS: We conducted a prospective cohort study to examine the immunogenicity of BNT162b2, mRNA-1273, ChAdOx1-S, and Ad26.COV2.S vaccines in adult PLWH without prior COVID-19, and compared to HIV-negative controls. The primary endpoint was the anti-spike SARS-CoV-2 IgG response after mRNA vaccination. Secondary endpoints included the serological response after vector vaccination, anti-SARS-CoV-2 T-cell response, and reactogenicity. Between 14 February and 7 September 2021, 1,154 PLWH (median age 53 [IQR 44-60] years, 85.5% male) and 440 controls (median age 43 [IQR 33-53] years, 28.6% male) were included in the final analysis. Of the PLWH, 884 received BNT162b2, 100 received mRNA-1273, 150 received ChAdOx1-S, and 20 received Ad26.COV2.S. In the group of PLWH, 99% were on antiretroviral therapy, 97.7% were virally suppressed, and the median CD4+ T-cell count was 710 cells/µL (IQR 520-913). Of the controls, 247 received mRNA-1273, 94 received BNT162b2, 26 received ChAdOx1-S, and 73 received Ad26.COV2.S. After mRNA vaccination, geometric mean antibody concentration was 1,418 BAU/mL in PLWH (95% CI 1322-1523), and after adjustment for age, sex, and vaccine type, HIV status remained associated with a decreased response (0.607, 95% CI 0.508-0.725, p < 0.001). All controls receiving an mRNA vaccine had an adequate response, defined as >300 BAU/mL, whilst in PLWH this response rate was 93.6%. In PLWH vaccinated with mRNA-based vaccines, higher antibody responses were predicted by CD4+ T-cell count 250-500 cells/µL (2.845, 95% CI 1.876-4.314, p < 0.001) or >500 cells/µL (2.936, 95% CI 1.961-4.394, p < 0.001), whilst a viral load > 50 copies/mL was associated with a reduced response (0.454, 95% CI 0.286-0.720, p = 0.001). Increased IFN-γ, CD4+ T-cell, and CD8+ T-cell responses were observed after stimulation with SARS-CoV-2 spike peptides in ELISpot and activation-induced marker assays, comparable to controls. Reactogenicity was generally mild, without vaccine-related serious adverse events. Due to the control of vaccine provision by the Dutch National Institute for Public Health and the Environment, there were some differences between vaccine groups in the age, sex, and CD4+ T-cell counts of recipients. CONCLUSIONS: After vaccination with BNT162b2 or mRNA-1273, anti-spike SARS-CoV-2 antibody levels were reduced in PLWH compared to HIV-negative controls. To reach and maintain the same serological responses as HIV-negative controls, additional vaccinations are probably required. TRIAL REGISTRATION: The trial was registered in the Netherlands Trial Register (NL9214). https://www.trialregister.nl/trial/9214.

Diagnosis, treatment and supportive management of chronic lymphocytic leukemia: recommendations of the Dutch HOVON CLL working group.

Management of patients with chronic lymphocytic leukemia (CLL) is changing due to considerable advances in the therapeutic armamentarium, and new therapies will possibly continue to emerge in the near future. Therefore, the CLL working group of the Dutch-Belgium Haemato-Oncology Cooperative Group for Adults in the Netherlands (HOVON) necessitated revising the Dutch CLL guidelines. The current guideline is based on the expert opinion of the HOVON CLL working group members and focusses on well-designed clinical trials taking into account efficacy with special emphasis on toxicity, treatment duration and treatment intensity. This article provides recommendations on diagnosis, treatment strategies in front-line and relapsed setting and provides supportive care measurements during novel-based therapies as well as for infectious CLL-related complications. The recommendations presented here are intended to provide guidance for the management of CLL patients in the Netherlands, and take into account the availability of treatment strategies at the time of this publication.

Immunogenicity of the mRNA-1273 COVID-19 vaccine in adult patients with inborn errors of immunity.

BACKGROUND: Patients with inborn errors of immunity (IEI) are at increased risk of severe coronavirus disease-2019 (COVID-19). Effective vaccination against COVID-19 is therefore of great importance in this group, but little is known about the immunogenicity of COVID-19 vaccines in these patients. OBJECTIVES: We sought to study humoral and cellular immune responses after mRNA-1273 COVID-19 vaccination in adult patients with IEI. METHODS: In a prospective, controlled, multicenter study, 505 patients with IEI (common variable immunodeficiency [CVID], isolated or undefined antibody deficiencies, X-linked agammaglobulinemia, combined B- and T-cell immunodeficiency, phagocyte defects) and 192 controls were included. All participants received 2 doses of the mRNA-1273 COVID-19 vaccine. Levels of severe acute respiratory syndrome coronavirus-2-specific binding antibodies, neutralizing antibodies, and T-cell responses were assessed at baseline, 28 days after first vaccination, and 28 days after second vaccination. RESULTS: Seroconversion rates in patients with clinically mild antibody deficiencies and phagocyte defects were similar to those in healthy controls, but seroconversion rates in patients with more severe IEI, such as CVID and combined B- and T-cell immunodeficiency, were lower. Binding antibody titers correlated well to the presence of neutralizing antibodies. T-cell responses were comparable to those in controls in all IEI cohorts, with the exception of patients with CVID. The presence of noninfectious complications and the use of immunosuppressive drugs in patients with CVID were negatively correlated with the antibody response. CONCLUSIONS: COVID-19 vaccination with mRNA-1273 was immunogenic in mild antibody deficiencies and phagocyte defects and in most patients with combined B- and T-cell immunodeficiency and CVID. Lowest response was detected in patients with X-linked agammaglobulinemia and in patients with CVID with noninfectious complications. The assessment of longevity of immune responses in these vulnerable patient groups will guide decision making for additional vaccinations.

Predictive factors for vaccine failure to guide vaccination in allogeneic hematopoietic stem cell transplant recipients.

Vaccination after hematopoietic stem cell transplantation (HSCT) is essential to protect high-risk patients against potentially lethal infections. Though multiple studies have evaluated vaccine specific responses, no comprehensive analysis of a complete vaccination schedule post-HSCT has been performed and little is known about predictors for vaccine failure. In this context, allogeneic HSCT (alloHSCT) patients were included and vaccinated starting one year post-transplantation. Antibody responses were measured by Multiplex Immuno Assay for pneumococcal (PCV13), meningococcal C, diphtheria, pertussis, tetanus and Haemophilus influenza type b one month after the last vaccination and correlated to clinical and immunological parameters. Vaccine failure was defined as antibody response above vaccine-specific cut-off values for less than four out of six vaccines. Ninety-six patients were included of which 27.1% was found to have vaccine failure. Only 40.6% of all patients responded adequately to all six vaccines. In multivariate analysis, viral reactivation post-HSCT (OR 6.53; P = 0.03), B-cells <135 per mm3 (OR 7.24; P = 0.00) and NK-cells <170 per mm3 (OR 11.06; P = 0.00) were identified as predictors for vaccine failure for vaccination at one year post-alloHSCT. Measurement of antibody responses and an individualized approach for revaccination guided by clinical status and immune reconstitution of B-cells and NK-cells may improve vaccine responses.

Yersinia pseudotuberculosis infection with severe localised inflammation and ulceration of the ileum in a heart transplant patient.

In this case, we present an uncommon gastrointestinal infection in an immunocompromised patient that was solely diagnosed because of close collaboration between treating physicians and microbiologists. The patient is a 42-year-old male who underwent heart transplantation 5 years earlier. He presented with fever, weight loss, diarrhoea and tiredness. Initial investigations could not elucidate the aetiology of his symptoms. The patient was referred to the department of infectious diseases for further evaluation. Serology for Yersinia species was ordered and the result was suggestive for the possibility of a Yersinia species infection. Close collaboration between treating physicians and microbiologists followed and led to additional investigations, which revealed the diagnosis of a Yersinia pseudotuberculosis infection with extensive lesions in the gastrointestinal tract. Treatment with ciprofloxacin resulted in complete resolution of symptoms and healing of the gastrointestinal lesions. In conclusion, this case underlines the need for a multidisciplinary approach to complex patients of which symptoms have yet to be understood.

Barriers to an early switch from intravenous to oral antibiotic therapy in hospitalised patients with CAP.

Do physicians apply an early-switch strategy (from intravenous to oral antibiotics) in clinically stable patients hospitalised with community-acquired pneumonia (CAP)? If not, why not? In a multicentre prospective cohort study, adult patients admitted for i.v. CAP treatment were included. On day 3 of antibiotic treatment, clinical stability was assessed and treating resident physicians were interviewed on their switch strategies. Additionally, treating physicians were interviewed to evaluate their knowledge of and adherence to guideline advice. 149 (92%) out of 162 patients were included and 97 (91%) out of 107 physicians were interviewed. A switch to oral antibiotics was possible in 68 (46%) out of 149 patients on day 3 of treatment but not performed in 27 (40%) out of 68. Patient factors delaying the switch were high CURB-65 (confusion of new onset, urea >7 mmol · L(-1), respiratory rate of ≥ 30 breaths · min(-1), blood pressure <90 mmHg or diastolic blood pressure ≤ 60 mmHg, and age ≥ 65 yrs) score (on admission) (p=0.04) and oxygen treatment (p=0.04), high temperature (p=0.00) and high respiration rate (p=0.04) (day 3). Physicians' barriers to an early switch in clinically stable patients included misconceptions (26 (55%) out of 47), practical considerations (13 (28%) out of 47) and organisational factors (eight (17%) out of 47). Strikingly, 91 (94%) out of 97 interviewed physicians were not aware of guideline advice. The switch from i.v. to oral antibiotics is often unnecessarily delayed in patients hospitalised with CAP due to different types of barriers.

Impact of different empirical antibiotic treatment regimens for community-acquired pneumonia on the emergence of Clostridium difficile.

BACKGROUND: Treatment of community-acquired pneumonia (CAP) with newer fluoroquinolones may contribute to selection for Clostridium difficile. We studied the prevalence of C. difficile carriage and C. difficile infection (CDI) on admission, and nosocomial acquisition rates in patients hospitalized for CAP and compared different empirical treatment strategies. METHODS: In a prospective study among patients admitted for antibiotic treatment of CAP, consecutive stool and skin samples were collected and cultured for C. difficile. Cultured isolates were typed by PCR ribotyping and characterized for toxinogenicity. RESULTS: In total, 20 of 107 (18.7%) patients included carried C. difficile. Various ribotypes were found and 14 (70%) isolates were toxinogenic. On admission, prevalence of C. difficile carriage was 9.4% (n=9), of which 22% also carried C. difficile on the skin and one patient had mild CDI with persistent positive cultures. The overall nosocomial acquisition rate of C. difficile carriage was 11.2%. No nosocomially acquired CDI occurred. Acquisition rates of C. difficile were 11.9% (5/45) in moxifloxacin-, 11.1% (5/47) in ß-lactam- and 9.0% (1/14) in ß-lactam plus macrolide- or fluoroquinolone-treated patients (P=0.84). Risk factors for C. difficile carriage were intravenous antibiotic treatment >7 days [odds ratio (OR) 3.89; 95% confidence interval (CI) 1.30 to 11.79] and hospitalization during the past 3 months (OR 4.08; 95% CI 1.40 to 11.90). CONCLUSIONS: In a non-outbreak setting with a low endemic rate, the prevalence of C. difficile carriage in patients admitted because of CAP is high and nosocomial acquisition rates for C. difficile colonization are 11%. Fluoroquinolones were not associated with increased acquisition rates for C. difficile as compared with other empirical regimens for CAP.

Genetic risk of acute pulmonary infections and sepsis.

The focus of this review is the genetic influence on pneumonia and sepsis. A large number of polymorphisms in a diverse collection of genes have been identified as potential candidates to explain the genetic variability in susceptibility to acute pulmonary infection and its adverse outcomes. Unfortunately, apart from polymorphisms in mannose-binding lectin, CD14 and the IgG2 receptor, there is little consensus on which polymorphisms are truly important. As well as discussing some of the major published findings, this review will focus on the reasons for failure to make more progress. We will also address the issues for future research, particularly the need to address the limitations of past studies, including the grouping of patients with different pathogens, as the relationship between genotype and phenotype may be highly pathogen dependent. Finally, our approach to reporting genetic studies needs to change to minimize the number of publications of spurious findings.

Pneumonia recovery: discrepancies in perspectives of the radiologist, physician and patient.

BACKGROUND: Chest radiographs are often used to diagnose community-acquired pneumonia (CAP), to monitor response to treatment and to ensure complete resolution of pneumonia. However, radiological exams may not reflect the actual clinical condition of the patient. OBJECTIVE: To compare the radiographic resolution of mild to moderately severe CAP to resolution of clinical symptoms as assessed by the physician or rated by the patient. DESIGN: Prospective cohort study. PARTICIPANTS: One hundred nineteen patients admitted because of mild to moderately severe CAP with new pulmonary opacities. MAIN MEASURES: Radiographic resolution and clinical cure of CAP were determined at day 10 and 28. Radiographic resolution was defined as the absence of infection-related abnormalities; clinical cure was rated by the physician and defined by improvement of signs and symptoms. In addition, the CAP score, a patient-based symptom score, was calculated. KEY RESULTS: Radiographic resolution, clinical cure and normalization of the CAP score were observed in 30.8%, 93% and 32% of patients at day 10, and in 68.4%, 88.9% and 41.7% at day 28, respectively. More severe CAP (PSI score >90) was independently associated with delayed radiographic resolution at day 28 (OR 4.7, 95% CI 1.3-16.9). All 12 patients with deterioration of radiographic findings during follow-up had clinical evidence of treatment failure. CONCLUSIONS: In mild to moderately severe CAP, resolution of radiographic abnormalities and resolution of symptoms scored by the patient lag behind clinical cure assessed by physicians. Monitoring a favorable disease process by routine follow-up chest radiographs seems to have no additional value above following a patient's clinical course.

Patterns of resolution of chest radiograph abnormalities in adults hospitalized with severe community-acquired pneumonia.

BACKGROUND: Timing of follow-up chest radiographs for patients with severe community-acquired pneumonia (CAP) is difficult, because little is known about the time to resolution of chest radiograph abnormalities and its correlation with clinical findings. To provide recommendations for short-term, in-hospital chest radiograph follow-up, we studied the rate of resolution of chest radiograph abnormalities in relation to clinical cure, evaluated predictors for delayed resolution, and determined the influence of deterioration of radiographic findings during follow-up on prognosis. METHODS: A total of 288 patients who were hospitalized because of severe CAP were followed up for 28 days in a prospective multicenter study. Clinical data and scores for clinical improvement at day 7 and clinical cure at day 28 were obtained. Chest radiographs were obtained at hospital admission and at days 7 and 28. Resolution and deterioration of chest radiograph findings were determined. RESULTS: At day 7, 57 (25%) of the patients had resolution of chest radiograph abnormalities, whereas 127 (56%) had clinical improvement (mean difference, 31%; 95% confidence interval, 25%-37%). At day 28, 103 (53%) of the patients had resolution of chest radiograph abnormalities, and 152 (78%) had clinical cure (mean difference, 25%; 95% confidence interval, 19%-31%). Delayed resolution of radiograph abnormalities was independently associated with multilobar disease (odds ratio, 2.87; P < or = .01); dullness to percussion at physical examination (odds ratio, 6.94; P < or = .01); high C-reactive protein level, defined as >200 mg/L (odds ratio, 4.24; P < or = .001); and high respiratory rate at admission, defined as >25 breaths/min (odds ratio, 2.42; P < or = .03). There were no significant differences in outcome at day 28 between patients with and patients without deterioration of chest radiograph findings during the follow-up period (P > .09). CONCLUSIONS: Routine short-term follow-up chest radiographs (obtained <28 days after hospital admission) of hospitalized patients with severe CAP seem to provide no additional clinical value.