Analysis of scoring systems for primary immunodeficiency diagnosis in adult immunology clinics.

Failure to spot the signs of primary immunodeficiency (PID) often results in delayed diagnosis. Scoring systems to identify PID exist, such as the immunodeficiency disease-related (IDR) score. This research aims to analyse and improve the diagnostic sensitivity and specificity of the IDR scoring system in a small preselected group of adult patients referred to immunology with clinical suspicion of a PID. Records of all patients presenting for the first time to an adult immunology clinic in 2018 at Addenbrooke's Hospital, Cambridge, were scored using the unmodified IDR score and modified versions of it. Included records were searched for a subsequent diagnosis of PID, and the diagnostic sensitivity and specificity of the scoring systems were analysed. Of 400 patients, 213 were excluded: 141 due to secondary immunodeficiency, 69 due to no clinical suspicion of a PID, and hence no investigation for PID, and three due to ongoing diagnostic investigations. Of 187 included patients, 71 were found to have a clinically significant PID. The unmodified IDR score was useful in discriminating between those with and without PID. Modification of the scoring system with seven additional criteria improved the sensitivity and specificity for PID diagnosis to the greatest extent. A modified IDR score with seven additional criteria validated in adults referred to immunology with suspicion of a PID could be used clinically to aid PID diagnosis, although further validation in different patient cohorts is required before it is used in other contexts.

Primary pneumococcal peritonitis can be the first presentation of a familial complement factor I deficiency1.

Primary pneumococcal peritonitis is a rare infection that has been described in women but has not been previously linked with immunodeficiency. The complement system plays a central role in immune defence against Streptococcus pneumoniae and, in order to evade complement attack, pneumococci have evolved a large number of mechanisms that limit complement-mediated opsonization and subsequent phagocytosis. We investigated an apparently immunocompetent woman with primary pneumococcal peritonitis and identified a family with deficiency for complement factor I. Primary pneumococcal peritonitis should be considered a possible primary immunodeficiency presentation.

Neutralising antibodies in Spike mediated SARS-CoV-2 adaptation.

SARS-CoV-2 Spike protein is critical for virus infection via engagement of ACE2, and amino acid variation in Spike is increasingly appreciated. Given both vaccines and therapeutics are designed around Wuhan-1 Spike, this raises the theoretical possibility of virus escape, particularly in immunocompromised individuals where prolonged viral replication occurs. Here we report chronic SARS-CoV-2 with reduced sensitivity to neutralising antibodies in an immune suppressed individual treated with convalescent plasma, generating whole genome ultradeep sequences by both short and long read technologies over 23 time points spanning 101 days. Although little change was observed in the overall viral population structure following two courses of remdesivir over the first 57 days, N501Y in Spike was transiently detected at day 55 and V157L in RdRp emerged. However, following convalescent plasma we observed large, dynamic virus population shifts, with the emergence of a dominant viral strain bearing D796H in S2 and ΔH69/ΔV70 in the S1 N-terminal domain NTD of the Spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype diminished in frequency, before returning during a final, unsuccessful course of convalescent plasma. In vitro, the Spike escape double mutant bearing ΔH69/ΔV70 and D796H conferred decreased sensitivity to convalescent plasma, whilst maintaining infectivity similar to wild type. D796H appeared to be the main contributor to decreased susceptibility, but incurred an infectivity defect. The ΔH69/ΔV70 single mutant had two-fold higher infectivity compared to wild type and appeared to compensate for the reduced infectivity of D796H. Consistent with the observed mutations being outside the RBD, monoclonal antibodies targeting the RBD were not impacted by either or both mutations, but a non RBD binding monoclonal antibody was less potent against ΔH69/ΔV70 and the double mutant. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy associated with emergence of viral variants with reduced susceptibility to neutralising antibodies.

Chronic norovirus infection and common variable immunodeficiency.

Chronic infection with norovirus is emerging as a significant risk for patients with immunodeficiency - either primary or secondary to therapeutic immunosuppression. Patients with primary immunodeficiency present a range of pathological responses to norovirus infection. Asymptomatic infections occur and differentiating viral carriage or prolonged viral shedding after self-limiting infection from infection causing protracted diarrhoea can be challenging, due to relatively mild pathological changes that may mimic other causes of diarrhoea in such patients (for instance pathogenic bacteria or parasites or graft-versus-host disease). However, a subset of patients with common variable immunodeficiency (CVID) experience a severe norovirus-associated enteropathy leading to intestinal villous atrophy and malabsorption. Symptomatic infection of up to 8 years has been demonstrated with clinical and histological recovery on viral clearance. Although oral immunoglobulins and nitazoxanide have been used to treat noroviral infections associated with immunosuppression, ribavirin is the only agent to date that has been linked to viral clearance in the Noroviral enteropathy associated with CVID.

Cytomegalovirus Infection and Rates of Antiviral Resistance Following Intestinal and Multivisceral Transplantation.

BACKGROUND: Cytomegalovirus (CMV) disease is a common and clinically significant complication following intestinal or multivisceral transplantation. CMV disease is more common in cases of serologic mismatch between donor and recipient. Though in some cases it may be asymptomatic, in the immunosuppressed population it often manifests with evidence of systemic infection or end-organ disease. METHODS: We conducted a retrospective review of all patients undergoing intestinal or multivisceral transplantation over 8 years at our institution. RESULTS: Forty-eight transplantations were performed, with 40% of the patients (19/48) having ≥1 episode of CMV viremia, which rose to 90% in the "donor-positive, recipient-negative" (DPRN) serologic mismatch group. The median time to 1st episode following transplantation was 22.3 weeks (range, 1-78) and median duration of each episode was 4.9 weeks (range, 1.6-37.4). Six of the 19 viremic patients (31.6%) developed virologic resistance with 4 of these occurring in the DPRN group. Four of the 6 patients with drug-resistant CMV died with CMV viremia. All patients with drug resistance acquired ganciclovir resistance; these patients were more challenging to manage with second-line toxicity-limited treatments, including foscarnet, cidofovir, and leflunomide. CMV immunoglobulin has been used and we briefly discuss the use of CMV-specific adoptive T-lymphocyte transfer in the management of 1 case. CONCLUSIONS: Post-transplantation CMV disease continues to be challenging to manage, and there is little consensus on optimal management strategies in this patient group, with a significant requirement for novel therapies; these may be pharmacologic or cell based. Extensive multidisciplinary discussion is important for most cases, but particularly for those patients who acquire virologic resistance.

Infectious diseases among travellers and migrants in Europe, EuroTravNet 2010.

To investigate trends in travel-associated morbidity with particular emphasis on emerging infections with the potential for introduction into Europe, diagnoses of 7,408 returning travellers presenting to 16 EuroTravNet sites in 2010 were compared with 2008 and 2009. A significant increase in reported Plasmodium falciparum malaria (n=361 (6% of all travel-related morbidity) vs. n=254 (4%) and 260 (5%); p<0.001), P. vivax malaria (n=51 (1%) vs. n=31 (0.5%) and 38 (1%); p=0.027) and dengue fever (n=299 (5%) vs. n=127 (2%) and 127 (2%); p<0.001) was observed. Giardia lamblia was identified in 16% of patients with acute diarrhoea, with no significant annual variation. The proportion of acute diarrhoea due to Campylobacter increased from 7% in 2008 to 12% in 2010 (p=0.001). We recorded 121 patients with pulmonary tuberculosis in 2010, a threefold increase in the proportionate morbidity from 2008 to 2010. In 2010, 60 (0.8%) cases of chronic Chagas disease, 151 (2%) cases of schistosomiasis and 112 (2%) cases of cutaneous larva migrans were reported. Illness patterns in sentinel travellers, captured by EuroTravnet, continue to highlight the potential role of travellers in the emergence of infectious diseases of public health concern in Europe and the relevance of offering medical travel advice and enforcing specific and adequate prophylaxis.

Risk factors for mortality in Clostridium difficile infection in the general hospital population: a systematic review.

BACKGROUND: Clostridium difficile infection (CDI) is one of the most important healthcare-associated infections, causing considerable mortality. Numerous severity scores have been proposed to identify patients with CDI at risk of mortality, but a systematic review of the evidence upon which these are based has never been published. Such a review could permit future development of scores that better predict mortality. AIM: A systematic review of the published literature investigating clinically useful risk markers for mortality in CDI. METHODS: We searched MEDLINE 1950 to present, Web of Science with conference proceedings 1899 to present and BIOSIS Citation Index 1969 to present using PubMed and Web of Knowledge. Potential risk markers that had been evaluated by at least four studies were extracted. FINDINGS: Twenty-six studies, of 1617 initially identified, met inclusion criteria. The majority were retrospective cohort studies, mostly based in the USA. Older age, higher white blood cell count (WBC), higher creatinine level, lower albumin levels and, to a lesser extent, corticosteroid use were most frequently associated with mortality. Presence of fever, haemoglobin/haematocrit level, diarrhoea severity, presence of renal disease, diabetes, cancer, or nasogastric tube use did not appear to be associated with mortality. CONCLUSION: Our results support the use of age, WBC, serum creatinine, serum albumin level and possibly pre-existing corticosteroid use as potentially useful risk markers for mortality in CDI. Our results do not support the use of fever, haemoglobin/haematocrit, diarrhoea severity and several comorbidities as useful risk markers, raising questions about their inclusion in CDI severity scores.

The association between prior infection with five serotypes of Coxsackievirus B and incident type 2 diabetes mellitus in the EPIC-Norfolk study.

AIMS/HYPOTHESIS: Infections with Coxsackieviruses have been linked to beta cell dysfunction. Given the importance of beta cell dysfunction in the aetiology of type 2 diabetes, we hypothesised that prior infection with Coxsackieviruses B would increase the risk of type 2 diabetes. The aims of the study were to estimate cross-sectional associations between potential predictors of previous infection and seropositivity for Coxsackievirus B serotypes 1-5 (CBV1-5), and then to assess the association between seropositivity and incident type 2 diabetes. METHODS: Using a case-cohort design nested within the European Prospective Investigation of Cancer (EPIC)-Norfolk study, we ascertained n = 603 cases of incident type 2 diabetes. From within the entire cohort we identified a random subcohort of n = 835, without diabetes at baseline. The presence of Coxsackievirus B neutralising antibodies against serotypes 1-5 was assessed using a plaque neutralisation assay. Weighted Cox regression was used to examine the association between presence of antibodies to CBV1-5 and the development of type 2 diabetes. RESULTS: Seropositivity in the subcohort for CBV1-5 was 50%, 67%, 66%, 75% and 45%, respectively. After adjustment for age, sex, BMI, physical activity and family history of diabetes, the presence of antibodies against CBV1-5 was not associated with incident type 2 diabetes, over a mean follow-up of 5.7 years (HR [95% CIs] 0.94 [0.72,1.25], 0.92 [0.68, 1.23], 1.33 [0.98,1.81], 1.16 [0.83,1.61] and 1.03 [0.77,1.39] for CBV1-5, respectively). CONCLUSIONS/INTERPRETATION: The presence of antibodies against any of five serotypes of Coxsackievirus B was not associated with incident type 2 diabetes.

Travel-related imported infections in Europe, EuroTravNet 2009.

The aim of this study was to investigate travel-associated morbidity in European travellers in 2009 in comparison with 2008, with a particular emphasis on emerging infectious diseases with the potential for introduction into Europe. Diagnoses with demographic, clinical and travel-related predictors of disease from ill returning travelers presenting to 12 core EuroTravNet sites from January to December 2009 were analysed. A total of 6392 patients were seen at EuroTravNet core sites in 2009, as compared with 6957 in 2008. As compared with 2008, there was a marked increase in the number of travellers exposed in North America and western Europe. Respiratory illnesses, in particular pandemic A(H1N1) influenza, influenza-like syndromes, and tuberculosis, were also observed more frequently. A significant increase in reported dengue cases in 2009 as compared with 2008 was observed (n = 172, 2.7% vs. n = 131, 1.90%) (p 0.002). The numbers of malaria and chikungunya cases were also increasing, although not significantly. Two deaths were recorded: visceral leishmaniasis and sepsis in a Sudanese migrant, and Acinetobacter sp. pneumonia in a patient who had visited Spain. This is the most comprehensive study of travel-related illness in Europe in 2009 as compared with 2008. A significant increase in travel-related respiratory and vector-borne infections was observed, highlighting the potential risk for introduction of these diseases into Europe, where competent vectors are present. The number of traveller deaths is probably underestimated. The possible role of the travellers in the emergence of infectious diseases of public health concern is highlighted.

Clinical, molecular and epidemiological description of a cluster of community-associated methicillin-resistant Staphylococcus aureus isolates from injecting drug users with bacteraemia.

Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is an increasing problem, predominantly in previously healthy individuals including notable risk groups such as the homeless, those who play close-contact sports, military personnel, men who have sex with men (MSM) and injecting drug users (IDUs). Over a 5-month period, four IDUs were admitted to Addenbrooke's Hospital, Cambridge, UK, with MRSA bacteraemia. All four patients presented with complex clinical features, with more than one focus of infection, and were linked epidemiologically. The atypical antibiogram of the MRSA isolates (ciprofloxacin-susceptible) prompted further characterization, both phenotypically (antibiotic resistance typing; phage typing) and genotypically (detection of toxin genes by PCR; pulsed-field gel electrophoresis (PFGE); Staphylococcal chromosome cassette (SCC) mec typing; multi-locus sequence typing (MLST)). All four isolates had similar antibiograms, were Panton-Valentine Leucocidin (PVL) toxin gene-negative, harboured SCCmec type IV and were closely related as shown by phage typing and PFGE. These isolates were representatives of a community-associated clone, ST1-MRSA-IV, known to be circulating in IDUs in the UK since 2001. This paper presents a detailed description of the clinical, microbiological and epidemiological features of a series of CA-MRSA bacteraemias in IDUs in the UK.