Neuroimaging of CNS infection in haematological malignancy: important signs and common diagnostic pitfalls.

Patients with haematological malignancy are at increased risk of developing central nervous system (CNS) infections, which are associated with significant morbidity and mortality. Neuroimaging plays a pivotal role in the diagnostic pathway of these patients; however, layers of complexity are added to image interpretation by the heterogeneity in imaging manifestations of haematological malignancies in the CNS, overlapping imaging features of CNS infection, treatment-related parenchymal changes and the presence of intracranial comorbidity. In this article, we review important intracranial findings of CNS infection cases accrued in 1,855 studies over more than a decade at a specialist tertiary centre. We offer schema to identify common and important neuroimaging features, discuss key differential diagnoses and frequent diagnostic pitfalls.

Cause of death among HIV patients in London in 2016.

OBJECTIVES: Since 2013, the London HIV Mortality Review Group has conducted annual reviews of deaths among people with HIV to reduce avoidable mortality. METHODS: All London HIV care Trusts reported data on 2016 patient deaths in 2017. Deaths were submitted using a modified Causes of Death in HIV reporting form and categorized by a specialist HIV pathologist and two HIV clinicians. RESULTS: There were 206 deaths reported; 77% were among men. Median age at death was 56 years. Cause was established for 82% of deaths, with non-AIDS-related malignancies and AIDS-defining illnesses being the most common causes reported. Risk factors in the year before death included: tobacco smoking (37%), excessive alcohol consumption (19%), non-injecting drug use (10%), injecting drug use (7%) and opioid substitution therapy (6%). Thirty-nine per cent of patients had a history of depression, 33% chronic hypertension, 27% dyslipidaemia, 17% coinfection with hepatitis B virus and/or hepatitis C virus and 14% diabetes mellitus. At the time of death, 81% of patients were on antiretroviral therapy (ART), 61% had a CD4 count < 350 cells/µL, and 24% had a viral load ≥ 200 HIV-1 RNA copies/mL. Thirty-six per cent of deaths were unexpected; 61% of expected deaths were in hospital. Two-thirds of expected deaths had a prior end-of-life care discussion documented. CONCLUSIONS: In 2016, most deaths were attributable to non-AIDS-related conditions and the majority of patients were on ART and virally suppressed. However, several potentially preventable deaths were identified and underlying risk factors were common. As London HIV patients are not representative of people with HIV in the UK, a national mortality review is warranted.

18F-Fluorodeoxyglucose positron emission tomography-computed tomography imaging in HIV-infected patients with lymphadenopathy, with or without fever and/or splenomegaly.

We audited whether 18F-Fluorodeoxyglucose positron emission tomography-computed tomography (18FDG PET-CT) imaging could discriminate between different diagnoses in HIV-infected patients presenting with lymphadenopathy, with or without fever and/or splenomegaly. Maximum standardised uptake (SUVmax) values were similar in lymphoma and mycobacterial and fungal infections and were lower but similar in those with human herpesvirus (HHV) 8-associated disease and HIV-associated reactive lymphadenopathy. Nodal 18FDG avidity, with SUVmax ≥10, excluded diagnoses of HHV 8-associated disease and miscellaneous conditions, and HIV-associated reactive lymphadenopathy was additionally excluded in those who had undetectable plasma HIV viral loads. This audit suggests 18FDG PET-CT imaging did not permit discrimination between specific diagnoses but has utility in identifying lymph nodes with increased avidity that could be targeted for biopsy and in ruling out significant pathology.

Burkitt non-Hodgkin lymphoma presenting with mental neuropathy ('numb chin' syndrome) in an HIV-positive patient.

Mental nerve neuropathy is usually due to local trauma or dental causes, but may be a manifestation of malignancy. A patient with virologically controlled human immunodeficiency virus (HIV) infection presented with a 'numb chin' on the background of long-standing night sweats, malaise and weight loss, worsening respiratory symptoms, and lymphadenopathy. Burkitt non-Hodgkin lymphoma was diagnosed from histology of a lymph node. Imaging (magnetic resonance imaging and 18fluorodeoxyglucose [FDG]-positron emission tomography-computed tomography [PET-CT]) showed abnormal intracranial enhancement of the right mandibular nerve and extensive 18FDG-avid lymphadenopathy above and below the diaphragm, focal lesions in the spleen and within the right mandible. The patient received chemotherapy and remains in clinical and radiological remission seven years later. This case highlights the need for clinicians to maintain a high index of suspicion for underlying malignancy when an HIV-infected patient presents with new onset of a 'numb chin'. Additionally, it demonstrates the importance of functional 18FDG-PET-CT and neuroimaging in order to identify site(s) of pathology.

Use of plasma human herpesvirus-8 viral load measurement: evaluation of practice in three UK HIV treatment centres.

A retrospective audit of plasma human herpesvirus-8 (HHV-8) viral load testing was performed in three HIV treatment centres over 24 months. Reasons for testing (360 tests) were: symptoms of systemic inflammatory response syndrome (SIRS) (fever, lymphadenopathy and raised inflammatory markers); monitoring in known HHV-8 pathology other than Kaposi sarcoma (KS); investigation of known/suspected KS, and other/no reason. Of patients with multicentric Castleman disease (MCD), 14/16 (88%) had detectable plasma HHV-8, as did 27/45 (60%) with biopsy proven or clinically confirmed KS, and 6/19 (32%) with lymphoma. Neither of the two patients with MCD and no detectable HHV-8 had SIRS symptoms at the time of the test. There was wide variation between centres in the indications prompting HHV-8 testing, with a more conservative approach resulting in a higher proportion of positive results. Measuring plasma HHV-8 in the absence of SIRS symptoms, established HHV-8 disease monitoring, or confirmed/suspected KS is unlikely to yield detectable HHV-8 thus allowing potential cost savings.

Systematic review of the efficacy and safety of biological therapy for inflammatory conditions in HIV-infected individuals.

Biologic therapies are injectable immunomodulatory agents directed against specific immune cell or chemical targets. They have transformed the lives of HIV-uninfected individuals with severe inflammatory conditions including psoriasis, rheumatoid arthritis, and ulcerative colitis. The perceived increased infection risk associated with these agents means that HIV-infected individuals have not been included in randomised control trials of these drugs. The literature for use of biologic therapies in HIV-infected populations is limited to case reports and case series. There are additional data on use of rituximab, a monoclonal antibody against B lymphocytes, in the setting of HIV-associated haematological malignancy. We performed a systematic review of efficacy and safety of biologic therapy for inflammatory conditions in HIV-infected individuals. Our systematic review identified 37 treatment episodes with six different biologic agents encompassing 10 different inflammatory conditions. Broadly, efficacy of the agents studied was comparable to reports from HIV-uninfected patients. Both infectious and non-infectious sequelae were also comparable with trial data from HIV-uninfected patients. HIV control, even for the minority of individuals not receiving anti-retroviral therapy (ART) at the time of biologic therapy, was not adversely affected. However, detail was limited concerning ART regimens and both immunological and virological parameters of follow-up. Overall available literature is of very low quality and likely subject to publication bias of successful cases. Firm conclusions are not possible regarding the efficacy and safety of biologic agents in HIV-infected individuals; however, there appear to be sufficient data to warrant inclusion of individuals with well-controlled HIV in future trial studies.

Tuberculosis screening in patients with HIV: An audit against UK national guidelines to assess current practice and the effectiveness of an electronic tuberculosis-screening prompt.

A retrospective clinical audit was performed to assess if the British HIV Association 2011 guidelines on routine screening for tuberculosis in HIV are being implemented in a large UK urban clinic, and if a tuberculosis-screening prompt on the electronic patient record for new attendees was effective. Of 4658 patients attending during the inclusion period, 385 were newly diagnosed first-time attendees and routine tuberculosis screening was recommended in 165. Of these, only 6.1% of patients had a completed tuberculosis screening prompt, and 12.1% underwent routine tuberculosis screening. This audit represents the first published UK data on routine screening rates for tuberculosis in HIV and demonstrates low rates of tuberculosis screening despite an electronic screening prompt designed to simplify adherence to the national guideline. Reasons why tuberculosis screening rates were low, and the prompt ineffective, are unclear. A national audit is ongoing, and we await the results to see if our data reflect a lack of routine tuberculosis screening in HIV-infected patients at a national level.

Clinical features, microbiology and surgical outcomes of infective endocarditis: a 13-year study from a UK tertiary cardiothoracic referral centre.

BACKGROUND: Infective endocarditis (IE) causes substantial morbidity and mortality. Patient and pathogen profiles, as well as microbiological and operative strategies, continue to evolve. The impact of these changes requires evaluation to inform optimum management and identify individuals at high risk of early mortality. AIM: Identification of clinical and microbiological features, and surgical outcomes, among patients presenting to a UK tertiary cardiothoracic centre for surgical management of IE between 1998 and 2010. DESIGN: Retrospective observational cohort study. METHODS: Clinical, biochemical, microbiological and echocardiographic data were identified from clinical records. Principal outcomes were all-cause 28-day mortality and duration of post-operative admission. RESULTS: Patients (n = 336) were predominantly male (75.0%); median age 52 years (IQR = 41-67). Most cases involved the aortic (56.0%) or mitral (53.9%) valves. Microbiological diagnoses, obtained in 288 (85.7%) patients, included streptococci (45.2%); staphylococci (34.5%); Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, Kingella (HACEK) organisms (3.0%); and fungi (1.8%); 11.3% had polymicrobial infection. Valve replacement in 308 (91.7%) patients included mechanical prostheses (69.8%), xenografts (24.0%) and homografts (6.2%). Early mortality was 12.2%, but fell progressively during the study (P = 0.02), as did median duration of post-operative admission (33.5 to 10.5 days; P = 0.0003). Multivariable analysis showed previous cardiothoracic surgery (OR = 3.85, P = 0.03), neutrophil count (OR = 2.27, P = 0.05), albumin (OR = 0.94, P = 0.04) and urea (OR = 2.63, P < 0.001) predicted early mortality. CONCLUSIONS: This study demonstrates reduced post-operative early mortality and duration of hospital admission for IE patients over the past 13 years. Biomarkers (previous cardiothoracic surgery, neutrophil count, albumin and urea), predictive of early post-operative mortality, require prospective evaluation to refine algorithms, further improve outcomes and reduce healthcare costs associated with IE.

Sulphadiazine-induced obstructive renal failure complicating treatment of HIV-associated toxoplasmosis.

A patient with newly-diagnosed HIV infection and biopsy-proven cerebral toxoplasmosis was treated with sulphadiazine and pyrimethamine. Despite adequate hydration and daily examination of urine for sulphadiazine crystals obstructive uropathy due to bilateral ureteric stones with hydronephrosis occurred, resulting in rapid onset renal failure. Sulphadiazine was discontinued and clindamycin was substituted. With intravenous fluid hydration and bilateral nephrostomies the urolithiasis resolved. This case serves to remind clinicians of the need for vigilance when treating cerebral toxoplasmosis with sulphadiazine, in order to avoid this potentially serious complication of treatment.

Nodal cryptococcal immune reconstitution inflammatory syndrome masquerading as tuberculosis in an HIV-infected patient.

An African HIV-infected patient presented with widespread necrotic lymphadenopathy five months after starting combination antiretroviral therapy (cART) and was thought to have disseminated tuberculosis in the context of an immune reconstitution inflammatory syndrome (IRIS) on the basis of typical imaging appearances and suggestive appearances from a fine needle aspirate of a nodal mass. The patient deteriorated despite empirical antituberculosis therapy and the correct diagnosis of nodal cryptococcal infection was subsequently established by histological examination of a core biopsy from a lymph node. IRIS should be borne in mind when considering the differential diagnosis in a patient who has recently started cART.

Acquired epidermodysplasia verruciformis due to multiple and unusual HPV infection among vertically-infected, HIV-positive adolescents in Zimbabwe.

BACKGROUND: We have previously described the presentation of epidermodysplasia verruciformis (EV)-like eruptions in almost a quarter of hospitalized adolescents with vertically-acquired human immunodeficiency virus (HIV) infection in Harare, Zimbabwe, a region with a high prevalence of HIV infection. METHODS: We performed a clinical case note review and skin biopsy from affected sites in 4 HIV-infected adolescents with EV-like lesions in Harare. Biopsies were processed for histology and for human papillomavirus (HPV) typing. RESULTS: All patients had long-standing skin lesions that pre-dated the diagnosis of HIV by several years. The histology of skin biopsies from all patients was consistent with EV. In each biopsy, EV-associated ß-HPV type 5 was identified (additionally, type 19 was found in 1 biopsy). Cutaneous wart-associated HPV types 1 and 2 were detected in all biopsies, together with genital lesion-associated HPV types 6, 16, and 52, (as well as ≥3 other genital lesion-associated HPV types). Despite immune reconstitution with combination antiretroviral therapy (cART), there was no improvement in EV-like lesions in any patient. CONCLUSIONS: EV is a disfiguring and potentially stigmatizing condition among this patient group and is difficult to treat; cART appears to have no impact on the progression of skin disease. Among adolescents with longstanding HIV-induced immunosuppression and with high levels of sun exposure, close dermatological surveillance for potential skin malignancy is required.

A prognostic scoring tool for identification of patients at high and low risk of death from HIV-associated Pneumocystis jirovecii pneumonia.

A prognostic scoring tool (PST) was created to aid prediction of outcome from HIV-associated Pneumocystis jirovecii pneumonia (PCP) using data obtained from 577 episodes of PCP among 540 patients presenting to a specialist HIV treatment centre in London, UK. It used risk factors identifiable at/soon after hospitalization, previously identified as being associated with mortality: repeat episode of PCP, patient's age, haemoglobin (Hb) and oxygen partial pressure (PaO(2)) on admission, presence of medical co-morbidity (Comorb) and of pulmonary Kaposi sarcoma (PKS). The derived PST was 25.5+(age in years/10) + 2 (if a repeat episode of PCP) + 3 (if Comorb present) + 4 (if PKS detected) - PaO(2) (kPa) - Hb (g/dL), and produced scores that ranged between 0 and 19. Patients were divided into five groups according to their prognostic score: 0-3.9 = group 1 (0% mortality), 4-7.9 = group 2 (3% mortality), 8-10.9 = group 3 (9% mortality), 11-14.9 = group 4 (29% mortality) and ≥ 15 = group 5 (52% mortality). This PST facilitates rapid identification of patients early in their hospitalization who have mild or severe HIV-associated PCP and who are at high and low risk of in-hospital death from PCP. The PST may aid assessment of severity of illness and in directing treatment strategies, but requires validation in patient cohorts from other health-care institutions.

Can plasma HHV8 viral load be used to differentiate multicentric Castleman disease from Kaposi sarcoma?

We measured plasma human herpesvirus 8 (HHV8) DNA load in consecutive patients presenting with HIV-associated multicentric Castleman disease (MCD) and in contemporaneous patients who had Kaposi sarcoma (KS), lymphoma or other diagnoses. All 11 patients with MCD had detectable plasma HHV8 DNA compared with 18 (72%) of 25 patients with KS, none with lymphoma and one of 38 patients with other diagnoses. Detectable plasma HHV8 DNA levels were higher among MCD patients, median (interquartile range [IQR]) = 43,500 (5200-150,000) copies/mL, when compared with those with KS, median (IQR) = 320 (167-822) copies/mL and those with lymphoma and other diagnoses (one-way analysis of variance; P = 0.0303). Using receiver operating characteristic analysis, a cut-off of >1000 copies HHV8 DNA/mL of plasma helped to discriminate between MCD and other diagnoses, with a specificity of 94.7% and a negative predictive value of 97.3%. The level of HHV8 viraemia, while not diagnostic, may aid discrimination between patients with MCD and those with KS and other systemic illnesses.

Monocyte and macrophage dysfunction as a cause of HIV-1 induced dysfunction of innate immunity.

HIV-1 can establish both long lived and productive infection of macrophages (Mϕ) but circulating monocytes are less permissive to infection. Multiple studies have identified extensive changes to monocyte and Mϕ phenotype, differentiation or function. These include alterations in Toll-like receptor signaling and resultant changes to cytokine responses, specific defects in phagocytosis and microbial killing and modulation of apoptotic responses, all of which may perturb the important role of these cells in innate immunity. Interpretation of contradictory data however, is complicated by the use of different experimental models and many of the reported effects may be an indirect consequence of HIV 1 infection that result from exposure to viral products or from disruption of cellular and cytokine networks in the immune system, rather than the direct consequence of productive HIV 1 infection. Future research should focus on refining experimental models and on elucidating the physiological mechanisms of monocyte/ Mϕ dysfunction during HIV 1 infection.

Seasonal variation in mortality of Pneumocystis jirovecii pneumonia in HIV-infected patients.

A seasonal variation in the presentation of Pneumocystis jirovecii pneumonia (PCP) has been reported and a previous study from this centre noted a seasonal variation in mortality rates. This study examined seasonal influences (including climatic factors) within-host factors (clinical and laboratory-derived variables), the infectious burden of P. jirovecii in bronchoalveolar lavage (BAL) fluid, the presence of dihydropteroate synthase (DHPS) mutations in P. jirovecii, variations in knowledge and skills of junior medical staff, and mortality in 547 episodes of PCP occurring in 494 HIV-infected patients. The overall mortality rate was 13.5%. There was a seasonal variation in mortality: highest in autumn (21.2%) and lowest in spring (9.7%), P = 0.047. After adjustment was made for prognostic factors previously identified as being associated with mortality (increasing patient age, second/third episode of PCP, low haemoglobin, low PaO(2), presence of medical co-morbidity and pulmonary Kaposi sarcoma), there was no seasonal association with mortality, P = 0.249. The quantity of P. jirovecii DNA in BAL fluid showed no evidence of seasonal variation, P = 0.67; DHPS mutations were identified with equal frequency in each season and the mortality rate for February and August (when junior medical staff arrive in new posts) was 16.7%, only slightly greater than for other months (13.0%).

Should we implement 'opt-out' HIV testing for patients with lymphoma?

Patients with HIV are dying due to late diagnosis and physicians are being encouraged to increase HIV testing. The uptake of opt-in HIV screening for 113 lymphoma patients was audited at University College London Hospital. Of the 113 patients, 46 were not tested (41%). Previous research in the antenatal setting suggests that adopting opt-out screening would increase testing rates.

Suppurative iliac lymphadenitis masquerading as appendicitis in an HIV-infected patient.

An HIV-infected man presented with acute onset of right iliac fossa pain. Initial assessment of clinical and computed tomography findings suggested a diagnosis of appendicitis. A macroscopically normal appendix was removed. Further imaging performed postoperatively because of persistent symptoms showed a right iliac fossa mass; culture of pus aspirated from the mass grew group A beta-haemolytic Streptococcus confirming a diagnosis of suppurative iliac lymphadenitis.

Devolving of statin prescribing to general practitioners for HIV-infected patients receiving antiretroviral therapy.

Serious adverse events and medication errors are common in clinical practice and are associated with significant morbidity and mortality. Management of HIV-positive patients is likely to become more complex as people age, developing multiple medical conditions and thus requiring polypharmacy. We undertook a casenote review and interview of patients on antiretroviral therapy (ART) to audit the safety of devolving statin prescribing to general practitioners (GPs). Of 26 patients only 50% had their statin prescribing successfully been devolved to GPs. Many experienced significant difficulties and two of 26 (8%) were switched to simvastatin while receiving a protease inhibitor. We demonstrate that prescribing ART and non-ART medication by different practitioners on different sites can potentially expose patients to serious life-threatening adverse events. We make recommendations to minimize these risks and suggest that care pathways are reviewed to ensure they remain both convenient and user-friendly without compromising patient safety.

Recurrence of cryptococcal meningitis in HIV-infected patients following immune reconstitution.

Two HIV-infected patients had recurrent cryptococcal meningitis (CM) despite treatment with fluconazole and immune reconstitution with combination antiretroviral therapy (CART). Following treatment of CM with fluconazole, lumbar puncture should be performed either after completion of induction treatment for CM or before starting CART, in order to confirm cerebrospinal fluid sterility.