Philippe Blanche

Tenofovir-Related Fanconi Syndrome with Nephrogenic Diabetes Insipidus in a Patient with Acquired Immunodeficiency Syndrome: The Role of Lopinavir-Ritonavir-Didanosine

Tenofovir-related tubular damage, like all other recently reported cases, occurred in patients receiving the protease inhibitor (PI) ritonavir, often with lopinavir. Increased plasma concentrations of didanosine were also observed after the addition of tenofovir. It was suspected that tenofovir with PIs interacted with renal organic anion transporters, leading to nephrotoxic tubular concentrations of tenofovir and systemic accumulation of didanosine. Until there is a better understanding of these interactions, close monitoring is recommended for patients receiving tenofovir, PIs, and didanosine.

Drug-induced Hypersensitivity Syndrome: Clinical and Biologic Disease Patterns in 24 Patients

Drug-induced hypersensitivity syndrome (DIHS), also called drug rash with eosinophilia and systemic symptoms (DRESS), is a severe reaction usually characterized by fever, rash, and multiorgan failure, occurring 1-8 weeks after drug introduction. It is an immune-mediated reaction involving macrophage and T-lymphocyte activation and cytokine release, although no consensus has been reached as to its etiology. The skin, hematopoietic system, and liver are frequently involved. DIHS can mimic severe sepsis, viral infection, adult-onset Still disease (AOSD), or lymphoproliferation. We describe 24 consecutive patients with DIHS who were hospitalized between September 2004 and March 2008. Criteria for inclusion in this observational study were suspected drug reaction, eosinophilia ≥500/&mgr;L and/or atypical lymphocytes, involvement of at least 2 organs (skin being 1 of them), with suggestive chronology and exclusion of other diagnoses. Our cohort of 12 women and 12 men had a median age of 49 years (range, 22-82 yr), and 11 had skin phototype V or VI. Patients with mild or no rash were immunocompromised (7/24)- defined as treatment with prednisone (≥10 mg/d) and another immunosuppressant drug, or human immunodeficiency virus infection. All patients were febrile (>38 °C), 14 had localized or generalized edema, 7 had pharyngitis, 8 had lymphadenopathy, 22 had hepatitis, 4 had nephritis, 2 had noninfectious and nonlithiasic angiocholitis or cholecystitis. Ten patients were hypotensive, 5 of whom had associated laboratory signs and/or imaging findings suggestive of acute myocardial dysfunction. Half of the patients had hemogram abnormalities, including eosinophilia. Nine DIHS patients fulfilled the Fautrel criteria for AOSD diagnosis, including glycosylated ferritin <20% in 4/11, with or without laboratory characteristics of hemophagocytosis. Twenty DIHS episodes occurred during the less sunny months of October to March. We determined 25-hydroxyvitamin D3 (25[OH]D3) levels in 18 patients and found that 9 patients had vitamin D deficiency (<25 nmol/L or <10 &mgr;g/L) and 5 had vitamin D insufficiency (25-50 nmol/L). Moreover, 25(OH)D3 levels were inversely correlated with ferritin values. After culprit-drug withdrawal, outcomes were favorable for all patients, including those with cardiac abnormalities under slow tapering of glucocorticoids. We recommend looking for the frequent but underdiagnosed hypersensitivity myocarditis with noninvasive diagnostic tools, such as N-terminal probrain natriuretic peptide, and promptly withdrawing the culprit drug and starting glucocorticoids. Vitamin D deficiency might be a DIHS risk or severity factor, especially for patients with high skin phototype and during the winter. Because DIHS clinical and laboratory patterns share similarities with AOSD and hemophagocytosis, DIHS should be included in their differential diagnoses. Abbreviations: 25(OH)D3 = 25-hydroxyvitamin D3, AOSD = adult-onset Still disease, CRP = C-reactive protein, DIHS = drug-induced hypersensitivity syndrome, DRESS = drug rash with eosinophilia and systemic symptoms, EBV = Epstein-Barr virus, HHV6 = human herpesvirus 6, HIV = human immunodeficiency virus, IL = interleukin, LDH = lactate dehydrogenase, MRI = magnetic resonance imaging, N = upper limit of normal, NT-proBNP = N-terminal-probrain natriuretic peptide, SMX-TMP = sulfamethoxazole-trimethoprim, Th1-type = T-helper type 1.

Attitude, knowledge and factors associated with influenza and pneumococcal vaccine uptake in a large cohort of patients with secondary immune deficiency.

BACKGROUND Immunocompromised patients are at increased risk for severe influenza and invasive pneumococcal diseases. Population-specific vaccine recommendations are thus warranted. This study aimed to estimate the prevalence and predictors of influenza and pneumococcal vaccine uptake in a large cohort of patients with secondary immune deficiency. METHODS An anonymous online survey was submitted to the members of 11 French associations of immunocompromised patients. The questionnaire included questions concerning underlying disease, care and treatment, flu and pneumococcal vaccine uptake, attitudes and knowledge about vaccination. Factors associated with vaccine uptake were assessed by multivariate logistic regression. RESULTS Among the 10,897 solicited patients, 3653 agreed to participate (33.5%): 75% were female, 20% aged 65+, 79% were followed for an autoimmune disease, 13% were solid organ recipients or waiting for transplantation and 8% were treated for hematological malignancies. 3109 (85%) participants were treated with immunosuppressive therapy. Self-reported vaccine uptake was 59% (95%CI [57-60]) against seasonal influenza and 49% (95%CI [47-50]) against pneumococcal diseases. Better knowledge of and favorable attitudes toward vaccination were positively associated with vaccine uptake while being treated with a biological therapy was negatively associated. CONCLUSION Despite specific recommendations regarding immunocompromised patients, influenza and pneumococcal vaccination rates do not reach recommended levels. Targeted information campaigns on vaccination toward these populations should be implemented to improve vaccine coverage and thus reduce the burden of infections.

Patients with systemic inflammatory and autoimmune diseases are at risk of vaccine-preventable illnesses

OBJECTIVE To evaluate vaccine coverage and humoral immunity to tetanus, diphtheria and poliomyelitis in adults followed for systemic inflammatory and/or autoimmune diseases (SIADs). METHODS A cross-sectional study was conducted between June and August 2006 in a monocentric cohort of adults with SIAD. A standardized questionnaire was administered to collect medical, therapeutic and vaccine coverage data. Blood samples were collected in order to measure antibody titres against diphtheria, tetanus and poliomyelitis (DTP). RESULTS One hundred and eighty-six patients, 32% males, mean (s.d.) age 51 (16) years, 79% receiving CSs and/or immunosuppressants, were included. The vaccine coverage was 29% for diphtheria, 48% for tetanus and 33% for poliomyelitis. The percentages of patients with no humoral immunity against DTP were 44, 21 and 12%, respectively, decreasing to 37.5, 10 and 0%, respectively, for those who had received a vaccine booster in the last 10 years. In a multivariate analysis, age and CS treatment were associated with the absence of humoral immunity against diphtheria and female sex, CD4(+) T cell <200/mm(3) and an absence of tetanus vaccine booster in the last 10 years with the absence of humoral immunity to tetanus. CONCLUSION Vaccine coverage against tetanus, diphtheria and poliomyelitis is low in patients with SIAD despite the risk in this population of severe infection, especially when receiving immunosuppressants. A significant proportion of them had no humoral immunity against diphtheria or tetanus. Specific immunization schedules need to be optimized in these patients.

Pseudouveitis: a clue to the diagnosis of primary central nervous system lymphoma in immunocompetent patients.

Abstract: Primary oculocerebral non-Hodgkin lymphoma (NHL) of the immunocompetent patient is associated with significant morbidity and mortality, but early diagnosis and follow-up may improve prognosis. The eye, anatomically and embryologically part of the central nervous system (CNS), can be the primary site of the lymphomatous process. In patients with symptoms of atypical uveitis, vitrectomy can be of great help for early diagnosis of primary central nervous system lymphoma. We retrospectively reviewed the diagnostic features, treatment, and evolution of 10 patients with primary central nervous system lymphoma who presented with symptoms of pseudouveitis. The patients complained of chronic vitreal opacities, increasing with time. These symptoms contrasted with the absence of the usual signs of inflammation of the anterior segment or of the retina, which characterize true uveitis. Vitrectomy was proposed after lumbar puncture and cerebral magnetic resonance imaging. Six vitrectomies were carried out, 3 patients had a stereotaxic biopsy, and 1 patient had a cardiac biopsy. A pathologic diagnosis of large B-cell lymphoma was made on vitrectomy specimens in 100% of the patients who had this procedure. The mean time from onset of ocular symptoms to diagnosis was 24 months. This series was characterized by a rare systemic dissemination of the NHL (negative in 80%), a strong preponderance of B-cell NHL, and the absence of association with Epstein-Barr virus (EBV) among these immunocompetent patients. To our knowledge, this series includes the only reported case of oculocardiac lymphoma. Meningeal dissemination appeared to be associated with a poor prognosis. Neurologic complications of treatment combining radiotherapy and methotrexate were significant among patients older than 60 years of age. The current study suggests that primary central nervous system lymphoma should be suspected in patients with pseudouveitis, and that the diagnosis can be established quickly and without side effects by vitrectomy. These patients should be followed carefully in order to detect meningeal dissemination. Abbreviations: AIDS = acquired immunodeficiency syndrome, CNS = central nervous system, EBV = Epstein-Barr virus, HIV = human immunodeficiency virus, LDH = lactate dehydrogenase, MRI = magnetic resonance imaging, NHL = non-Hodgkin lymphoma, PCNSL = primary central nervous system lymphoma.

Maladie de Whipple diagnostiquée primitivement sarcoïdose

Resume Introduction La maladie de Whipple est une affection multisystemique liee au bacille non cultivable Tropheryma whipplei. Nous rapportons un cas trompeur de “sarcoidose” devenant “maladie de Whipple” avec endocardite. Observation Le diagnostic de sarcoidose a ete porte chez un patient de 61 ans sur des donnees cliniques, radiographiques, endoscopiques et histologiques. La reponse initiale a la corticotherapie a ete bonne mais le patient restait dependant de 35 mg/j de prednisone. L’apparition d’un syndrome inflammatoire clinique et biologique majeur a fait douter du diagnostic. Le diagnostic d’une endocardite a hemocultures negatives, sans possibilite de “decapitation” par antibiotherapie prealable a ete pose, avec mise en evidence echographique d’une masse arrondie de 1 cm de diametre appendue a la grande valve mitrale avec insuffisance mitrale grade 2. Les autres causes d’endocardites a hemocultures negatives ont ete ecartees. La maladie de Whipple a ete envisagee et le diagnostic retenu sur la positivite d’une biopsie duodenale en PCR pour Tropheryma whipplei, l’histologie restant negative. Un traitement par gentamycine et amoxicilline en intra-veineux a ete poursuivi 3 semaines, remplace par cotrimoxazole oral. L’echographie transoesophagienne de controle ne montrait plus la masse mitrale. Le patient, sous cotrimoxazole, sevre depuis 13 mois de prednisone, reste asymptomatique. Conclusion Ce cas illustre les difficultes de diagnostic differentiel entre sarcoidose et maladie de Whipple, mais aussi l’importance de cette distinction.

Treatment of central pontine myelinolysis with thyrotropin-releasing hormone.

INTRODUCTION Central pontine myelinolysis (CPM), demyelination of the brain stem, is a brain injury apparently due to osmotic forces. There is no consensus for its treatment. CASE We describe here a case of CPM that occurred in a young patient after correction of hyponatremia, its treatment by intravenous thyrotropin-releasing hormone, and its outcome. DISCUSSION Although very few instances of thyrotropin-releasing hormone treatment for CPM have been described, it appears to be effective and well tolerated. Studies are needed to assess its real efficacy.

Pneumococcal and influenza vaccination rates in patients treated with corticosteroids and/or immunosuppressive therapies for systemic autoimmune diseases: A cross-sectional study.

Joint Bone Spine - In Press.Proof corrected by the author Available online since jeudi 23 juin 2016

Staphylococcus aureus osteo-articular infection: usefulness of the determination of daptomycin serum concentration to explain a treatment failure.

We report two cases of treatment failure in patients with osteoarticular infection associated with Staphylococcus aureus bacteremia and receiving daptomycin. Using a published population-pharmacokinetic model and daptomycin blood level in these patients, area under the curve (AUC) was calculated and compared to the pharmacological target. For the first patient, treated with 6 mg/kg every 48 hours due to acute renal failure and then every 24 hours, the AUC was 820 mg×h×L-1, with a minimal concentration of 23.5 mg/L confirming the right dose adjustment and the absence of underdosing. The methicillin-resistant Staphylococcus aureus (MRSA) strain was still susceptible to daptomycin, but it was not sufficient to observe a favorable outcome. For the second patient, treated with 10 mg/kg/d, the steady state residual concentration was 10.4 mg/L, and the calculated AUC value was 550 mg×h×L-1. AUC/MIC values evolved during treatment to be under the cut-off for bactericidal effects (> 800 hours), and the Staphylococcus aureus (SA) strain became daptomycin resistant. This study highlights the inter-individual pharmacokinetic variation leading sometimes to drug underdosing. Drug monitoring should be encouraged in order to avoid treatment failure.

Ga-67 in Castleman's disease.

Castlemans disease (CD) is a lymphoproliferative disorder with ubiquitous localizations (in the neck, mediastinum, axilla, shoulder, mesentery, pancreas, portacaval space, adrenal gland, retroperitoneum, and pelvis). Localized or multicentric forms and three histologic types (hyaline vascular, plasma cell, or mixed variant) are described. The localized form, usually in the mediastinum, is benign and had a hyaline vascular type in 80%. Treatment includes the complete surgical removal of involved lymph nodes. The multicentric form is generally a plasma cell type that affects patients primarily in the fifth decade of live or those who are positive for the human immunodeficiency virus or human herpes virus type 8 and requires treatment with corticosteroids, chemotherapy, or radiotherapy when organs are involved. Three cases showing the role of Ga-67 in CD are reported.