Muriel Alvarez

Evolution of Human Immunodeficiency Virus Type 1 Populations after Resumption of Therapy following Treatment Interruption and Shift in Resistance Genotype

Conventional genotyping of human immunodeficiency virus type 1 often reveals a shift from a drug-resistant genotype to a wild-type genotype after treatment interruption. A real-time polymerase chain reaction-based technique was used to detect minority resistant populations in 13 patients who showed genotype reversion after interruption of treatment for 3 months. Sixty-two percent of patients in whom the V82A and L90M protease mutations were no longer detectable by conventional genotyping still harbored minority resistant variants, in proportions ranging from 0.1% to 21%. None of the patients with these minority resistant variants who received a protease-inhibitor regimen on resumption of therapy had a response to treatment. However, population sequencing and clonal analysis of plasma samples obtained 1-2 months after resumption of treatment revealed the presence of wild-type virus during the initial decline in plasma virus load, which indicates that minority resistant variants were not rapidly selected.

Intermittent human immunodeficiency type 1 virus (HIV-1) shedding in semen and efficiency of sperm processing despite high seminal HIV-1 RNA levels

To study seminal excretion of human immunodeficiency virus type 1 (HIV-1) during 4 years of follow-up in an HIV-1-infected patient, the relationship between high viral excretion and inflammatory status of semen, and the efficiency of sperm processing methods in obtaining spermatozoa with undetectable RNA and proviral DNA levels. Case report. University hospital and research group on human fertility. One HIV-1-infected patient.Paired blood and semen samples were obtained during 4 years of follow-up.CD4 cell count; blood and seminal plasma viral load; and HIV-1 RNA and proviral DNA in different cell fractions obtained during sperm processing, as measured by the density gradient method and the swim-up method; sperm parameters; and polymorphonuclear granulocyte count. Shedding of HIV-1 in semen was intermittent. The highest seminal viral loads were associated with a markedly increased polymorphonuclear granulocyte count, which reflects inflammation of the genital tract. Spermatozoa with undetectable levels of HIV-1 RNA or DNA were obtained regardless of the viral load in semen. In an HIV-1-infected man with intermittent seminal viral excretion, sperm processing was effective in obtaining spermatozoa without detectable HIV-1 genomes.

Toxoplasmic encephalitis IRIS in HIV-infected patients: a case series and review of the literature

Background Toxoplasmic encephalitis associated with immune reconstitution inflammatory syndrome (TE-IRIS) is rarely described. Methods To identify TE-IRIS cases, the authors performed a retrospective study of all HIV-infected patients diagnosed as having TE in our unit between January 2000 and June 2009, and a review of published cases. Results Three patients out of 65 toxoplasmic encephalitis (TE) cases, together with six from the literature, fulfilled the unmasking TE-IRIS definition. None fulfilled the paradoxical TE-IRIS definition. TE occurred within a median time of 48.5 days (IQ25–75 21–56) after starting antiretroviral therapy. Cases did not have distinctive clinical or neuroimaging features from TE occurring without immune reconstitution. However: (1) cases occurred at a median CD4 lymphocytes count of 222/μl (IQ25–75 160–280); (2) TE occurred in five patients who were supposed to take an effective chemoprophylaxis; (3) two patients had a brain biopsy showing an intense angiocentric inflammatory infiltrating with predominantly CD8 lymphocytes; (4) in one patient, the abnormal length of evolution under treatment might be due to the heightened immune response. Conclusion Although rare, unmasking TE-IRIS exists and might occur despite effective prophylaxis and an unusually high CD4 lymphocyte count. Immune reconstitution inflammatory syndrome does not modify TE diagnosis and treatment but might extend its clinical course.

Acute Plasmodium falciparum Malaria Following Splenectomy for Suspected Lymphoma in 2 Patients

Two black African immigrants, with no history of recent travel outside France, received a diagnosis of a malignant lymphoproliferative disorder and splenomegaly, and they subsequently underwent splenectomy. A few weeks after surgery, both patients experienced an acute episode of Plasmodium falciparum malaria, so the initial diagnosis was corrected retrospectively and changed to hyperreactive malarial splenomegaly. These cases illustrate the difficulty in distinguishing hyperreactive malarial splenomegaly from malignant lymphoproliferative disorders and therefore underline the role of the spleen in the immune systems defense against malaria.

Hemophagocytic syndrome in patients with acute myeloid leukemia undergoing intensive chemotherapy

Hemophagocytic lymphohistiocytosis is a condition of immune dysregulation characterized by severe organ damage induced by a hyperinflammatory response and uncontrolled T-cell and macrophage activation. Secondary hemophagocytic lymphohistiocytosis typically occurs in association with severe infections or malignancies. Patients with acute myeloid leukemia may be prone to develop hemophagocytic lymphohistiocytosis because of an impaired immune response and a high susceptibility to severe infections. In a series of 343 patients treated by intensive chemotherapy over a 5-year period in our center, we identified 32 patients (9.3%) with fever, very high ferritin levels, and marrow hemophagocytosis (i.e. patients with hemophagocytic lymphohistiocytosis). Compared to patients without hemophagocytic lymphohistiocytosis, these 32 patients had hepatomegaly, pulmonary or neurological symptoms, liver abnormalities, lower platelet count and higher levels of C-reactive protein as well as prolonged pancytopenia. A microbial etiology for the hemophagocytosis was documented in 24 patients: 14 bacterial infections, 9 Herpesviridae infections and 11 fungal infections. The treatment of hemophagocytic lymphohistiocytosis consisted of corticosteroids and/or intravenous immunoglobulins along with adapted antimicrobial therapy. Patients with hemophagocytic lymphohistiocytosis had a median overall survival of 14.9 months, which was significantly shorter than that of patients without hemophagocytic lymphohistiocytosis (22.1 months) (P=0.0016). Hemophagocytic lymphohistiocytosis was significantly associated with a higher rate of induction failure, mainly due to deaths in aplasia. Hemophagocytic lymphohistiocytosis can be diagnosed in up to 10% of patients with acute myeloid leukemia undergoing intensive chemotherapy and is associated with early mortality. Fever, very high ferritin levels and marrow hemophagocytosis represent the cornerstone of the diagnosis. Further biological studies are needed to better characterize and recognize this syndrome in patients with acute myeloid leukemia.

Prophylaxis of invasive aspergillosis with voriconazole or caspofungin during building work in patients with acute leukemia

Background Invasive aspergillosis is a common life-threatening infection in patients with acute leukemia. The presence of building work near to hospital wards in which these patients are cared for is an important risk factor for the development of invasive aspergillosis. This study assessed the impact of voriconazole or caspofungin prophylaxis in patients undergoing induction chemotherapy for acute leukemia in a hematology unit exposed to building work. Design and Methods This retrospective cohort study was carried out between June 2003 and January 2006 during which building work exposed patients to a persistently increased risk of invasive aspergillosis. This study compared the cumulative incidence of invasive aspergillosis in patients who did or did not receive primary antifungal prophylaxis. The diagnosis of invasive aspergillosis was based on the European Organization for Research and Treatment of Cancer/Mycosis Study Group criteria. Results Two-hundred and fifty-seven patients (213 with acute myeloid leukemia, 44 with acute lymphocytic leukemia) were included. The mean age of the patients was 54 years and the mean duration of their neutropenia was 21 days. Eighty-eight received antifungal prophylaxis, most with voriconazole (n=74). The characteristics of the patients who did or did not receive prophylaxis were similar except that pulmonary antecedents (chronic bronchopulmonary disorders or active tobacco use) were more frequent in the prophylaxis group. Invasive aspergillosis was diagnosed in 21 patients (12%) in the non-prophylaxis group and four (4.5%) in the prophylaxis group (P=0.04). Pulmonary antecedents, neutropenia at diagnosis and acute myeloid leukemia with high-risk cytogenetics were positively correlated with invasive aspergillosis, whereas primary prophylaxis was negatively correlated. Survival was similar in both groups. No case of zygomycosis was observed. The 3-month mortality rate was 28% in patients with invasive aspergillosis. Conclusions This study suggests that antifungal prophylaxis with voriconazole could be useful in acute leukemia patients undergoing first remission-induction chemotherapy in settings in which there is a high-risk of invasive aspergillosis.

Plasmodium falciparum Isolates with Increased pfmdr1 Copy Number Circulate in West Africa

ABSTRACT Amplification of pfmdr1 in Plasmodium falciparum is linked to resistance to aryl-amino-alcohols and in reduced susceptibility to artemisinins. We demonstrate here that duplicated pfmdr1 genotypes circulate in West Africa. The monitoring of this prevalence in Africa appears essential for determining the antimalarial policy and to maintain the efficiency of artemisinin-based combination therapy (ACT) for as long as possible.

pfmdr1 Amplification Associated with Clinical Resistance to Mefloquine in West Africa: Implications for Efficacy of Artemisinin Combination Therapies

ABSTRACT We describe here a clinical failure in the treatment with mefloquine of acute falciparum malaria contracted in Africa and associated with in vitro mefloquine resistance and pfmdr1 copy number amplification. This case raises the question of the presence and the evolution of this genotype in Africa, which is also known to alter the susceptibility to artemisinin combination therapy (ACT).

Alveolar and Blood T Lymphocyte Profiles in Pneumocystis jirovecii–Positive Patients: Effects of HIV Status

BACKGROUND There are substantial differences in the risk evaluation, clinical presentation, and outcome of Pneumocystis pneumonia between human immunodeficiency virus (HIV)-positive and HIV-negative immunocompromised patients. To compare the host immune defenses against Pneumocystis jirovecii, the blood and alveolar lymphocyte profile was explored in these 2 populations. METHODS The total, CD3(+), CD4(+), and CD8(+) T-lymphocyte counts were measured in the blood and alveoli of immunocompromised patients with a P. jirovecii DNA detected in their bronchoalveolar lavage samples, according to their HIV status. RESULTS In blood and alveoli, the CD4(+) and CD8(+) T-lymphocyte counts were higher and lower, respectively, in the HIV-negative group. The threshold for initiating prophylaxis in HIV-positive persons, 200 CD4(+) T cells/μL, was not pertinent for HIV-negative patients. The P. jirovecii burden correlated with the blood CD4(+) T-cell counts in the HIV-positive but not in the HIV-negative group. Nevertheless, whatever the HIV status, a correlation was observed between alveolar CD4(+) T cells and the P. jirovecii burden. CONCLUSIONS The T-lymphocyte profile was different between HIV-positive and HIV-negative patients with P. jirovecii, suggesting a distinct pathogenesis. Alveolar CD4(+) T cells could be critical to explain the development of Pneumocystis pneumonia but may also be important for evaluation of disease risk, mostly among HIV-negative immunocompromised patients.

Disseminated osteomyelitis or bone metastases of breast cancer: 18 F-FDG-PET/CT helps unravel an unusual presentation

We present a case wherein striking 18F-FDG-PET/CT findings initially considered consistent with recurrent disseminated skeletal metastases of breast cancer were later identified as an unusual presentation of disseminated chronic pyogenic osteomyelitis with Staphylococcus aureus and warneri identified on microbiological culture. A 76-year-old female with previous history of breast cancer presented with a 6-month history of pyrexia, myalgia and weight loss. Besides neutrophilia and elevated C-reactive protein, other blood indices, cultures and conventional imaging failed to identify the cause of pyrexia of unknown origin (PUO). 18F-FDG-PET/CT demonstrated multiple widespread foci of intense FDG uptake in lytic lesions throughout the skeleton. Coupled with previous history of malignancy, findings were strongly suggestive of disseminated metastases of breast cancer. Through targeting an FDG avid lesion, 18F-FDG-PET/CT aided CT-guided biopsy, which instead identified the lesions as chronic pyogenic osteomyelitis. Following prolonged antibiotic therapy, repeat 18F-FDG-PET/CT demonstrated significant resolution of lesions. This case demonstrated an unusual presentation of disseminated osteomyelitis on 18F-FDG-PET/CT and highlighted the use of 18F-FDG-PET/CT as a trouble shooter in PUO but demonstrated that unusual presentations of benign or malignant pathologies cannot always reliably be differentiated on imaging alone without aid of tissue sampling. Furthermore, this case highlights the potential role 18F-FDG-PET/CT could provide in assessing response to antibiotic therapy.