Edouard Vannier

Persistent and Relapsing Babesiosis in Immunocompromised Patients

BACKGROUND Human babesiosis is a tickborne malaria-like illness that generally resolves without complication after administration of atovaquone and azithromycin or clindamycin and quinine. Although patients experiencing babesiosis that is unresponsive to standard antimicrobial therapy have been described, the pathogenesis, clinical course, and optimal treatment regimen of such cases remain uncertain. METHODS We compared the immunologic status, clinical course, and treatment of 14 case patients who experienced morbidity or death after persistence of Babesia microti infection, despite repeated courses of antibabesial treatment, with those of 46 control subjects whose infection resolved after a single course of standard therapy. This retrospective case-control study was performed in southern New England, New York, and Wisconsin. RESULTS All case patients were immunosuppressed at the time of acute babesiosis, compared with <10% of the control subjects. Most case patients experienced B cell lymphoma and were asplenic or had received rituximab before babesial illness. The case patients were more likely than control subjects to experience complications, and 3 died. Resolution of persistent infection occurred in 11 patients after 2-10 courses of therapy, including administration of a final antimicrobial regimen for at least 2 weeks after babesia were no longer seen on blood smear. CONCLUSIONS Immunocompromised people who are infected by B. microti are at risk of persistent relapsing illness. Such patients generally require antibabesial treatment for >or=6 weeks to achieve cure, including 2 weeks after parasites are no longer detected on blood smear.

Senescence of human skeletal muscle impairs the local inflammatory cytokine response to acute eccentric exercise

The impact of aging on the cytokine response of human skeletal muscle to exercise‐induced injury remains poorly understood. We enrolled physically active, young (23–35 years old, n=15) and old (66–78 years old, n=15) men to perform 45 min of downhill running (16% descent) at 75% VO2max. Biopsies of vastus lateralis were obtained 24 h before and 72 h after acute eccentric exercise. Transcripts for inflammatory (TNF‐α, IL‐1β) and anti‐inflammatory cytokines (IL‐6, TGF‐β1) were quantified by real‐time PCR. Before exercise, cytokine transcripts did not differ with age. At old age, exercise induced a blunted accumulation of transcripts encoding the pan‐leukocyte surface marker CD18 (young: 10.1‐fold increase, P<0.005; old: 4.7‐fold increase, P=0.02; young vs. old: P<0.05). In both age groups, CD18 transcript accumulation strongly correlated with TNF‐α (young, r=0.87, P<0.001; old, r=0.72, P=0.002) and TGF‐β1 transcript accumulation (young, r=0.80, P<0.001; old, r=0.64, P=0.008). At old age, there was no correlation between IL‐1 β and CD18 transcript accumulation. Furthermore, exercise induced IL‐6 transcript accumulation in young (3.6‐fold, P=0.057) but not in old men. Our results suggest that aging impairs the adaptive response of human skeletal muscle to eccentric exercise by differential modulation of a discrete set of inflammatory and anti‐inflammatory cytokine genes.

IL-1B and IL-1Ra gene polymorphisms and disease severity in rheumatoid arthritis: interaction with their plasma levels

The balance between interleukin-1 (IL-1) and its competitive antagonist IL-1 receptor antagonist (IL-1Ra) may contribute to the pathogenesis of rheumatoid arthritis (RA). We analysed the frequency of different alleles in the IL-1B gene (at −511 and at +3954) as well as in the IL-1Ra gene (at +2018) in an association study involving 297 RA patients and 112 healthy controls from the same geographic area. We tested associations with RA susceptibility or severity, and with circulating levels of IL-1Ra and IL-1β. Carriage of the rare IL-1B (+3954) allele 2 was increased in destructive arthritis (DRA) as compared to non-destructive arthritis (NDRA) (OR 1.7, 95% CI 1.1–2.8, 49.0% vs 35.9%) and controls (OR 1.7, 95% CI 1.1–2.8, 35.8%). Patients carrying this allele had a more destructive (Larsen wrist radiological index: mean ± s.e.m., 2.1 ± 0.2 vs 1.6 ± 0.1, P = 0.005; Steinbrocker functional index: 2.4 ± 0.1 vs 1.9 ± 0.1, P = 0.002) and active disease (Ritchie articular index: 8.1 ± 0.8 vs 5.3 ± 0.6, P = 0.002; erythrocyte sedimentation rate (ESR): 36.6 ± 2.9 mm/h vs 25.3 ± 1.8 mm/h, P = 0.002). This contribution was independent from that of HLA DR4/DR1 to severity. IL-1Ra plasma levels adjusted to ESR values were significantly lower in IL-1B2 (+3954) positive than negative RA patients (1.0 ± 0.1 vs 1.2 ± 0.1 ng/ml, P = 0.01). This IL-1B (+3954) gene polymorphism may be an important marker for the severity of joint destruction in RA and is associated with an imbalance in IL-1Ra production. As this genetic association was independent and additive to the risk of HLA DR4/DR1 status, it could be a useful addition to HLA-DR4/1 as a genetic prognostic marker early in the course of the disease.

Update on Babesiosis

Human babesiosis is an emerging tick-borne infectious disease caused by intraerythrocytic protozoan species of the genus Babesia with many clinical features similar to those of malaria. Over the last 50 years, the epidemiology of human babesiosis has changed from a few isolated cases to the establishment of endemic areas in the northeastern and midwestern United States. Episodic cases are reported in Europe, Asia, Africa, and South America. The severity of infection ranges from asymptomatic infection to fulminant disease resulting in death, although the majority of healthy adults experience a mild-to-moderate illness. People over the age of 50 years and immunocompromised individuals are at the highest risk of severe disease, including those with malignancy, HIV, lacking a spleen, or receiving immunosuppressive drugs. Asymptomatic carriers present a blood safety risk when they donate blood. Definitive diagnosis of babesial infection generally is made by microscopic identification of the organism on thin blood smear, amplification of Babesia DNA using PCR, and detection of Babesia antibody in acute and convalescent sera. Specific antimicrobial therapy consists of atovaquone and azithromycin or clindamycin and quinine. Exchange transfusion is used in severe cases. The use of multiple prevention strategies is recommended and consists of personal, residential, and community approaches.

Imbalance between interleukin‐1 agonists and antagonists: relationship to severity of inflammatory bowel disease

Interleukin (IL)‐1 is a key mediator in the pathogenesis of inflammatory bowel disease (IBD). Naturally occurring IL‐1 modulators include IL‐1 receptor antagonist (IL‐1Ra), IL‐1 soluble receptor Type I (IL‐1sRI), IL‐1sRII and IL‐1 receptor accessory protein (AcP). Systemic and mucosal levels of IL‐1 soluble receptors remain unknown in IBD. Plasma or colonic tissues were obtained from 185 consecutive unselected patients with Crohns disease (CD) or ulcerative colitis (UC) and from 52 control subjects. Plasma and colonic explant culture supernatants were assessed for IL‐1α, IL‐1β, IL‐1Ra, IL‐1sRI and IL‐1sRII. Plasma IL‐1Ra levels were higher in UC (+93%) than in healthy subjects. IL‐1α and IL‐1β were not detected. IL‐1sRII levels were marginally lower in CD (−10%) and UC (−9%), whereas IL‐1sRI levels were elevated in CD (+28%) only. Plasma IL‐1sRI levels correlated positively (P < 0·01) with Crohns disease activity index (r = 0·53), C‐reactive protein (r = 0·46) and α1‐acid glycoprotein (r = 0·42). In colonic explant cultures, IL‐1α and IL‐1Ra levels were elevated in non‐lesional (+233% and +185% respectively) and lesional CD (+353% and +1069%), lesional UC (+604% and +1138%), but not in non‐lesional UC. IL‐1β was elevated in lesional UC (+152%) and CD (+128%). In contrast, IL‐1sRII levels were elevated in non‐lesional CD (+65%), but remained unchanged in lesional CD, non‐lesional and lesional UC. IL‐1sRI levels did not differ between patient and control groups. These results indicate that (i) the proinflammatory moiety IL‐1sRI is a systemic marker of inflammation and activity in CD and (ii) local shedding of the functional antagonist IL‐1sRII may dampen colonic inflammation in CD, but not in UC.

Clinical, hematologic, and immunologic effects of interleukin-10 in humans.

We conducted a double-blind, placebo-controlled study to investigate the safety, pharmacokinetics, and immunological properties of interleukin-10 (IL-10) administration in healthy humans. Volunteers received a single intravenous bolus injection of recombinant human IL-10 (1, 10, or 25μg/kg) or placebo. Cytokine production in whole blood and peripheral blood mononuclear cells (PBMC) was assessed before and 3, 6, 24, and 48 hr after the injection. Peak serum concentrations of IL-10 (15±1.1, 208±20.1, and 505±22.3 ng/ml) occurred after 2–5 min for 1, 10, and 25μg/kg IL-10, respectively. The terminal-phase half-life was 3.18 hr. A transient leukocytosis (24–63% above baseline) was observed 6 hr after injection, which coincided with a dose-dependent decrease (12–24%) in neutrophil superoxide generation. There was a marked inhibition (60–95%) of endotoxin-induced IL-6 production from whole blood in each group receiving IL-10. Production of IL-8 in endotoxin-stimulated blood was reduced in the 10μg/kg group. In PBMC stimulated with phytohemagglutinin and phorbol ester, there was a decrease (72–87%) in interferon-γ (IFNγ) production 6 hr after IL-10 with a return to pre-IL-10 levels after 24 hr. This reduction was only partially associated with a decrease in the number of CD2-bearing cells. We conclude that IL-10 administration into humans is without significant side effects, and a single injection reducesex vivo production of IL-6, IL-8, and IFNγ.

Histamine enhances interleukin (IL)-1-induced IL-1 gene expression and protein synthesis via H2 receptors in peripheral blood mononuclear cells. Comparison with IL-1 receptor antagonist.

Histamine and IL-1 have been implicated in the pathogenesis of chronic inflammatory diseases, such as pulmonary allergic reactions and rheumatoid arthritis. We therefore investigated whether histamine modulated the synthesis of IL-1 beta. Human PBMC were stimulated with IL-1 alpha (10 ng/ml) in the absence or presence of histamine (10(-9)-10(-4) M). Histamine alone did not induce protein synthesis or mRNA accumulation for IL-1 beta. IL-1 alpha-induced IL-1 beta synthesis was enhanced two to threefold by histamine concentrations from 10(-6)-10(-4) M. Cimetidine, an H2 receptor antagonist, reversed the histamine (10(-5) M)-mediated increase in IL-1 alpha-induced IL-1 beta synthesis. Diphenhydramine, an H1 receptor antagonist, had no effect. Indomethacin, a cyclooxygenase inhibitor, significantly reduced IL-1 alpha-induced IL-1 beta synthesis, but had no effect on the histamine-mediated increase in IL-1 alpha-induced IL-1 beta synthesis. Histamine (10(-5) M) enhanced and sustained IL-1 beta mRNA levels in IL-1 alpha-stimulated PBMC. However, histamine reduced IL-1 beta mRNA half-life (2.4 vs 1.2 h), suggesting that histamine enhances IL-1 alpha-induced IL-1 beta synthesis at the level of transcriptional activation. On the other hand, histamine (10(-5) M) did not affect IL-1 alpha-induced synthesis of IL-1 receptor antagonist. These results suggest that mast cells may sustain chronic inflammatory processes by upregulating self-induction of IL-1 through histamine release.

Both C3a and C3adesArg Regulate Interleukin-6 Synthesis in Human Peripheral Blood Mononuclear Cells

Synthesis of complement components is part of the acute-phase response. Interleukin-6 (IL-6) is a critical mediator of the acute-phase response during infections and injuries. Plasma levels of C3a and IL-6 have been proposed as prognostic indicators in sepsis and trauma. The effects of C3a and C3a(des)Arg on IL-6 gene expression and protein production in human peripheral blood mononuclear cells (PBMC) were investigated. Neither C3a nor C3a(des)Arg alone induced detectable IL-6 protein or mRNA levels. However, C3a and C3a(des)Arg affected endotoxin-induced IL-6 synthesis in a dose-dependent manner. In nonadherent PBMC, C3a or C3a(des)Arg suppressed, while in adherent PBMC, C3a or C3a(des)Arg enhanced IL-6 protein and mRNA levels. These results suggest that C3a and C3a(des)Arg may provide a control mechanism of acute-phase responses by enhancing IL-6 synthesis in adherent monocytes at local inflammatory sites and by inhibiting IL-6 synthesis in circulating monocytes.

Coinfection by Ixodes Tick-Borne Pathogens: Ecological, Epidemiological, and Clinical Consequences.

Ixodes ticks maintain a large and diverse array of human pathogens in the enzootic cycle, including Borrelia burgdorferi and Babesia microti. Despite the poor ecological fitness of B. microti, babesiosis has recently emerged in areas endemic for Lyme disease. Studies in ticks, reservoir hosts, and humans indicate that coinfection with B. burgdorferi and B. microti is common, promotes transmission and emergence of B. microti in the enzootic cycle, and causes greater disease severity and duration in humans. These interdisciplinary studies may serve as a paradigm for the study of other vector-borne coinfections. Identifying ecological drivers of pathogen emergence and host factors that fuel disease severity in coinfected individuals will help guide the design of effective preventative and therapeutic strategies.

Interleukin- 1β, interleukin-1 receptor antagonist, and soluble interleukin-1 receptor type II secretion in chronic fatigue syndrome

Chronic fatigue syndrome is a condition that affects women in disproportionate numbers, and that is often exacerbated in the premenstrual period and following physical exertion. The signs and symptoms, which include fatigue, myalgia, and low-grade fever, are similar to those experienced by patients infused with cytokines such as interleukin-1. The present study was carried out to test the hypotheses that (1) cellular secretion of interleukin-1β (IL-1β), interleukin-1 receptor antagonist (IL-1Ra), and soluble interleukin-1 receptor type II (IL-1sRII) is abnormal in female CFS patients compared to age- and activity-matched controls; (2) that these abnormalities may be evident only at certain times in the menstrual cycle; and (3) that physical exertion (stepping up and down on a platform for 15 min) may accentuate differences between these groups. Isolated peripheral blood mononuclear cells from healthy women, but not CFS patients, exhibited significant menstrual cycle-related differences in IL-1β secretion that were related to estradiol and progesterone levels (R2 = 0.65, P < 0.01). IL-1Ra secretion for CFS patients was twofold higher than controls during the follicular phase (P = 0.023), but luteal-phase levels were similar between groups. In both phases of the menstrual cycle, IL-1sRII release was significantly higher for CFS patients compared to controls (P = 0.0002). The only changes that might be attributable to exertion occurred in the control subjects during the follicular phase, who exhibited an increase in IL-1β secretion 48 hr after the stress (P = 0.020). These results suggest that an abnormality exists in IL-1β secretion in CFS patients that may be related to altered sensitivity to estradiol and progesterone. Furthermore, the increased release of IL-1Ra and sIL-1RII by cells from CFS patients is consistent with the hypothesis that CFS is associated with chronic, low-level activation of the immune system.