Hematologic manifestations of babesiosis.

BACKGROUND: Babesiosis, a zoonotic parasitic infection transmitted by the Ixodes tick, has become an emerging health problem in humans that is attracting attention worldwide. Most cases of human babesiosis are reported in the United States and Europe. The disease is caused by the protozoa of the genus Babesia, which invade human erythrocytes and lyse them causing a febrile hemolytic anemia. The infection is usually asymptomatic or self-limited in the immunocompetent host, or follows a persistent, relapsing, and/or life threatening course with multi-organ failure, mainly in the splenectomized or immunosuppressed patients. Hematologic manifestations of the disease are common. They can range from mild anemia, to severe pancytopenia, splenic rupture, disseminated intravascular coagulopathy (DIC), or even hemophagocytic lymphohistiocytosis (HLH). CASE PRESENTATION: A 70 year old immunocompetent female patient living in New York City presented with a persistent fever, night sweats, and fatigue of 5 days duration. Full evaluation showed a febrile hemolytic anemia along with neutropenia and thrombocytopenia. Blood smear revealed intraerythrocytic Babesia, which was confirmed by PCR. Bone marrow biopsy was remarkable for dyserythropoiesis, suggesting possible HLH, supported by other blood workup meeting HLH-2004 trial criteria. CONCLUSION: Human babesiosis is an increasing healthcare problem in the United States that is being diagnosed more often nowadays. We presented a case of HLH triggered by Babesia microti that was treated successfully. Also, we presented the hematologic manifestations of this disease along with their pathophysiologies.

Presumptive treatment for malaria is not justified in children receiving cancer chemotherapy.

BACKGROUND: Predominant etiologies of febrile neutropenia (FN) during the course of cancer chemotherapy include infections with bacteria, fungi, and viruses. Infection with malarial parasite is a possibility in regions that are endemic for malaria. Over-diagnosis and over-treatment of malaria is increasingly being recognized as a serious concern in malaria endemic regions. Aim was to determine the incidence of malarial infection in episodes of FN in children receiving chemotherapy for malignant disorders. METHODS: Children, with malignant disorders, on chemotherapy, who fulfilled the definition of FN were enrolled prospectively. Standard microscopy, quantitative buffy coat, and antigen detection (OptiMAL) were performed in each episode of FN. RESULTS: One hundred episodes of FN involving 82 children were investigated. The age ranged from 2 to 13 years (mean: 5.8 ± 2.8). Eighty-one episodes were in children with acute lymphoblastic leukemia, 15 in acute myeloid leukemia, and remaining 4 in other malignancies. Evidence for malaria was not found in any case by any of the three methods. CONCLUSIONS: Malaria was not found to be a causative agent for FN in children with various malignant disorders, in a region with low endemicity for malaria. Presumptive administration of antimalarials in children with FN is unjustified. Pediatric oncologists constantly face the challenge of managing febrile illnesses in immunocompromised patients. Those practicing in malaria endemic regions can effectively exploit diagnostic tools for malaria for a rational decision.

Cross-talk in the innate immune system: neutrophils instruct recruitment and activation of dendritic cells during microbial infection.

Type I inflammatory cytokines are essential for immunity to many microbial pathogens, including Toxoplasma gondii. Dendritic cells (DC) are key to initiating type 1 immunity, but neutrophils are also a source of chemokines and cytokines involved in Th1 response ignition. We found that T. gondii triggered neutrophil synthesis of CC chemokine ligand (CCL)3, CCL4, CCL5, and CCL20, chemokines that were strongly chemotactic for immature DC. Moreover, supernatants obtained from parasite-stimulated polymorphonuclear leukocytes induced DC IL-12(p40) and TNF-alpha production. Parasite-triggered neutrophils also released factors that induced DC CD40 and CD86 up-regulation, and this response was dependent upon parasite-triggered neutrophil TNF-alpha production. In vivo evidence that polymorphonuclear leukocytes exert an important influence on DC activation was obtained by examining splenic DC cytokine production following infection of neutrophil-depleted mice. These animals displayed severely curtailed splenic DC IL-12 and TNF-alpha production, as revealed by ex vivo flow cytometric analysis and in vitro culture assay. Our results reveal a previously unrecognized regulatory role for neutrophils in DC function during microbial infection, and suggest that cross-talk between these cell populations is an important component of the innate immune response to infection.

Experimental Babesia gibsoni infection in coyotes (Canis latrans).

Four 5 mo old captive raised coyotes (Canis latrans) were experimentally inoculated with approximately 1 x 10(6) Babesia gibsoni organisms. Parasites were detected 1 wk post-inoculation in all coyotes with maximum parasitemia of 8-11% occurring at 34 wk. Parasitemias remained at or above 1% for at least 12 wk and were still detectable 20 wk post-inoculation. All experimentally infected coyotes developed pale mucous membranes, splenomegaly, and a positive heme reaction in urine while one coyote exhibited mild depression and inappetence. Infected coyotes also developed a regenerative anemia, thrombocytopenia, and neutropenia. The mild clinical signs coupled with the high level and long duration of parasitemia indicate that coyotes could serve as reservoirs for B. gibsoni. Entrance of this foreign parasite into the United States suggests the need for strict quarantines and thorough health and blood film examinations for imported animals.

Entamoeba histolytica: acute granulomatous intestinal lesions in normal and neutrophil-depleted mice.

To study the role of neutrophils in the innate resistance to Entamoeba histolytica intestinal infection in mice, animals were treated with anti-neutrophil monoclonal antibodies prior to intracecal parasite inoculation and the resulting lesions were compared with normal mice that had been equally infected. In contrast to our previous finding that neutrophils are critical in eliminating E. histolytica infection in the liver, we show here that neutrophils are not absolutely required to eliminate E. histolytica infection from the intestine. Although the neutrophils are not critical for resolution of the E. histolytica infection, neutrophils do appear to provide some measure of protection as the intestinal amoeba burden was higher at early timepoints after infection in the neutropenic animals. In addition, we found that while both the normal and the neutrophil-depleted mice developed ulcerative lesions in the colon, the neutropenic mice had an increased frequency of granulomas that formed around the amoeba. Thus, our findings appear to be the first evidence showing that granulomatous inflammation can occur after intestinal infection in mice using axenically cultured amoeba.

Rapid recruitment of neutrophils containing prestored IL-12 during microbial infection.

Neutrophils are well known to rapidly migrate to foci of infection, where they exert microbicidal functions. We sought to determine whether neutrophils responding to in vivo infection with the protozoan pathogen Toxoplasma gondii were capable of IL-12 production as suggested by recent in vitro studies. Intraperitoneal infection induced a neutrophil influx by 4 h, accompanied by ex vivo IL-12 p40 and p70 release. Approximately 85% of the neutrophils displayed intracellular stores of IL-12, as determined by flow cytometry and confocal fluorescence microscopy. Neutrophils from IFN-gamma knockout mice also expressed IL-12, ruling out an IFN-gamma-priming requirement. Neither infected nor uninfected peritoneal macrophages displayed intracellular IL-12, but these cells were strongly IL-10(+). Infection per se was unnecessary for IL-12 production because peritoneal and peripheral blood neutrophils from uninfected animals contained IL-12(+) populations. Expression of the granulocyte maturation marker Gr-1 (Ly-6G) was correlated with IL-12 production. Mice depleted of their granulocytes by mAb administration at the time of infection had decreased serum levels of IL-12 p40. These results suggest a model in which neutrophils with prestored IL-12 are rapidly mobilized to an infection site where they are triggered by the parasite to release cytokine. Our findings place neutrophils prominently in the cascade of early events leading to IL-12-dependent immunity to T. gondii.

A case of Balamuthia mandrillaris meningoencephalitis.

Balamuthia mandrillaris is a newly described pathogen that causes granulomatous amebic encephalitis, an extremely rare clinical entity that usually occurs in immunosuppressed individuals. We report a case of pathologically proven Balamuthia encephalitis with unusual laboratory and radiologic findings. A 52-year-old woman with idiopathic seizures and a 2-year history of chronic neutropenia of unknown cause had a subacute illness with progressive lethargy, headaches, and coma and died 3 months after the onset of symptoms. Cerebrospinal fluid (CSF) glucose concentrations were extremely low or unmeasurable, a feature not previously described (to our knowledge). Cranial magnetic resonance imaging scans showed a single large temporal lobe nodule, followed 6 weeks later by the appearance of 18 ring-enhancing lesions in the cerebral hemispheres that disappeared after treatment with antibiotics and high-dose corticosteroids. The initial brain biopsy specimen and analysis of CSF samples did not demonstate amebae, but a second biopsy specimen and the postmortem pathologic examination showed Balamuthia trophozoites surrounded by widespread granulomatous inflammation and vasculitis. The patient's neutropenia and antibiotic use may have caused susceptibility to this organism. Amebic meningoencephalitis should be considered in cases of subacute meningoencephalitis with greatly depressed CSF glucose concentrations and multiple nodular lesions on cerebral imaging. Arch Neurol. 2000;57:1210-1212

B cell-deficient mice are highly resistant to Leishmania donovani infection, but develop neutrophil-mediated tissue pathology.

Resolution of Leishmania infection is T cell-dependent, and B lymphocytes have been considered to play a minimal role in host defense. In this study, the contribution of B lymphocytes to the response against Leishmania donovani was investigated using genetically modified IgM transmembrane domain (muMT) mutant mice, which lack mature B lymphocytes. When compared with wild-type mice, muMT mice cleared parasites more rapidly from the liver, and infection failed to establish in the spleen. The rapid clearance of parasites in muMT mice was associated with accelerated and more extensive hepatic granuloma formation compared with wild-type mice. However, the liver of infected muMT mice also showed signs of destructive pathology, associated with the presence of increased numbers of neutrophils. The role of neutrophils in controlling parasite growth in the viscera was determined by depletion with the mAb RB6-8C5. This treatment led to a dramatic enhancement of parasite growth in both the liver and spleen of muMT and wild-type mice. As assessed by transfer of both normal and chronic-infection serum, Ig protects microMT mice from destructive hepatic pathology, but minimally alters their resistance compared with wild-type mice. However, adoptive transfer of CD4+ and CD8+ T cells into recombinase activating gene 1 (RAG1-/-) recipients, suggested that T cell function was not altered by maturation in a B cell-deficient environment. Taken together, these data suggest an inhibitory role for B lymphocytes in resistance to L. donovani unrelated to the presence or absence of Ig. However, Ig protects muMT mice from the exaggerated pathology that occurs during infection.

Failure of systemic empirical treatment with amphotericin B to prevent candidemia in neutropenic patients with cancer.

We undertook a retrospective review of all patients with hematologic malignancies in whom candidemia developed during chemotherapy-induced neutropenia in 1989 and 1990. Candidemia developed in 11 patients; five were receiving therapeutic doses of amphotericin B at the time of infection. Disseminated infection occurred in 2 of 5 patients with breakthrough infection and 3 of 6 patients with candidemia before receipt of amphotericin B. Among patients with breakthrough candidemia there was a trend toward more-prolonged neutropenia prior to infection (P = .069), but otherwise they were indistinguishable from other candidemic patients with regard to risk factors for candidemia. Amphotericin B-susceptible Candida albicans was isolated from two patients and Candida krusei from three patients with breakthrough infection. All patients were treated with amphotericin B; all breakthrough infections responded to treatment. Neutropenic patients with breakthrough candidemia were clinically similar to those whose candidemia preceded amphotericin B therapy, and there was no increase in morbidity and mortality among individuals with breakthrough infection.