Leonidas Christou

The new global map of human brucellosis

The epidemiology of human brucellosis, the commonest zoonotic infection worldwide, has drastically changed over the past decade because of various sanitary, socioeconomic, and political reasons, together with the evolution of international travel. Several areas traditionally considered to be endemic--eg, France, Israel, and most of Latin America--have achieved control of the disease. On the other hand, new foci of human brucellosis have emerged, particularly in central Asia, while the situation in certain countries of the Near East (eg, Syria) is rapidly worsening. Furthermore, the disease is still present, in varying trends, both in European countries and in the USA. Awareness of this new global map of human brucellosis will allow for proper interventions from international public-health organisations.

Brucella as a biological weapon.

Abstract.Brucella has traditionally been considered a biological weapon. It was the subject of extensive offensive research in the past, and still belongs to category B pathogens on most lists. Its propensity for airborne transmission and induction of chronic debilitating disease requiring combined antibiotic regimens for treatment, its abundance around the world and its vague clinical characteristics defying rapid clinical diagnosis are some of the characteristics that apply to the pathogen’s weapons potential. Yet minimal mortality, availability of treatment options, protracted inoculation period and the emergence of new, more virulent potential weapons means that its inclusion among agents of bioterrorism is nowadays mainly of historical significance. Nevertheless, in the interest of literacy and of avoiding panic, physicians and the public both should be aware of the most common zoonosis worldwide.

The global burden of bacterial and viral zoonotic infections

Abstract Bacterial and viral zoonotic infections comprise a practically endless, ever-expanding list of pathogens that have the potential to induce human disease of varying severity, with varying means of transmission to humans (including vector-borne and foodborne agents) and of varying epidemiology. Not all theoretically zoonotic pathogens are truly zoonotic in practice, the prime example being influenza viruses; aviann H5N1 influenza remains strictly zoonotic, whereas novel H1N1 influenza displays an anthropocentric cycle that led to a pandemic, despite being of zoonotic origin. The burden of disease induced by zoonotic and viral pathogens is enormous: there are more than ten bacterial zoonoses, each of which affects hundreds of thousands patients annually, often leading to chronic infections and causing significant economic losses of a medical and livestock-related nature. Viral zoonotic agents are constantly emerging or re-emerging, and are associated with outbreaks of limited or expanded geographical spread: the typical trends of viral zoonotic infections, however, is to extend their ecological horizon, sometimes in an unexpected but successful manner, as in the case of West Nile virus, and in other instances less effectively, as was the case, fortunately, in the case of avian influenza. The majority of bacterial and viral zoonotic infections attract disproportionately low scientific and public health interest. Understanding their burden may allow for improved surveillance and prevention measures.

Baseline cholesterol is associated with the response to antiviral therapy in chronic hepatitis C

Background:  Hepatitis C virus (HCV) partially interacts with low‐density lipoprotein (LDL) receptors, suggesting a role for lipids in regulating HCV clearance. Our aim was to study if baseline lipids can discriminate responders from non‐responders among patients with HCV infection.

Serum levels of IL-6 and its soluble receptor (sIL-6R) in Waldenström's macroglobulinemia

Abstract: Background: Interleukin‐6 (IL‐6) is a multifunctional cytokine that plays roles in the immune response, inflammation and hematopoiesis. Serum IL‐6 levels have reported to reflect disease severity and high tumor burden in multiple myeloma (MM) patients and to correlate with several other laboratory parameters. Serum‐soluble IL‐6 receptor (sIL‐6R) plays an agonist role in IL‐6 signaling, enhancing its biological activity tenfold. Purpose–Methods: We measured IL‐6 and sIL‐6R levels in 11 patients (7 male, 4 female, mean age 66.9 yr) with Waldenströms macrobulinemia (WM) using a commercially available enzyme‐linked immunoassay in order to investigate their biological role and to find any possible relationship with disease severity, tumor burden or response to treatment. Results: Serum IL‐6 and sIL‐6R concentrations at diagnosis were significantly higher than in healthy controls (Mann–Whitney U‐test, p<0.001 and p<0.01, respectively). Patients who were effectively treated had a significant reduction in IL‐6 levels (p=0.017). With regard to sIL‐6R levels, no specific tendency was observed. In some of the responsive patients the levels increased whereas in others they decreased. No correlation was found between IL‐6 and sIL‐6R levels at diagnosis (p=0.9, r=0.036) or after treatment (p=0.083, r=0.3). Conclusions: Our results suggest that IL‐6 may be a marker reflecting tumor burden, disease severity and response to treatment in WM. With regard to sIL‐6R, we believe that it does not seem to be of much value, and its role remains to be clarified. However, future studies are needed to confirm and further extend the present results.

Future trends in human brucellosis treatment

The global burden of human brucellosis remains enormous. Existing treatment options, largely based on experience gained > 30 years ago, are adequate but not optimal. The evolving understanding of the pathophysiology of the disease may augment in designing and evaluating alternative approaches that may prove to be superior. Current alternative approaches such as co-trimoxazole-containg regimens, should be widely evaluated as being more cost-effective. New methods of delivery such as gentamicin-loaded microparticles, neutralisation of the environment where Brucella resides and use of novel antibiotics such as tigecycline may be of importance in the future. The role of immunomodulation, widely but inconsistently applied in ‘chronic’ brucellosis, should be further evaluated in all disease stages to define if it is of any use. The development of a subcellular vaccine would be an important step forward although one has to take into account the multiple interactions between Brucella and the immune system, various technical problems and the lack of funds. Reviewing existing attempts at the development of such a vaccine, the authors conclude that a trivalent subcellular vaccine may be needed for adequate efficacy.

Treatment of plasma cell leukemia with vincristine, liposomal doxorubicin and dexamethasone

Abstract: Primary plasma cell (PCL) leukemia is a rare lymphoproliferative disorder characterized by a malignant proliferation of plasma cells in the bone marrow and peripheral blood. Survival with standard therapy using melphalan is very poor. Doxorubicin encapsulated with liposomes has less cardiotoxicity, is at least as efficient and has fewer side effects than conventional doxorubicin. Two female patients (69 and 54 yr old) with primary PCL are described in this study. They both received a modified form of VAD (vincristine, doxorubicin and dexamethasone), a regimen which includes liposomal doxorubicin (40 mg/m2 for 1 d), vincristine (2 mg for 1 d) and dexamethasone 40 mg per os on days 1–4, 9–12 and 17–20.

Administration of a modified chemotherapeutic regimen containing vincristine, liposomal doxorubicin and dexamethasone to multiple myeloma patients: preliminary data.

Abstract: For elderly patients with multiple myeloma (MM), conventional melphalan and prednisone (MP) therapy has been the treatment of choice; the vincristine, doxorubicin and dexamethasone (VAD) regimen is preferred for younger patients who also receive high‐dose melphalan in combination with autologous or allogeneic bone marrow transplantation (BMT). Although survival time is similar in both the MP and VAD regimens, the continuous infusion of doxorubicin which the latter treatment entails constitutes a disadvantage along with the 4‐day hospitalization required. Doxorubicin also induces cardiotoxicity, particularly in the elderly. A modified form of VAD therapy includes liposomal doxorubicin (Caelyx®) (40 mg/kg for 1 d), oncovin (2 mg for 1 d) and dexamethasone 40 mg for 4 d per os. Doxorubicin encapsulated with liposomes has less cardiotoxicity, is more efficient and has fewer side effects than conventional doxorubicin, and it can be administered on an outpatient basis: dexamethasone can be given orally and vincristine in bolus infusion. In order to estimate its efficacy and tolerability, we administered this regimen to 12 patients (first‐line treatment in 6 patients, salvage therapy in 6 patients). All patients exhibited good tolerance to liposomal doxorubicin with no severe side effects. Eight patients achieved complete hematological remission and three partial response. One patient died before completing the treatment.

Rituximab (Anti-CD20 Monoclonal Antibody) Administration in a Young Patient with Resistant B-Prolymphocytic Leukemia

Following the administration of the human anti-CD20 monoclonal antibody IDEC-C2B8 (rituximab), a 31-year-old woman with B-prolymphocytic leukemia, who had been resistant to CHOP, fludarabine, pentostatin and 2-CdA, achieved complete remission. Rituximab was administered intravenously once a week for 4 weeks. The patient only had mild but tolerable side effects during the first cycle of therapy. She remains in complete remission 8 months following the discontinuation of treatment.

Cutaneous Vasculitis as the Initial Manifestation in Acute Myelomonocytic Leukemia

Vasculitides are a heterogeneous group of clinical disorders that are idiopathic (polyarteritis nodosa, Wegener granulomatosis) and that may be associated with connective tissue diseases (systemic lupus erythematosus, rheumatoid arthritis, scleroderma); with sepsis; or with neoplasia [1, 2], especially leukemias and lymphomas [3-11]. In vasculitides, the basic histopathologic characteristic is inflammatory changes in vessel walls. The inflammatory infiltrate can be predominantly neutrophilic (usually accompanied by leukocytoclasis), lymphocytic, or granulomatous. Necrotizing changes (usually of fibrinoid type) of the vessel wall may be present or absent. Acute myelomonocytic leukemia is a neoplastic disorder of the granulocytic and monocytic lineage that is characterized by a mixture of immature cells, mainly myeloblasts and monoblasts in the peripheral blood and bone marrow. Patients with acute myelomonocytic leukemia may present with extramedullary neoplastic infiltrates in the liver, gingiva, skin, and central nervous system. Skin involvement in acute myelomonocytic leukemia includes three types of lesions: nonspecific, leukemic cutis, and granulocytic sarcoma [12, 13]. Nonleukemic skin vasculitis in patients with acute myelogenous leukemia has rarely been reported [9-11]. For this reason, we describe three patients presenting with skin vasculitis as the initial clinical manifestation in whom a diagnosis of acute myelomonocytic leukemia was subsequently established by peripheral blood smear and bone marrow aspirate examinations. Methods Three patients, 2 women and 1 man, were hospitalized with symptoms of skin lesions affecting primarily the lower extremities. They had complete physical examinations; routine laboratory tests; urinalysis; blood and urine cultures; chest roentgenograms; tuberculin skin tests; and immunology tests, including rheumatoid factor, antinuclear antibodies, antibodies to extractable nuclear antigens, antineutrophil cytoplasmic antibodies, cryoglobulins, and complement levels (C3, C4). In addition, skin biopsy specimens, blood smears, and bone marrow aspirates were obtained from all patients. Patient 1 A 30-year-old man, with Down syndrome, was hospitalized on June 1990 because of skin rash and low-grade fever. In November 1989, he had low-grade fever and skin rash affecting primarily the lower extremities. His past medical history was unremarkable. His temperature was 37.8 C, and he had necrotic skin lesions affecting the lower extremities Figure 1 and forearms. Other test results were negative. The laboratory evaluation showed the following: hemoglobin, 102 g/L; leukocyte count, 6.5 109/L; and platelet count, 30 109/L. Other laboratory and immunologic test results were negative or within normal limits. Figure 1. Skin lesions of leukocytoclastic vasculitis affecting the legs of patient 1. A skin biopsy specimen was obtained, and histologic examination showed a moderately intense inflammatory infiltrate predominantly around capillaries and small vessels of the dermis (Figure 2). The infiltrate consisted mainly of neutrophils, many eosinophils, and a few mononuclear cells. Swelling of endothelial cells and fibrinoid degeneration of vascular walls were also observed. The diagnosis was consistent with leukocytoclastic vasculitis (Figure 2). Test results from peripheral blood smear and bone marrow examinations showed acute myelomonocytic leukemia. Chemotherapy with idarubicin and cytosine arabinoside was started; the patient had a complete clinical remission, and the skin lesions disappeared. Figure 2. Skin biopsy specimen from patient 1. arrow heads Patient 2 A 30-year-old woman was hospitalized with symptoms of skin rash, arthralgias, and myalgias that occurred 2 months earlier. Peripheral blood smear and bone marrow examinations showed acute myelomonocytic leukemia. A skin biopsy specimen showed a histologic picture compatible with leukocytoclastic vasculitis. She was treated with idarubicin and cytosine arabinoside; she had a complete clinical response, and the skin lesions resolved. Patient 3 A 29-year-old woman was hospitalized with symptoms of skin rash and nonproductive cough. The skin biopsy specimen showed a typical histologic pattern of leukocytoclastic vasculitis. Peripheral blood smear and bone marrow examinations showed acute myelomonocytic leukemia. She was treated successfully with idarubicin, cytosine arabinoside, and prednisone. Discussion Small-vessel vasculitis involving predominantly the skin belongs to the hypersensitivity group of vasculitides. It can be a distinct clinicopathologic syndrome or can be associated with many diverse processes, such as infectious, autoimmune diseases, cryoglobulinemia, neoplastic diseases, drug-induced conditions, or other nosologic entities. Clinically, the cutaneous lesions are mainly characterized by palpable purpura and maculopapular eruptions. Other dermatologic manifestations include urticarial and petechial lesions and ulcers. The lesions have a histopathologic characteristic of necrotizing leukocytoclastic inflammation affecting primarily post-capillary venules and, less frequently, capillaries and arterioles, usually within the superficial dermis [1, 2]. Patients with malignant neoplasia may have symptoms related to the tumor itself or its metastases or may have symptoms and signs related to a paraneoplastic disorder, such as polymyalgia rheumatica, dermatomyositis, and vasculitis [14, 15]. Cutaneous and systemic vasculitis can be associated with malignant disorders. They may appear before the discovery of the neoplasia, simultaneously, or after its diagnosis [8-11]; however, none of these possibilities seems to make the prognosis worse. Among malignant diseases, a statistically significant association between cutaneous vasculitis and lympho- or myeloproliferative malignancies was noted, when compared with solid tumors [10]; the reason for this association is unknown. Hairy cell leukemia seems to correlate more frequently with vasculitis and especially with the polyarteritis nodosa type of vasculitis [6, 7]. Other hematologic malignancies associated with paraneoplastic cutaneous vasculitis include chronic lymphocytic leukemias, B- or T-cell lymphomas, Hodgkin disease, multiple myeloma, and chronic or acute myelogenous leukemias. We have described three patients who were hospitalized because of cutaneous vasculitis. The patients did not have polyarteritis nodosa, Wegener granulomatosis, mixed cryoglobulinemia, systemic lupus erythematosus, or other connective tissue disorders. None of our patients had septicemia or tuberculosis, and none was taking medication, such as antibiotics or diuretics, that are known to cause hypersensitive vasculitis. Skin biopsy specimens from affected areas showed leukocytoclastic vasculitis. In all of our patients, cutaneous vasculitis preceded the diagnosis of acute myelomonocytic leukemia by an interval ranging from 2 to 8 months. We found that all patients had acute myelomonocytic leukemia and that cutaneous vasculitis was the initial manifestation of the disorder. Paraneoplastic small-vessel vasculitis associated with acute myelogenous leukemia has been rarely reported. After reviewing the literature by Longley and colleagues [9], Greer and colleagues [10], and Beylot and colleagues [11] describing 25 patients with either lympho- or myeloproliferative diseases associated with cutaneous vasculitis or arthritis (or both), only 5 patients had acute myelogenous leukemia (4 patients had acute myelogenous leukemia that was not further specified and 1 patient had acute myeloblastic leukemia). Another patient had granulocytic sarcoma. The specific immunologic or inflammatory events mediating vasculitis in these patients remain speculative, and several possible pathogenic mechanisms have been postulated. Tumor-associated antigens may play a key role in mediating vascular damage, either directly or indirectly through 1) formation of immune complexes of tumor-associated antigens/antibodies [16]; 2) a direct vascular lesion by antibodies directed against leukemic cells cross-reacting with endothelial cells [17]; and 3) a direct effect of leukemic cells on the vascular wall [18]. However, conclusive data are lacking because abnormal levels of immunoglobulins affecting humoral immunity or circulating immune complexes, abnormal activation of complement, or abnormal use of complement components was identified neither in our patients nor in patients described in the literature [10]. Also, abnormal levels of cells involved in cell-mediated immunity were not found in our patients. Paraneoplastic vasculitides are usually restricted to the skin, but systemic involvement may be also found in some patients [8-11]. The prognosis of systemic vasculitis was very poor until the introduction of cyclophosphamide therapy [19, 20]. Patients with paraneoplastic vasculitis do not necessarily have a bad prognosis. Specific treatment of the underlying disease with or without steroids may yield an excellent response [8]. In two of our patients, skin lesions disappeared after the first cycle of chemotherapy, although in the third patient, they disappeared after introduction of corticosteroids. In contrast, other investigators have reported that oral corticosteroids or chemotherapy for the underlying disorder inconsistently affected the clinical course of cutaneous vasculitis, and recurrence of skin vasculitis was not prevented. The course of vasculitis appeared to lessen in severity as bone marrow function deteriorated [10, 11]. Our results suggest that patients with acute myelomonocytic leukemia can present with skin vasculitis as the initial manifestation. Patients with unexplainable or persistent small-vessel vasculitic syndromes should be studied carefully because of the possibility of vasculitis caused by a malignant disorder.