Could ehrlichial infection cause some of the changes associated with leukemia, myelodysplastic diseases and autoimmune disorders, and offer antibiotic treatment options?

We hypothesize that a large group of medical conditions of unknown etiology including leukemia, multiple myeloma, myelodysplastic and autoimmune disorders, may be associated with or caused by an obscure group of intracellular obligate parasitic bacteria named Ehrlichia/Anaplasma (EA). Ensconced in the stem cells of the bone marrow, EA may disrupt the normal development and function of many of the cells of immunity, manifesting itself as different syndromes. Recent studies of the activity of EA suggest direct effects on the immune system consistent with the manifestations of leukemia. We reference here three leukemia patients with direct or indirect evidence of EA infection. Moreover, EA have been shown to be most sensitive to rifamycins. Two moribund leukemia patients with levels of platelets and white cells incompatible with life were treated with therapeutic doses of Rifampin. Though they did not survive, their condition improved dramatically for a time, suggesting Rifampin provided some therapeutic benefit. We assert that these results warrant more extensive study.

Gastroduodenal lesions in polycythaemia vera: frequency and role of Helicobacter pylori.

The prevalence of gastroduodenal lesions is higher in polycythaemia vera (PV) than in the general population. However, the role of Helicobacter pylori (H. pylori) in the pathogenesis of such lesions is unknown. The aim of our study was to evaluate the prevalence of gastroduodenal lesions in PV patients and dyspeptic controls, and to assess the role of PV and H. pylori infection in inducing them. Thirty-five PV patients fulfilling selection criteria and 73 age- and sex-matched controls underwent upper gastrointestinal endoscopy. Six gastric mucosal biopsies were taken in all patients and controls, and analysed for presence of H. pylori; serum anti-CagA was assayed by Western blot. Data were analysed with descriptive statistics and multivariate regression analysis. Compared with controls, PV patients showed a significantly higher frequency of erosions (46% versus 12%), ulcers (29% versus 7%), H. pylori positivity (83% versus 57%), and anti-CagA positivity (66% versus 37%). Fourteen out of 20 (70%) asymptomatic PV patients had gastroduodenal lesions. At multivariate analysis, H. pylori, presence of PV alone, and both PV and anti-CagA were significantly and strongly associated with a higher frequency of gastroduodenal lesions (P < 0.05, P < 0.01 and P < 0.05 respectively). Both PV and H. pylori infection were independent risk factors for gastroduodenal lesions; the underlying pathogenetic mechanism responsible for gastroduodenal lesions in PV possibly involves blood mucosal flow and trophism. The higher susceptibility of H. pylori infection and the high frequency of asymptomatic gastroduodenal lesions in PV patients suggest a surveillance of these patients.

Expression of HERV-K proviruses in human leukocytes.

HERV-K is a 50-copy, human endogenous, class 1 retroviral element that contains some polycistrons with gag, pol, and env open reading frames. Although expression of HERV-K proviruses has been shown in cultured human cell lines, expression of these elements has not been shown in human blood leukocytes. Using both reverse transcriptase-polymerase chain reaction and ribonuclease protection techniques, we show HERV-K pol gene expression in human blood leukocytes. Expression in blood leukocytes from 7 normal individuals was from a variety of different HERV-K proviruses, while restricted expression was observed in blood cells of 5 leukemia patients and 3 polycythemia vera patients. Evidence is presented suggesting that the restricted expression in leukemia blood cells is a result of gene regulation, not gene amplification.

Expression of human endogenous retrovirus (HERV-K) in chronic myeloid leukemia.

We have previously demonstrated the presence of a reverse transcriptase-like enzyme in retroviral particles from patients with essential thrombocythemia, polycythemia vera, and chronic myelogenous leukemia. It was subsequently shown that the human genome contains 50 copies of HERV-K. HERV-K is a human endogenous class I retroviral element that contains gag, pol, and env open reading frames. Using both reverse transcriptase-polymerase chain reaction and ribonuclease protection assays, it is demonstrated that the HERV-K pol is expressed in human blood leukocytes. The data indicates that this expression is restricted in CML white cells and is the result of gene regulation.

Detection of retrovirus in patients with myeloproliferative disease.

RNA-directed DNA polymerase (reverse transcriptase) activity was detected in platelets from 4/4 patients with primary proliferative polycythaemia (PPP), 7/7 patients with essential thrombocythaemia (ET), 1/4 patients with relative "stress" polycythaemia, 0/2 patients with secondary polycythaemia, and 0/3 normal subjects. The activity appeared to be particle-associated and was detected under conditions not appropriate for any known cellular enzymes. Active particulate fractions from 1 patient with PPP and 1 patient with ET were examined by electron microscopy and revealed objects with the features of retroviruses. Similar retrovirus-like particles were observed in 2/2 further patients with PPP and 2/2 further patients with ET but in 0/3 controls.

Staphylococcus aureus bacteremia in patients with hematological malignancies and/or agranulocytosis.

A total of 6,253 cases of Staphylococcus aureus bacteremia, including 274 (4.4%) endocarditis cases, were registered in Denmark in the period 1975-1984. Patients with hematological malignancies and/or agranulocytosis accounted for 479 of the bacteremia cases. The incidence of endocarditis in this group of patients was only 0.4% as compared to 4.7% in other patients with staphylococcal bacteremia (p less than 0.01). The lower incidence of endocarditis complicating bacteremia in these patients may justify a shorter course of therapy than usually recommended for suspected endocarditis. Patients with hematological malignancies and other patients with agranulocytosis had a higher mortality (49 and 46%, respectively) than other patients with S. aureus bacteremia (33%). The highest mortality was found in patients with multiple myeloma (71%, p less than 0.01), the lowest in patients with acute lymphocytic leukemia (28%, p less than 0.01). The higher mortality in these patients may indicate that empiric antibiotic regimens in granulocytopenic patients should include a specific anti-staphylococcal agent.

Effect of busulfan on oncornavirus-like activity in platelets and chromosomes in polycythemia vera and essential thrombocythemia.

The effect of busulfan therapy on the activity of oncornavirus-like particles and chromosome patterns in patients with polycythemia vera and essential thrombocythemia was studied. Three patients had pretreatment platelet counts greater than 1 million/microliter, abnormal bone marrow karyotypes, and electron microscopic and biochemical evidence of oncornavirus. The results demonstrated that in all 3 patients virus-like particles and reverse transcriptase-like activity could no longer be found in the platelets within 2-4 weeks after the initiation of busulfan treatment. The platelet count was still elevated at this point for each patient, although the count returned to normal levels within 2-3 weeks after virus-like activity was no longer detectable. The chromosome patterns, characterized by aneuploidy (30-50%) before treatment, improved after therapy.

Particle-associated RNA dependent DNA polymerase and high-molecular-weight RNA in a human cell line derived from polycythemia vera bone marrow.

A particle fraction with a density of 1.15-1.19 g/cm3 was isolated from the cytoplasm of a human cell line established in culture from the bone marrow of an untreated patient with polycythemia vera. Electron micrographs of cross sections of cells and cell homogenates revealed virus-like particles on which DNA could be synthesized. An RNA-dependent DNA polymerase, isolated from the particles, preferred poly(rA)-oligo(dT) over poly(dA)-oligo(dT) and was able to polymerize deoxyguanosine monophosphate in a reaction stimulated by poly(rC)-oligo(dG).

Helper activity of human leukemic tissue extracts for leukemia virus expression in mice.

Extracts of cultured human leukemic tissues increased the spleen focus-forming activity of Friend leukemia virus preparations in BALB/c and other partially resistant mice. Such mice carry the Fv-1(b) gene, which inhibits the expression of helper virus indigenous to the Friend virus complex, and allows co-infecting leukemia viruses of mice, cats, or chickens to substitute for the inhibited helper virus and increase the expression of the spleen focus-forming virus. The helper activity of extracts from human leukemic tissues shared several important properties with that associated with known leukemogenic viruses of animals.