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Bone marrow suppression is an adverse effect associated with many antibiotics, especially when administered for prolonged treatment courses. Recent advances in our understanding of steady-state hematopoiesis have allowed us to explore the effects of antibiotics on hematopoietic progenitors in detail using a murine model. Antibiotic-treated mice exhibited anemia, thrombocytosis, and leukopenia, with pronounced pan-lymphopenia as demonstrated by flow cytometric analysis of peripheral blood. Bone marrow progenitor analysis revealed depletion of hematopoietic stem cells and multipotent progenitors across all subtypes. Granulocytes and B cells were also diminished in the bone marrow, whereas the number of CD8 + T cells increased. Reductions in progenitor activity were not observed when cells were directly incubated with antibiotics, suggesting that these effects are indirect. Hematopoietic changes were associated with a significant contraction of the fecal microbiome and were partially rescued by fecal microbiota transfer. Further, mice raised in germ-free conditions had hematopoietic abnormalities similar to those seen in antibiotic-treated mice, and antibiotic therapy of germ-free mice caused no additional abnormalities. The effects of antibiotics were phenocopied in Stat1-deficient mice, with no additional suppression by antibiotics in these mice. We conclude that microbiome depletion as a result of broad-spectrum antibiotic treatment disrupts basal Stat1 signaling and alters T-cell homeostasis, leading to impaired progenitor maintenance and granulocyte maturation. Methods to preserve the microbiome may reduce the incidence of antibiotic-associated bone marrow suppression., (© 2017 by The American Society of Hematology.)

Although liver involvement is frequently seen in brucellosis, acute hepatitis is a rare clinical entity. In its progress, haematological findings are non-specific and vary in respect to severity. In this paper, we present a case of brucellosis with acute hepatitis and bicytopenia without anaemia. A 19-year-old man presented with a 2-week history of fever, sweating, low back and leg pain, lassitude, loss appetite, nausea and vomiting. He gave a history of raw milk ingestion and animal contact. Physical examination showed signs of icteric skin and sclera, tenderness in the right hypochondriac region and hepatosplenomegaly. On admission to hospital, laboratory tests showed WBC 3500/mmc (polymorphs 63% and lymphocytes 33%), haemoglobin 13.8 g/dL, platelet 89000/mmc, erythrocyte sedimentation rate 19 mm/h, and C-reactive protein 21.7 mg/dL (N<0.8 mg/dL). Biochemical tests were as follows: AST 771 U/L, ALT 471 U/L, ALP 355 U/L, GGT 432 U/L, total bilirubin 2.61 mg/dL, direct bilirubin 1.45 mg/dL and albumin 3.7 g/dL. Viral hepatitis markers were found to be negative (HBsAg, anti-HBc total, anti-HBc IgM, anti-HAV IgM, and anti-HCV). Blood culture grew Brucella melitensis. Leukopenia and thrombocytopenia returned to normal levels at the 7th and 14th day of his admission, respectively. Liver function tests improved at the 28th day. Treatment of the brucellosis was performed with antibiotics (tetracycline 500 mg orally four times daily for 6 weeks and streptomycin 1 g IM once daily for 21 days). Finally, a case of brucellosis with acute hepatitis and bicytopenia was treated with a successful outcome. In conclusion, we suggest that due consideration be taken of bicytopenia/pancytopenia and acute hepatitis in brucellosis cases in Turkey, an endemic region.

Background and Objectives: Carboxypeptidase B2 (CPB2) is a basic carboxypeptidase with fibrin and complement C3a and C5a as physiological substrates. We hypothesized that in polymicrobial sepsis, CPB2-deficient mice would have sustained C5a activity, leading to disease exacerbation., Methods: Polymicrobial sepsis was induced by cecal ligation and puncture (CLP)., Results: Contrary to our hypothesis, Cpb2(-/-) mice had significantly improved survival, with reduced lung edema, less liver and kidney damage, and less disseminated intravascular coagulation. Hepatic pro-CPB2 was induced by CLP, leading to increased pro-CPB2 levels. Thrombomodulin present on mesothelium supported thrombin activation of pro-CPB2. Both wild-type and Cpb2(-/-) animals treated with a C5a receptor antagonist had improved survival, demonstrating that C5a was detrimental in this model. Treatment with a fibrinolysis inhibitor, tranexamic acid, caused a decrease in survival in both genotypes; however, the Cpb2(-/-) animals retained their survival advantage. Administration of a C3a receptor antagonist exacerbated the disease in both wild-type and Cpb2(-/-) mice and eliminated the survival advantage of Cpb2(-/-) mice. C5a receptor is expressed in both peritoneal macrophages and neutrophils; in contrast, C3a receptor expression is restricted to peritoneal macrophages, and C3a induced signaling in macrophages but not neutrophils., Conclusions: While C5a exacerbates the peritonitis, resulting in a deleterious generalized inflammatory state, C3a activation of peritoneal macrophages may limit the initial infection following CLP, thereby playing a diametrically opposing protective role in this polymicrobial sepsis model., (© 2015 International Society on Thrombosis and Haemostasis.)

Background: Necrotizing pneumonia attributed to Panton-Valentine leukocidin-positive Staphylococcus aureus has mainly been reported in otherwise healthy children and young adults, with a high mortality rate. Erythroderma, airway bleeding, and leukopenia have been shown to be predictive of mortality. The objectives of this study were to define the characteristics of patients with severe leukopenia at 48-h hospitalization and to update our data regarding mortality predicting factors in a larger population than we had previously described., Methods: It was designed as a case-case study nested in a cohort study. A total of 148 cases of community-acquired, necrotizing pneumonia were included. The following data were collected: basic demographic information, medical history, signs and symptoms, radiological findings and laboratory results during the first 48 h of hospitalization. The study population was divided into 2 groups: (1) with severe leukopenia (leukocyte count ≤3,000 leukocytes/mL, n=62) and (2) without severe leukopenia (>3,000 leukocytes/mL, n=86)., Results: Median age was 22 years, and the male-to-female gender ratio was 1.5. The overall in-hospital mortality rate was 41.2%. Death occurred in 75.8% of severe leukopenia cases with median survival time of 4 days, and in 16.3% of cases with leukocyte count >3,000/mL (P<0.001). Multivariate analysis indicated that the factors associated with severe leukopenia were influenza-like illness (adjusted odds ratio (aOR) 4.45, 95% CI (95% confidence interval) 1.67-11.88, P=0.003), airway bleeding (aOR 4.53, 95% CI 1.85-11.13, P=0.001) and age over 30 years (aOR 2.69, 95% CI 1.08-6.68, P=0.033). A personal history of furuncles appeared to be protective (OR 0.11, 95% CI 0.01-0.96, P=0.046)., Conclusion: S. aureus-necrotizing pneumonia is still an extremely severe disease in patients with severe leukopenia. Some factors could distinguish these patients, allowing better initial identification to initiate adapted, rapid administration of appropriate therapy.

Objective: To describe clinical findings and the use of a tick-associated pathogen panel in a series of patients with human granulocytic anaplasmosis (HGA) at a suburban Boston hospital., Patients and Methods: Medical records were reviewed for inpatients and outpatients at Newton-Wellesley Hospital with a positive polymerase chain reaction (PCR) result for Anaplasma phagocytophilum during the study period March 1 through November 30, 2009. A PCR panel was used to test for tick-borne pathogens. Postal ZIP code data from the patients' areas of residence were used to estimate the area of disease transmission., Results: Thirty-three cases were confirmed during the 2009 transmission season, and 14 of these patients (42%) required hospitalization. Thrombocytopenia and/or leukopenia were observed at the time of presentation in 25 of 30 patients (86%) in whom both white blood cell and platelet counts were determined, and 28 of 33 patients (85%) reported fever. Rash occurred in only 2 of the 33 patients (6%), and 25 (76%) reported one or more respiratory or gastrointestinal symptom. Cases were geographically distributed diffusely throughout the hospital catchment area, with one possible focus of infection identified in Weston, MA. Due to a lack of clinical data reporting to the Massachusetts Department of Public Health, only 20 of 32 HGA cases (63%) fulfilled the case confirmation criteria., Conclusion: Diagnosis of HGA requires a high suspicion for infection even in endemic areas. Use of a tick-associated pathogen panel that includes PCR assays for several organisms could improve detection of underrecognized tick-borne diseases in endemic areas. Lack of epidemiological follow-up to confirm corroborating clinical findings prevents accurate case reporting and assessment of the true HGA burden., (Copyright © 2012 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Pathology data from the anthrax animal models show evidence of significant increases in vascular permeability coincident with hemostatic imbalances manifested by thrombocytopenia, transient leucopenia, and aggressive disseminated intravascular coagulation. In this study we hypothesized that anthrax infection modulates the activity of von Willebrand factor (VWF) and its endogenous regulator ADAMTS13, which play important roles in hemostasis and thrombosis, including interaction of endothelial cells with platelets. We previously demonstrated that purified anthrax neutral metalloproteases Npr599 and InhA are capable of cleaving a variety of host structural and regulatory proteins. Incubation of human plasma with these proteases at 37 degrees C in the presence of urea as a mild denaturant results in proteolysis of VWF. Also in these conditions, InhA directly cleaves plasma ADAMTS13 protein. Npr599 and InhA digest synthetic VWF substrate FRETS-VWF73. Amino acid sequencing of VWF fragments produced by InhA suggests that one of the cleavage sites of VWF is located at domain A2, the target domain of ADAMTS13. Proteolysis of VWF by InhA impairs its collagen binding activity (VWF:CBA) and ristocetin-induced platelet aggregation activity. In plasma from anthrax spore-challenged DBA/2 mice, VWF antigen levels increase up to 2-fold at day 3 post-infection with toxigenic Sterne 34F(2) strain, whereas VWF:CBA levels drop in a time-dependent manner, suggesting dysfunction of VWF instead of its quantitative deficiency. This conclusion is further supported by significant reduction in the amount of VWF circulating in blood in the ultra-large forms. In addition, Western blot analysis shows proteolytic depletion of ADAMTS13 from plasma of spore-challenged mice despite its increased expression in the liver. Our results suggest a new mechanism of anthrax coagulopathy affecting the levels and functional activities of both VWF and its natural regulator ADAMTS13. This mechanism may contribute to hemorrhage and thrombosis typical in anthrax.

We evaluated the virulence of Pseudomonas aeruginosa carrying bla(IMP), a metallo-beta-lactamase gene, and the efficacy of ceftazidime, imipenem-cilastatin, and ciprofloxacin in the endogenous bacteremia model. The presence of bla(IMP) did not practically change the virulence of the parent strain, and ciprofloxacin was effective against infection with P. aeruginosa carrying bla(IMP).

BAL5788 is a water-soluble prodrug of BAL9141, a new broad-spectrum cephalosporin with high levels of in vitro activity against methicillin- and vancomycin-resistant staphylococci and penicillin-resistant streptococci. In plasma BAL5788 is rapidly converted to BAL9141. We studied the activity of BAL5788 in a mouse model of acute pneumococcal pneumonia. Leukopenic female Swiss albino mice were challenged intratracheally with 10(7) CFU of clinical Streptococcus pneumoniae strains P-52181 (Pen(s) Cro(s) Ctx(s)), P-15986 (Pen(r) Cro(s) Ctx(s)), P-40422 (Pen(r) Cro(r) Ctx(r)), and P-40984 (Pen(r) Cro(r) Ctx(r)). Infected mice received subcutaneous (s.c.) injections of BAL5788 or ceftriaxone starting 3 h after pneumococcal challenge. Uninfected nonleukopenic mice received single s.c. doses of BAL5788 to determine the BAL9141 concentration-time profiles in serum and lungs. Untreated control mice died within 5 days postinfection. Ten-day cumulative survival rates for infected mice receiving BAL5788 (total daily doses of BAL9141 equivalents, 2.1 to 75 mg/kg of body weight) ranged from 57 to 100%, whereas with ceftriaxone (total daily doses, 10 to 400 mg/kg), the survival rates varied between 13 and 100%. In mice infected with P-15986, the survival rates achieved with BAL5788 (BAL9141 equivalent, 8.4 mg/kg) and those achieved with ceftriaxone (50 mg/kg) were significantly different (93 versus 13%; P < 0.0001) in favor of BAL5788; the outcomes of the trials with all other strains were not significantly different between the two antibiotics, but markedly lower doses of BAL5788 than ceftriaxone were required to obtain similar survival rates. Pharmacokinetic data showed that BAL9141 was effective against the four pneumococcal strains tested at very low values of the time above the MIC (T > MIC), which ranged from 9 to 18% of the dosing interval, whereas the values of T > MICs for ceftriaxone ranged from 30 to 50% of the dosing interval.

The agent of human granulocytic ehrlichiosis (aoHGE) is a tick-borne, obligate intracellular, granulocytotropic bacterium able to infect numerous host species. Given its unique niche and the leukopenia often noted with infection, we investigated the effect of acute aoHGE infection on neutrophil activation by evaluating surface expression of the beta 2 integrin CD11b/CD18 in a mouse model using FACS analysis. Infection resulted in neutrophil activation with up-regulation of CD11b/CD18 in multiple strains of mice, however, hematologic analysis showed no apparent role for CD11b/CD18 in mediating peripheral leukopenia. Because IFN-gamma is an important cytokine during granulocytic ehrlichiosis and is known to activate leukocytes, we investigated the potential role of IFN-gamma in CD11b/CD18 up-regulation. Neutrophils from IFN-gamma knock-out mice became activated during aoHGE infection, however, the kinetics of activation differed from wild-type mice. In addition, activation correlated directly with the presence of bacteria because neutrophils with large intracytoplasmic morula also expressed higher levels of CD11b/CD18. CD11b/CD18 seemed to be critical to early bacterial clearance and killing in vivo because infection of mice with targeted genetic disruption of CD11b/CD18 resulted in an initial increase in bacterial burden compared with wild-type mice. Similarly, in vitro culture of neutrophils from infected CD11b/CD18 knock-out mice resulted in a marked increase in bacterial proliferation compared with congenic controls. The data support crucial roles of CD11b/CD18 and IFN-gamma-mediated cell activation as mechanisms that limit bacterial replication.

Long-circulating liposomes (LCL) may be used as targeted antimicrobial drug carriers as they localize at sites of infection. As a result, LCL-encapsulated gentamicin (LE-GEN) has demonstrated superior antibacterial activity over the free drug in a single-dose study of immunocompetent rats with Klebsiella pneumoniae pneumonia. In the present study, the therapeutic efficacy of LE-GEN was evaluated by monitoring rat survival and bacterial counts in blood and lung tissue in clinically relevant models, addressing the issue of impaired host defense and low bacterial antibiotic susceptibility. The results show that in immunocompetent rats infected with the high-GEN-susceptibility K. pneumoniae strain, a single dose of LE-GEN is clearly superior to an equivalent dose of free GEN. Yet complete survival can also be obtained with multiple doses of free GEN. In leukopenic rats infected with the high-GEN-susceptible K. pneumoniae strain, free GEN at the maximum tolerated dose (MTD) was needed to obtain survival. However, with the addition of a single dose of LE-GEN to free-GEN treatment, complete survival can be obtained using a sevenfold-lower cumulative amount of GEN than with free-GEN treatment alone. In leukopenic rats infected with low-GEN-susceptible K. pneumoniae cells, free GEN at the MTD did not result in survival. The use of LE-GEN is needed for therapeutic success. Increasing LE-GEN bilayer fluidity resulted in an increased GEN release from the liposomes and hence improved rat survival, thus showing the importance of the liposome lipid composition for therapeutic efficacy. These results warrant further clinical studies of liposomal formulations of aminoglycosides in immunocompromised patients with severe infections.

Retrospectively we evaluated the records of 68 children with brucellosis. We found 58.2% had consumed unpasteurized milk and dairy products. Nonspecific manifestations included: arthralgia (78%), fever (75%) and sweating (60%). Localized manifestations included limping (75%) and arthritis (54%). Leukopenia was found in 51% of children and anaemia in 24%. Brucella species was cultured for blood of 16 (23.5%) patients. Combination therapy containing streptomycin was more effective than gentamicin combinations.

Pseudomonas aeruginosa orbital infections have been described very rarely in patients with neutropenia after chemotherapy. We report the case of a woman with the unusual association of Sjögren's disease and myelodysplasia, who suffered from a Pseudomonas aeruginosa orbital phlegmon after chemotherapy for her myelodysplastic syndrome. Partial intestinal antibiotic decontamination with ciprofloxacine did not prevent the infection. She was treated successfully with intravenous ceftazidime, netilmicin and granulocyte-colony stimulating factor (G-CSF). The normalization of the granulocyte count seems to play a crucial role for recovery. We present the clinical and radiological findings, discuss the therapy and review the literature concerning ocular infections due to Pseudomonas. Other infections due to this germ in immunocompromised hosts are briefly reviewed.

The increasing emergence of penicillin-resistant and multidrug-resistant strains of Streptococcus pneumoniae will create a serious therapeutic problem in coming years. Trovafloxacin is a novel naphthyridone quinolone with promising activity against S. pneumoniae, including penicillin-resistant strains (MIC for 90% of the isolates tested, 0.25 microg/ml). We compared its in vivo efficacy with that of other fluoroquinolones (ciprofloxacin, temafloxacin, and sparfloxacin) and a reference beta-lactam (amoxicillin) in a model of acute experimental pneumonia. Immunocompetent Swiss mice were infected by peroral tracheal delivery of a virulent, penicillin-susceptible strain (MIC, 0.03 microg/ml); leukopenic Swiss mice were infected with three poorly virulent, penicillin-resistant strains (MICs, 4 to 8 microg/ml) and a ciprofloxacin-resistant strain (MIC, 32 microg/ml). Treatments were started 6 h (immunocompetent mice) or 3 h (leukopenic mice) after infection. Doses ranging from 12.5 to 300 mg/kg were given at 12- or 8-h intervals for 3 days. Trovafloxacin (25 mg/kg) was the most effective agent in vivo against penicillin-susceptible and -resistant strains. Corresponding survival rates were 2- to 4-fold higher than with 50-mg/kg sparfloxacin or temafloxacin and 8- to 16-fold higher than with 100-mg/kg ciprofloxacin. The ratios of the area under the concentration-time curve to the MIC in serum and lung tissue were more favorable with trovafloxacin than with the other quinolones. Efficacy in vivo correlated with pharmacokinetic parameters. Trovafloxacin shows potential for the treatment of infections due to penicillin-susceptible and -resistant S. pneumoniae but appears to be ineffective against a ciprofloxacin-resistant strain.

The cardiopulmonary response elicited by intravenous bacteria or endotoxin is well characterized in swine and has two major components. The first represents the acute pulmonary and broncho-constrictive phase (0-2 h) and the second phase (3-8 h) represents increased microvascular permeability, hypotension, and enhanced leukocyte-endothelial adhesion. The pulmonary vasoconstriction and bronchoconstriction of phase 1 results in acute pulmonary hypertension and airway dysfunction, which may result in rapid mortality. Because this acute pulmonary response may not mimic the development of human septic shock, we sought to block this early phase and examine the role of tumor necrosis factor in the latter septic phase (3-8 h). Employing a thromboxane A2 (TXA2) receptor antagonist (BAY U 3405) in the presence of LD100 Escherichia coli challenge, we blocked the acute pulmonary hypertensive phase and prevented early mortality, however, TXA2 blockade did not affect the latter development of septic shock and death. This latter lethal phase, characterized by prolonged leukopenia, was blocked in a dose-dependent manner by tumor necrosis factor monoclonal antibody. We conclude that the TXA2-blocked E. coli-challenged swine may provide a novel animal model in which to investigate the pathophysiology of acute septic shock.

Acute, sublethal infection of mice with murine cytomegalovirus (MCMV) resulted in up to 80% decreases in the number of cells recoverable from the bone marrow, and a decrease in peripheral blood leucocyte counts during the first week of infection. Depopulation of the leucopoietic areas of the marrow was evident from examination of histological sections. The severity of bone marrow atrophy in MCMV-infected mice of different strains correlated with previously described genetically determined sensitivity to MCMV disease. Although the phenomenon only occurred when mice were inoculated with infectious virus preparations, fewer than one in 10(5) marrow cells were productively infected, suggesting that atrophy was not due to lytic infection of large numbers of bone marrow cells. Interestingly, increases in serum colony-stimulating activity were observed and these were proportional to the severity of bone marrow atrophy. After MCMV infection, we observed increases in the proportions of cells expressing some B-cell and myeloid cell markers and a decrease in the proportion of cells expressing an erythroid cell marker. There was no change in the frequency of marrow cells expressing mature T-cell markers. The numbers of myeloid lineage-committed progenitor cells (GM-CFU) in the marrow decreased 10- to 20-fold in BALB/c nu/+ mice, while there was a threefold decrease in their numbers in BALB/c nu/nu mice. In addition, increases in serum colony-stimulating activity were greater in BALB/c nu/+ mice than in BALB/c nu/nu mice. Our results suggest that growth factors produced after MCMV infection may accelerate the maturation and migration of cells from the marrow to sites of virus replication and inflammation, thus accounting for the depletion in numbers of marrow cells observed soon after MCMV infection.

To examine effects of pseudorabies virus (PrV) on immune cells, we investigated the ability of PrV to infect and replicate in porcine peripheral blood leukocytes (PBLs). Flow cytometric analysis revealed a leukopenia after challenge, with loss of 40% of circulating monocytes and 50% of circulating lymphocytes. Virus was isolated from PBLs of challenged pigs by cocultivation with porcine kidney cells, indicating that PBLs were infected in vivo. Presence of virus in PBLs coincided with the appearance of neurological signs 1 to 2 days prior to death. Lymphocytes stimulated with mitogens and infected in vitro sustained a low-level infection (10(5) median tissue culture infective dose per 2 x 10(6) cells). In vivo challenge perturbed the CD4/CD8 ratio of circulating lymphocytes. Survival was associated with low CD4/CD8 ratios and high levels of CD8+ cells. Mortality was associated with low levels of CD8+ cells and CD4/CD8 ratios greater than one. A maturational deficiency of CD8+ cells was found in young pigs. Our results support a mechanism of PrV immunosuppression through direct infection of circulating lymphocytes, with CD8+ T lymphocytes being important for survival.

The efficacy of SCH 39304 (SCH) against Aspergillus fumigatus was assessed with an immunosuppressed, temporarily leukopenic rabbit model of invasive aspergillosis. Therapy with SCH at 10 or 15 mg/kg of body weight per day was begun 24 h after lethal challenge and compared with therapy with amphotericin B at 1.5 mg/kg/day. Compared with untreated controls, SCH reduced mortality and also reduced the tissue burden of A. fumigatus 100- to 1,000-fold in liver, kidney, and lung tissues. SCH at 15 mg/kg/day and amphotericin B eliminated A. fumigatus in liver, kidney, and lung tissues. In addition, both dosages of SCH significantly eliminated the organism from brain tissues, compared with controls. Both SCH and amphotericin B decreased or eliminated circulating aspergillus antigen. These results show that new azoles can be as effective as amphotericin B in eradicating the organism from tissues and offer promise in improving the treatment of invasive aspergillosis.

The antibacterial activities of ciprofloxacin and ceftazidime against Klebsiella pneumoniae in vitro and in vivo were compared. Although there was only a minor difference between the MBCs of both drugs, the bacterial killing rate of ciprofloxacin in vitro was very fast in comparison with that of ceftazidime. Similarly, the intravenous administration of ciprofloxacin at 1 h after bacterial inoculation resulted in effective bacterial killing in the lungs of leukopenic rats. This killing was dose dependent, in contrast to the dose-independent bactericidal effect of ceftazidime. The high antibacterial activity of ciprofloxacin in the lungs as compared with that of ceftazidime was also reflected in its therapeutic efficacy in K. pneumoniae pneumonia and septicemia in leukopenic rats when these infections were treated at 6-h intervals over 4 days, starting at 5 h after bacterial inoculation. Concentrations of ciprofloxacin and ceftazidime in lung tissue were not significantly different. Regarding the antibacterial activity of both drugs against K. pneumoniae in relation to the bacterial growth rate in vitro and in the lungs of leukopenic rats, ciprofloxacin killed K. pneumoniae organisms that were not actively growing, whereas ceftazidime did not. In addition, it was demonstrated that when the intravenous administration of antibiotic was delayed from 1 h up to 24 h after bacterial inoculation, ceftazidime lost its antibacterial activity in the lungs and blood of leukopenic rats, whereas ciprofloxacin was still very effective. These data suggest that the capacity of an antibiotic to kill bacteria at a slow growth rate may be relevant for its therapeutic effect in established infections, in which slowly growing bacteria form a substantial part of the total bacterial population.

Fifty-six of 67 patients with antibody to cytomegalovirus before transplantation shed cytomegalovirus from urine and/or saliva postoperatively. Symptomatic reactivation occurred in 17 (25%) patients, five of whom had pneumonitis. The symptomatic patients were more likely to have received a cadaver kidney (P = 0.004) and high-dosage antithymocyte globulin (P = 0.003) and to be viremic (P < 0.0001), compared to patients with silent infection. Forty-eight of 49 patients treated with antithymocyte globulin received cadaver or parent donor kidneys. Twenty-four were given a low-dosage intramuscular regimen, and 25 received a higher dosage intravenously. In the latter group 48% experienced symptomatic reactivation adn 48% viremia, compared to 21% and 17%, respectively, in the former group (P < 0.05 for both comparisons). There were no symptomatic cytomegaloviral infections among 18 patients not treated with antithymocyte globulin, all of whom received related donor kidneys. Renal transplant patients who receive both a poorly matched graft and antithymocyte globulin are at increased risk of morbidity due to cytomegalovirus.

We report two cases of a T cell lymphoproliferative disease not previously described, with cytologic and clinical features similar to those associated with Galton's "prolymphocytic" leukemia (PL). Our patients, like those with Galton's PL, had massive splenomegaly and minimal or absent hepatomegaly and lymphadenopathy. In contrast, however, our patients had leukopenia, as well as low percentages of leukemic cells in the peripheral blood and in the bone marrow. In splenic imprints, the nuclear chromatin pattern of most of the leukemic cells was intermediate between those of mature lymphocytes and those of lymphoblasts, and the nuclei contained single, centrally located, conspicuous nucleoli. In sections of the spleen, the leukemic cells diffusely infiltrated the red pulp in a pattern strikingly similar to that of hairy cell leukemia; however, when the leukemic cells were studied cytochemically, the cytoplasmic acid phosphatase positivity was punctate and tartrate-sensitive. The leukemic cells were sheep erythrocyte rosette-positive and expressed T cell-associated antigens. Initially, both patients responded well to therapeutic splenectomy. One patient received combination chemotherapy after splenectomy and is alive and well 24 months after diagnosis. The other patient was in complete clinical remission for one year after splenectomy and received chemotherapy at relapse. He died, however, 23 months after splenectomy, with disseminated disease. IgG antibody titers against human T lymphotropic virus type I (HTLV-I) were detected in one patient and against HTLV-II in the other. The leukemia in these patients represents a distinct clinicopathologic entity within the spectrum of peripheral T cell lymphoproliferative diseases that includes Galton's PL of T cell derivation, T cell chronic lymphocytic leukemia, T cell hairy cell leukemia, and adult T cell leukemia/lymphoma.

The course of experimental cutaneous Candida albicans infections produced in mice made leucopenic by the administration of cyclophosphamide was compared to that in untreated animals. In the latter, neutrophils characteristically infiltrated the area of infection and the organisms were virtually always confined to the epidermis. However, even though many fewer foci of infection were associated with neutrophils in the cyclophosphamide-treated animals, a majority of these foci were also unable to penetrate past the epidermis. Although Candida yeast proliferated relatively poorly when cultured in homogenates of skin lacking the epidermis, Candida pseudohyphae could invade into the dermis if inoculated skin was isolated from normal animals and cultured in vitro, or if the epidermis was removed by gentle scraping prior to inoculation with Candida yeast onto the remaining skin of leucopenic animals. Therefore, in the absence of neutrophil contact and killing of Candida pseudohyphae in the epidermis, other cutaneous defense mechanisms appear to be capable of preventing invasion of a majority of the organisms into the dermis. These findings may help to explain why deep Candida infections are rare in patients who have extensive superficial candidiasis.

The influence of leukocytes and Haemophilus influenzae type b (Hib) capsule on blood brain barrier permeability (BBBP) to circulating 125I-albumin in normal and leukopenic rats was assessed after intracisternal inoculation of encapsulated (Rd-/b+/02) or unencapsulated (Rd-/b-/02) isogenic strains of Hib. Both normal and leukopenic animals had increased BBBP 18 h after inoculation, with normal rats demonstrating significantly increased BBBP after challenge with the encapsulated strain. Despite cerebrospinal fluid (CSF) pleocytosis in normal rats, CSF bacterial concentrations were not lower. Normal rats cleared unencapsulated Rd-/b-/02 more effectively than leukopenic rats, with BBBP correlating with CSF bacterial density and not leukocyte concentrations. Challenge with heat-killed Rd-/b+/02 resulted in increased BBBP in both normal and leukopenic rats, with greater BBBP at higher bacterial concentrations. The data suggest: (a) significant increases in BBBP occur in the near absence of CSF leukocytes; (b) CSF leukocytes can augment changes in BBBP; (c) type b capsule inhibits host clearance mechanisms within the CSF; and (d) BBBP appears to correlate with bacterial concentrations within the CSF.