Rare case of severe rhabdomyolysis secondary to human granulocytic anaplasmosis.

Anaplasma phagocytophilum (AP) is the causative agent of human granulocytic anaplasmosis (HGA), a tick-borne illness with highest incidence in north-eastern regions of the United States. This condition presents with vague constitutional symptoms and has been associated with laboratory derangements such as leukopenia, thrombocytopenia and transaminitis1. Rhabdomyolysis, however, is not one of these associations. We report a case of confirmed HGA associated with severe rhabdomyolysis, where no other cause was identified. The etiology of rhabdomyolysis secondary to AP infection is still unknown. A presumptive diagnosis of HGA can be made in the presence of fever, non-specific symptoms such as myalgias, laboratory derangements such as leukopenia and thrombocytopenia in an individual residing in an endemic area3. Serological confirmation should not delay treatment, given the rapid progression of this dangerous infection. Rhabdomyolysis should also be considered as part of supporting data in the diagnostic consideration for HGA.

Antibiotics impair murine hematopoiesis by depleting the intestinal microbiota.

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.

A Mouse Model of Post-Stroke Pneumonia Induced by Intra-Tracheal Inoculation with Streptococcus pneumoniae.

BACKGROUND: Stroke-induced immunodeficiency increases the risk of infectious complications, which adversely affects neurological outcome. Among those, pneumonia affects as many as one third of stroke patients and is the main contributor to mortality in the post-acute phase of stroke. Experimental findings on post-stroke susceptibility to spontaneous pneumonia in mice are contradictory. Here, we established a mouse model inducing standardized bacterial pneumonia and characterized the impaired pulmonary cellular and humoral immune responses after experimental stroke. METHODS: Bacterial pneumonia was induced by intra-tracheal inoculation with Streptococcus pneumoniae at different time points after transient middle cerebral artery occlusion (MCAO). Bacterial counts in lungs and blood, histological changes, and cytokine production in the lungs were assessed. Furthermore, we investigated the effect of pneumonia on stroke outcome. RESULTS: Intra-tracheal inoculation resulted in reproducible pneumonia and bacteraemia, and demonstrated post-stroke susceptibility to streptococcal pneumonia developing with a delay of at least 24 h after MCAO. Higher bacterial counts in mice infected 3 days after stroke induction correlated with reduced neutrophil and macrophage infiltration in the lungs and lower levels of pro-inflammatory cytokines in the broncho-alveolar lavage compared to sham-operated animals. Pneumonia increased mortality without affecting brain-infiltrating leukocytes. CONCLUSIONS: In this standardized mouse model of post-stroke pneumonia, we describe attenuated leukocyte infiltration and cytokine production in response to bacterial infection in the lungs that has a profound effect on outcome.

Severe leukopenia in Staphylococcus aureus-necrotizing, community-acquired pneumonia: risk factors and impact on survival.

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.

Role of cerebrospinal fluid pleocytosis and Haemophilus influenzae type b capsule on blood brain barrier permeability during experimental meningitis in the rat.

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.

Interaction of pseudorabies virus with porcine peripheral blood lymphocytes.

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.

A case of brucellosis presenting with acute hepatitis and bicytopenia.

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.

Adherence to an established diagnostic threshold for ventilator-associated pneumonia contributes to low false-negative rates in trauma patients.

BACKGROUND: The diagnosis of ventilator-associated pneumonia (VAP) in our institution has followed an established diagnostic threshold (DT) of equal to or greater than 10 colony-forming units (CFU) per milliliter on bronchoalveolar lavage (BAL) based on our previous study (PS). Because mortality from VAP is related to treatment delay, some have advocated a lower DT. The purpose of the current study (CS) was to evaluate the impact of adherence to this DT for VAP on false-negative (FN) rates and mortality in trauma patients. METHODS: Consecutive patients over 9 years with VAP (defined as ≥10 CFU/mL in the BAL effluent) subsequent to the PS were identified. Data regarding each BAL performed and the colony counts of each organism identified were recorded. An FN BAL result was defined as any patient who had less than 10 CFU/mL and developed VAP with the same organism up to 7 days after the previous culture. The CS was then compared with the PS. RESULTS: Over 9 years, 1,679 patients underwent 3,202 BALs. Of these, 79% were male, 88% experienced blunt injury, mean age and Injury Severity Score (ISS) were 44 years and 31, respectively. Overall, there were 73 FN BAL results (2.3%) in the CS compared with 3% in the PS (p = 0.092). In those patients with 10 organisms, the FN rate was reduced (7.5% vs. 11%, p = 0.045), and mortality was unchanged (5.4% vs. 8.3%, p = 0.361) in the CS compared with the PS. The use of the threshold equal to or greater than 10 resulted in a cumulative reduction in antibiotic charges of $1.57 million. CONCLUSION: Continued adherence to the diagnostic threshold of equal to or greater than 10 for quantitative BAL in trauma patients has maintained a low incidence of FN BALs and reduced patient charges without impacting mortality. The purported benefit of a lower threshold is not supported. In addition, the potential sequelae of increased resistant organisms, antibiotic-related complications, and costs associated with prolonged unnecessary antibiotic exposure are minimized. LEVEL OF EVIDENCE: Prognostic study, level III.

Carboxypeptidase B2 deficiency reveals opposite effects of complement C3a and C5a in a murine polymicrobial sepsis model.

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.

Characteristics of dermal invasion in experimental cutaneous candidiasis of leucopenic mice.

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.

Thromboxane-blocked swine as an experimental model of severe intravascular inflammation and septic shock.

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.

Infectious complications of febrile leukopenia.

It can be foreseen that in the years to come major improvements in neutropenic host infections will be achieved regarding the exact identification of risk factors, allowing better patient stratification; the application of molecular techniques to recognize pathogens; the development of effective new oral antimicrobials allowing home therapy or abbreviated hospitalization; the development of new antifungals; and the development of new effective immunomodulators and cytokines to ameliorate chemotherapy-induced neutropenia. In the years to come the threat of nosocomial infections unfortunately will not be eliminated, while the development of major new parenteral antibiotics cannot be foreseen. It is therefore the caregiver/physician himself who, by applying rational antibiotic policies and strict handwashing rules, will probably escape, for his neutropenic patient's sake, the imminent threat of multiresistant pathogens.

Pseudomonas aeruginosa orbital phlegmon in a patient treated for myelodysplastic syndrome with concomitant Sjögren's syndrome.

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.

Emergency department presentations of typhoid fever.

Typhoid fever, a systemic infectious disease caused by Salmonella typhi, is classically characterized by fever, paradoxical bradycardia, abdominal pain, and a rose colored rash. This was a retrospective review of 21 confirmed cases over a 5-year period. Mean age was 32.6 years (range 2-60 years), and Mexico (7/21) and El Salvador (3/21) represented the most common countries of origin. Recent travel to an endemic area was noted in 14 patients. The most common complaints were fever (15/21), headache (10/21), abdominal pain (9/21), and diarrhea (6/21). Average duration of symptoms before presentation to the Emergency Department (ED) was 7.9 days. High fever associated with bradycardia was noted in 12 patients. Leukopenia was present in 7 patients. Blood culture was the most sensitive confirmatory test while the Widal test was positive in 7 out of 11 cases. Fever of unknown origin (12/21), followed by presumed typhoid fever (3/21) were the most common ED diagnoses. It is important to recognize that patients with typhoid fever may present to EDs in the US and this disease should be included in the differential diagnosis of febrile patients from Latin America or those with a history of recent travel to endemic countries.

Brucellosis in children in south Jordan.

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.

Comparative study between paratyphoid A and typhoid fever cases.

Twenty eight positive blood culture paratyphoid A fever cases were studied. Forty two positive blood culture typhoid cases were taken as controls. Cases and controls were subjected to: 1) careful history, 2) thorough clinical examination, 3) two blood cultures for salmonella, 4) Widal agglutination test, 5) total and differential white blood count, 6) urine and stool cultures following therapy. There was no significant difference in the clinical picture between acute paratyphoid A fever and acute typhoid fever except the significant decrease of anorexia (57%), toxic look (54%), coated tongue (64%) in acute paratyphoid A cases when compared to acute typhoid cases. The prevalence of extraintestinal symptoms in paratyphoid A cases may mimic viral infections. Three of the 4 classical signs namely; toxic look (54%), bronchitic chest (50%), splenomegaly (72%) and tympanitis (64%) were good bed side suggestive clinical diagnostic aids in paratyphoid A cases. Blood culture was the cornerstone of diagnosis of paratyphoid A cases. In 6 (21%), only the second blood sample was positive stressing the value of multiple cultures. Significant Widal antibody titre was elicited in only about half (57%) of paratyphoid A cases which was significantly lower than typhoid cases (83%). Leucopenia was found in only 25% of paratyphoid A cases. Eosinopenia was constant and is considered as a diagnostic and prognostic aid. No correlation was elicited between either the height of antibody titre or the height of leucocytic count and the severity of illness. There was no significant difference in the response to therapy or the occurrence of complications between paratyphoid A cases and typhoid cases. Up to the current knowledge, this is the first report on comparative study between acute paratyphoid A fever and acute typhoid fever in Egypt from clinical, diagnostic, therapeutic and prognostic points of view.

Comparative study on different recent diagnostic and therapeutic regimens in acute typhoid fever.

Forty five positive blood culture acute typhoid cases were studied during a 2 years period (1997-1999) in Abbassia Fever hospital, Cairo, Egypt. Their ages ranged between 4-23 (12 +/- 2.5) years. Male: Female ratio was 1:1. Three of the 4 classical signs namely: toxic look (84%), bronchitic chest (47%), tumid tympanitic abdomen (84%) and just palpable receding spleen (69%) were found in almost all cases and offer a good bed side clinical diagnostic test. Blood picture revealed anaemia, within normal white blood count and thrombocytopenia. Liver function tests showed within normal total serum bilirubin, two or more folds increase of ALT and within normal serum alkaline phosphatase. Comparing the 3 tests, namely significant Widal titre (56%), modified Widal test (89%) and bright spleen (78%), it was found that modified Widal test is the most sensitive serological test. Ultrasonographic finding of bright spleen is an easy, safe, noninvasive and sensitive technique which is relatively cheap. Each of the 3 drugs in our study namely chloramphenicol, quinolones and ceftriaxone resulted in improvement of general condition, drop of fever, increase in haemoglobin, white blood count and platelet count. Also, there was a significant improvement of liver function tests by either of the 3 drugs. Ceftriaxone is the best drug from the clinical and laboratory points of view followed by quinolones in multidrug resistant (MDR) acute typhoid cases. Chloramphenicol is still the drug of choice in chloramphenicol sensitive salmonellae.

Clinical findings and diagnosis in human granulocytic anaplasmosis: a case series from Massachusetts.

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.

Case studies of lower respiratory tract infections: community-acquired pneumonia.

Community-acquired pneumonia (CAP) is a common and potentially serious illness with significant human and economic costs to society. The recent collaborative statement from the Infectious Diseases Society of America (IDSA) and the American Thoracic Society (ATS) represents the most up-to-date evidence-based guidelines from North America, incorporating important advances in the management of patients with CAP. The cases presented in this review highlight many of the recent recommendations from the IDSA/ATS guidelines.