Persistent neutrophilic meningitis. Report of four cases and review of the literature

Persistent neutrophilic meningitis is a poorly described variant of chronic meningitis characterized by the persistence of neutrophils in the CSF over extended periods of time (greater than 1 wk) in association with ongoing signs of meningeal inflammation and negative CSF cultures for bacteria and other pathogens. Although the incidence of persistent neutrophilic meningitis is difficult to ascertain, a review of available literature on CNS infections suggests that this entity is not rare. Etiologies of this syndrome are both infectious and noninfectious. Among infectious causes, bacteria such as Nocardia and Actinomyces and systemic mycoses such as Aspergillus and the zygomycetes are the predominant pathogens. The pathogenesis of the persistent neutrophilic CSF response is unknown; with some infectious etiologies, there may be a correlation between neutrophil response and the morphology of the invading organism. Mycelial-like pathogens appear to be the primary stimulus for an ongoing neutrophilic inflammatory response. In cases of persistent neutrophilic meningitis, epidemiologic features and clinical setting frequently offer clues to the etiologic agent, especially in the immunocompromised host. Evaluation should include repetitive cultural and serologic studies of the CSF with special emphasis upon special cultural methods, antigen detection and detection of characteristic metabolic byproducts. Biopsy of extraneural sites of disease should be pursued whenever possible to provide data for an inferential diagnosis of CNS disease. CNS biopsies should be selectively performed in those patients undergoing craniotomy for evaluation of mass lesions. Therapy must be individualized. However, in the immunocompromised host, consideration should be given to the empiric use of amphotericin B with or without a sulfonamide in undiagnosed cases that manifest progressive clinical deterioration.     

The immune response to fungal infections

During the past two decades, invasive fungal infections have emerged as a major threat to immunocompromised hosts. Patients with neoplastic diseases are at significant risk for such infections as a result of their underlying illness and its therapy. Aspergillus, Candida, Cryptococcus and emerging pathogens, such as the zygomycetes, dark walled fungi, Trichosporon and Fusarium, are largely opportunists, causing infection when host defences are breached. The immune response varies with respect to the fungal species and morphotype encountered. The risk for particular infections differs, depending upon which aspect of immunity is impaired. This article reviews the current understanding of the role and relative importance of innate and adaptive immunity to common and emerging fungal pathogens. An understanding of the host response to these organisms is important in decisions regarding use of currently available antifungal therapies and in the design of new therapeutic modalities.     

Herpes simplex virus type 2 infections of the central nervous system: A retrospective study of 49 patients

Herpes simplex virus type 2 (HSV-2) infections of the central nervous system (CNS) are rare with meningitis as the most common clinical presentation. We have investigated the clinical spectrum of CNS infections in 49 adult consecutive patients with HSV-2 genome in the cerebrospinal fluid (CSF). HSV-2 in the CSF was determined by polymerase chain reaction (PCR), and patients were diagnosed as encephalitis or meningitis according to predefined clinical criteria by retrospective data information from consecutive clinical journals. The annual crude incidence rate of HSV-2 CNS disease was 0.26 per 100,000. 43 (88%) had meningitis of whom 8 (19%) had recurring lymphocytic meningitis. Six patients (12%) had encephalitis. 11 of 49 patients (22%) had sequelae recorded during follow-up. None died as a result of HSV-2 CNS disease. Thus, the clinical presentation of HSV-2 infection of the CNS is mainly meningitis but encephalitis does occur and neurological sequelae are common. Recurring lymphocytic meningitis is associated with reactivation of HSV-2 and the condition might be underdiagnosed.     

Cytokines and fungal infections

The very poor outcome of invasive fungal infections (IFI) in patients with haematological malignancies or recipients of haematopoietic stem cell transplantation is largely attributed to their compromised host defence mechanisms. The restoration or augmentation of immune responses in these patients is now considered as one of the cornerstones of effective antifungal therapy. Major advances in the field of experimental immunology have provided insight on the important regulatory role of cytokines in both innate and adaptive immunity to fungal pathogens. Preclinical studies have convincingly demonstrated that immunomodulation with cytokines can enhance the antifungal activity of neutrophils and monocytes/macrophages as well as upregulate protective T-helper type 1 adaptive immune responses. Evidence on the clinical use of cytokines in immunocompromised hosts with IFI is, however, still scant and inconclusive. The present review summarizes experimental and clinical data on the role of cytokines in the immune response to fungal pathogens and on their potential use for prevention or treatment of fungal infections. Implications for future research are also briefly discussed.     

Antiviral therapy for respiratory tract infections

Viruses are important pathogens causing respiratory tract infections both in the community and health-care facility settings. They are extremely common causes of morbidity in the competent hosts and some are associated with significant mortality in the compromised individuals. With wider application of molecular techniques, novel viruses are being described and old viruses are found to have new significance in different epidemiological and clinical settings. Some of these emerging pathogens may have the potential to cause pandemics or global spread of a severe disease, as exemplified by severe acute respiratory syndrome and avian influenza. Antiviral therapy of viral respiratory infections is often unnecessary in the competent hosts because most of them are selflimiting and effective agents are not always available. In the immunocompromised individuals or for infections caused by highly pathogenic viruses, such as avian influenza viruses (AIV), antiviral treatment is highly desirable, despite the fact that many of the agents may not have undergone stringent clinical trials. In immunocompetent hosts, antiviral therapy can be stopped early because adaptive immune response can usually be mounted within 5-14 days. However, the duration of antiviral therapy in immunosuppressed hosts depends on clinical and radiological resolution, the degree and duration of immunosuppression, and therefore maintenance therapy is sometimes needed after the initial response. Immunotherapy and immunoprophylaxis appear to be promising directions for future research. Appropriate and targeted immunomodulation may play an important adjunctive role in some of these infections by limiting the extent of end-organ damage and multi-organ failure in some fulminant infections.     

Noninfectious lung disease in the immunocompromised host.

Patients with compromised immune function suffer a wide variety of lung insults. Infections are the most common causes of both acute and chronic lung diseases, but many noninfectious conditions affect the lungs. The clinical presentation of these noninfectious conditions often mimic infections, thus causing diagnostic dilemmas. The spectrum of noninfectious lung injury and response in the immunosuppressed host includes interstitial edema, interstitial fibrosis, diffuse idiopathic pneumonia, acute respiratory distress syndrome, and obliterative bronchiolitis. Alveolar hemorrhage may complicate any of these conditions. Lung injury in the immunosuppressed host is associated with a diversity of etiologies: sepsis, irradiation, graft rejection, reperfusion injury, graft-versus-host disease, and chemotherapeutic agents and other drug reactions. These injuries most often present as diffuse pulmonary infiltrates on chest radiograph. Establishing a specific diagnosis and etiology for the injury is often problematic. From a pragmatic standpoint, excluding the possibility of infection is the principal aim of diagnostic testing.     

Parasitic diseases in immunocompromised hosts

In patients with compromised host defenses, diseases caused by protozoans and nematodes appeared, a few years ago, to be declining in importance. However, the outbreak of the acquired immunodeficiency syndrome (AIDS) among homosexual men, parenteral drug abusers, and other groups has made it necessary for physicians to familiarize themselves again with the manifestations of these diseases in abnormal hosts. The groups of patients at greatest risk, the usual clinical syndromes in abnormal hosts, and current approaches to diagnosis, treatment, and prevention of infections due to Pneumocystis carinii, Toxoplasma gondii, Strongyloides stercoralis, and organisms of the genus Cryptosporidium are reviewed. Because so many cases of these infections have recently occurred among patients with AIDS, recent experience with these diseases in AIDS patients at Memorial Sloan-Kettering Cancer Center is summarized.     

中枢神经系统少见真菌感染35例临床分析

目的 了解中枢神经系统少见真菌感染的临床特点.方法 收集1997年至2010年复旦大学附属华山医院收治的中枢神经系统少见真菌感染病例,共35例,对其病原菌种类、临床特点、疗效等进行回顾性分析,统计学方法采用秩和检验和Fisher确切概率法.结果 35例患者中确诊29例,临床诊断6例.30例患者存在一种或多种易感因素,占86%,致病菌主要有曲霉感染16例,念珠菌感染14例.常见的临床表现有发热22例.头痛19例,脑神经受累12例,脑膜刺激征12例.脑脊液变化为WBC增多、蛋白含量升高及糖含量降低.其中曲霉感染患者多存在免疫力低下的基础疾病,常由邻近部位感染或血流播散所致,以头痛和脑神经受累等脑实质损害为主;而念珠菌感染患者多继发于颅脑手术或外伤后,以发热、脑膜刺激征以及脑脊液异常等脑膜炎表现为主.总有效率为77%(27/35),其中曲霉感染患者以颅内病灶手术清除联合抗真菌药物疗效较佳;念珠菌感染由于多继发于颅脑手术.尤其是脑脊液外引流术,抗真菌药物治疗同时更换或拔除引流管可达到较好疗效.结论 近年来曲霉、念珠菌等中枢神经系统少见真菌感染有明显增多趋势,而早期诊断和及时治疗是改善预后的关键.

Abstract：

Objective To analyze the clinical features of patients with uncommon fungal infections in central nervous system (CNS).Methods Thirty-five patients with uncommon CNS fungal infections who were admitted to Huashan Hospital from 1997 to 2010 were retrospectively reviewed.The pathogens,symptoms and signs.treatments of patients were evaluated.The data were analyzed by rank sum test and Fisher'S exact test.Results Twenty-nine of the 35 patients met the definition criteria of prover CNS fungal infections,while the other 6 had probable diagnosis.Predisposing factors were found in 86% of all patients.The most common pathogens were Aspergillus and Candida species.The symptoms and signs commonly occurred including fever(22 cases),headache(19 cases), cranial neuropathy(12 cases),and meningeal irritation sign(12 cases).High white blood cell count,high protein level,and low glucose level were the main findings of cerebrospinal fluid (CSF) analysis.Patients with cerebral aspergillosis were more frequently accompanied with immunocompromised conditions, and they often got CNS aspergillosis from hematogenous dissemination or direct extension of paranasal sinus infection.Cerebral granuloma and abscess were the common clinical characteristics of CNS aspergillosis.Cerebral candidiasis often arose from neurosurgical surgery or traumatic brain injury,and these patients were usually presented with meningitis.All patients were treated with antifungal drugs and (or) surgical intervention and 77%(27/35) of the patients achieved complete or partial responses. Antifungal agents combined with surgical resection might improve outcome of patients with CNS aspergillosis; while removal or replacement of drainage tubes in combination with antifungal treatment showed satisfactory efficacy in patients with cerebral candidiasis who usually had shunt manipulation. Conclusions The incidence of CNS fungal infection, such as cerebral aspergillosis and candidiasis, is increasing. Early diagnose and therapeutic intervention are crucial for improving outcome.     

Trimethoprim-sulfamethoxazole therapy for Nocardia infections

The optimal therapy for infections due to Nocardia species has not been established. To assess the efficacy of trimethoprim-sulfamethoxazole (TMP-SMX), we reviewed the records of 19 patients with Nocardia infections seen at Duke University Medical Center, Durham, NC, who were treated with this drug, either alone or in combination with other antibiotics or a surgical procedure. Underlying diseases or therapy causing immunosuppression were present in all but five cases. Sites of involvement were lung (ten of 19), wound (two of 19), and brain (two of 19); five of 19 patients had disseminated disease. The mean duration of therapy was 7.2 months. Overall cure or improvement was achieved in 89% (17/19) of cases; 80% of patients with disseminated disease and 60% of those with CNS involvement recovered. This experience, and accumulated clinical evidence in the literature, indicates that TMP-SMX should be considered the therapeutic drug of choice in infections due to Nocardia species.     

Persistent neutrophilic meningitis

Persistent neutrophilic meningitis is an unusual but distinct clinical variant of chronic meningitis characterized by CSF neutrophilia with hypoglycorrhachia which persists for more than 1 week on serial CSF studies. Documented etiologies include selected bacteria and higher bacteria such as Brucella, Nocardia and Actinomyces as well as "opportunistic" fungi such as Candida, Aspergillus, the Zygomycetes, and Pseudallescheria. Recognition of the syndrome is important, as empiric therapy (e.g., cotrimoxazole and amphotericin B) may differ significantly from that used for classic chronic meningitis.     

Central nervous system infections in patients with systemic lupus erythematosus

OBJECTIVE: To evaluate the clinical profiles of patients with systemic lupus erythematosus (SLE) with central nervous system (CNS) infections. METHOD: We retrospectively reviewed patients with SLE with CNS infections from January 1983 to June 2003. The clinical features, laboratory data, and prognoses of these patients were recorded. RESULTS: During the 20-year review period, 17 SLE patients with CNS infections were identified. The mean age at CNS infection was 29.6 +/- 15.3 years. Cryptococcal infection was identified in 10 patients and bacterial meningitis in 7. Most patients (94%) had active SLE at the time of CNS infection. Fifteen patients received corticosteroid therapy and of these, 7 received it in conjunction with immunosuppressive agents. The most common presentation was headache, fever, and vomiting. The mortality rate among the 17 patients was high (41.2%). CONCLUSION: Cryptococcal meningitis played the major role in CNS infection of patients with SLE, and it cannot be ruled out even when the cerebrospinal fluid (CSF) white blood cell count is within normal range. CSF India ink and latex agglutination testing for cryptococcal antigen should be performed and are effective screening tools to establish an early diagnosis.     

Immune suppression at high altitude

This paper is a review and interpretation of prior studies that have investigated the effects of hypoxia on immune function. A summary of current methods used to assess immune effector cell function in human beings is presented using in vitro models of mononuclear cell activation. Animal studies indicate that impaired host defenses against bacterial pathogens may be compromised, but that resistance to virus infections may remain intact. Data from human studies and animal models indicate that active immunization and B cell function are unimpaired, whereas T cell function is blunted following exposure to hypoxia. Mechanisms that may be responsible for alterations in normal immunoregulation are presented. The implications of altered immune function in subjects exposed to high altitude are discussed.     

Oral candidiasis.

Candida spp. can frequently cause oral infections in the elderly. A number of factors, including yeast virulence factors and compromised host defenses, contribute to outcomes of clinical disease. Precise mechanisms that determine the varied clinical appearances of oral candidiasis have not been delineated fully. Oral candidiasis should be suspected at the clinical level when oral mucosal lesions consistent with the various presentations of candidiasis are observed in patients at risk. Culture remains the gold standard for assessment, although results may be equivocal. Topical or systemic antifungal therapy may result in resolution of symptoms and lesions, but lesions may recur if underlying risk factors remain.     

Meningitis Caused by Toscana Virus Is Associated with Strong Antiviral Response in the CNS and Altered Frequency of Blood Antigen-Presenting Cells

Toscana virus (TOSV) is a Phlebotomus-transmitted RNA virus and a frequent cause of human meningitis and meningoencephalitis in Southern Europe during the summer season. While evidence for TOSV-related central nervous system (CNS) cases is increasing, little is known about the host defenses against TOSV. We evaluated innate immune response to TOSV by analyzing frequency and activation of blood antigen-presenting cells (APCs) and cytokine levels in plasma and cerebrospinal fluid (CSF) from patients with TOSV neuroinvasive infection and controls. An altered frequency of different blood APC subsets was observed in TOSV-infected patients, with signs of monocytic deactivation. Nevertheless, a proper or even increased responsiveness of toll-like receptor 3 and 7/8 was observed in blood APCs of these patients as compared to healthy controls. Systemic levels of cytokines remained low in TOSV-infected patients, while levels of anti-inflammatory and antiviral mediators were significantly higher in CSF from TOSV-infected patients as compared to patients with other infectious and noninfectious neurological diseases. Thus, the early host response to TOSV appears effective for viral clearance, by proper response to TLR3 and TLR7/8 agonists in peripheral blood and by a strong and selective antiviral and anti-inflammatory response in the CNS.     

Defects in the host defense system predisposing the patient to infection

The normal host defense mechanisms against infection include (1) normal skin and mucous membranes, (2) phagocytic system, (3) humoral immunity, and (4) cellular immunity. The compromised host is an individual who has one or more defects in these defense mechanisms. Defects in each aspect of host defense increase the risk of infection caused by specific groups of microorganisms. Knowledge of these defects and potential infections in the compromised host will guide the initial (empiric) selection of antibiotics, the dosage and duration of antibiotic therapy, and decisions regarding antibiotic prophylaxis and the use of immunomodulators that are likely to augment host defenses.     

Recent advances in the pathogenesis and pathophysiology of bacterial meningitis

Bacterial meningitis continues to account for worldwide morbidity and mortality despite the advent of effective bactericidal antibiotic therapy. Recent advances over the past 10 years in the development of experimental animal models as well as basic investigation into critical bacterial surface virulence factors have begun to clarify a conceptual framework for understanding the mechanism of meningitis development in humans. Basic observations regarding competing host defenses and bacterial virulence factors have supported a pathogenetic sequence of mucosal colonization with a meningeal pathogen; systemic host invasion with intravascular replication; blood brain barrier penetration and unimpeded CSF proliferation amid the impaired host defenses in the CSF milieu; and pathophysiologic sequelae including vasogenic, cytotoxic, and interstitial brain edema (and other processes) accounting for irreversible neuronal injury and death. Only through continued basic investigation into each of these pathogenetic steps will significant reductions in morbidity and mortality ensue.     

Tuberculous and syphilitic meningitis in a patient infected with the human immunodeficiency virus

This report examines simultaneous tuberculous and syphilitic meningitis in a patient with human immunodeficiency virus (HIV). The 41-year-old homosexual patient presented with meningitis and hydrocephalus. His CD4+ and CD8+ T-lymphocyte counts per microliter were 60 and 71, respectively. His clinical presentation was of a rapid-onset cerebral attack incompatible with tuberculous meningitis. Imaging indicated fatal bilateral cerebral infarction at the basal nuclei, and basal meningitis. We believe that syphilitic meningitis in HIV exacerbated the central nervous system (CNS) damage caused by tuberculosis and syphilis. The combination of three pathogens, Mycobacterium tuberculosis, Treponema pallidum, and HIV, has a great potential to cause serious CNS damage.     

Immune responses in parasitic diseases. Part A: general concepts

Parasitic infections are incredibly varied and distinct in terms of interactions between hosts and pathogens as well as in complexity of life cycle, host range, vector or intermediary host requirements, forms of reproduction, and elicited response. A number of protozoan parasites are intracellular pathogens capable of surviving and multiplying within microbicidal cells such as macrophages. In contrast, nematodes generally do not multiply within the host, a trait that dramatically alters the epidemiologic, clinical, and immunologic consequences of infection. Parasites have acquired apparently effective mechanisms for escape from normal host defenses and clearance. These mechanisms may be classified as antigenic mimicry, antigenic depletion, antigenic variation, immunologic indifference, immunologic diversion, and immunologic subversion. A determination of the importance and relevance of these subterfuges to parasitic infection in humans and to therapeutic or prophylactic strategies is of the utmost urgency.     

Fungal and yeast infections of the central nervous system. A clinical review

In the past 20 years, there has been a marked increase in the number of reported cases of meningitis and brain abscess due to fungi and yeasts. This increase is due in part to better diagnostic techniques and greater awareness of the possibility of fungal invasion of the nervous system; but the increase can also be attributed to a growing pool of severely compromised hosts, many of whom are undergoing treatment with adrenal glucocorticoids or immunosuppressive agents. The diagnosis and treatment of aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, cryptococcosis, infections caused by dematiaceous fungi, histoplasmosis, paracoccidioidomycosis, petriellidosis, and sporotrichosis, as well as relatively rare infections of the central nervous system caused by other fungi, are discussed. The efficacy of amphotericin B and 5-fluorocytosine in the treatment of CNS fungal and yeast infections is also evaluated.     

Pulmonary cryptococcosis

Cryptococcosis is an invasive fungal infection (IFI), caused predominantly by Cryptococcus neoformans or Cryptococcus gattii, that affects both immunocompromised (IC) and non-IC patients. Although the most serious disease manifestation is meningoencephalitis, cryptococcal pneumonia is underdiagnosed and may disseminate to the central nervous system (CNS) and other sites depending upon host defenses and administration of appropriate antifungal therapy. The clinical presentation of pulmonary cryptococcosis varies along a spectrum from asymptomatic infection to severe pneumonia and respiratory failure, and the radiological presentation can be characterized by an array of findings, including nodules, consolidation, cavitary lesions, and a diffuse interstitial pattern. Diagnosis most often relies upon isolation of Cryptococcus from a pulmonary specimen in the appropriate clinical and radiological context. Treatment recommendations include induction therapy with an amphotericin B preparation and flucytosine for IC patients and those with severe disease and fluconazole for mild-to-moderate, localized disease. Knowledge of the pathophysiology, epidemiology, clinical presentation, and treatment of pulmonary cryptococcosis may lead to greater recognition of this underdiagnosed IFI and improved outcomes.