Pitfalls of "hyper"-IgM syndrome: a new CD40 ligand mutation in the presence of low IgM levels. A case report and a critical review of the literature.

Here, we report on a male infant with low serum IgG, IgA and IgM levels who suffered from Pneumocystis jirovecii and cytomegalovirus (CMV) pneumonia. The patient was tested to be HIV-negative. Absolute and relative numbers of lymphocyte subsets were normal, excluding the diagnosis of an X-linked agammaglobulinaemia (Bruton's disease). Despite the decreased serum IgM level, an X-linked hyper-IgM syndrome (X-HIGM) was considered. X-HIGM is a rare immunodeficiency usually characterised by recurrent severe opportunistic infections, low serum IgG and IgA, but normal or increased serum IgM. The syndrome is caused by mutations of the CD40 ligand (CD40L) gene. In our patient, CD40L mutation analysis proved a novel mutation at codon 257 associated with non-detectable expression of CD40L on the surface of activated T cells. A literature search revealed that approximately 6.4% of X-HIGM patients had been found to have low serum IgM levels. Our statistical analysis of the IgM levels as reported by different studies arouses suspicion that many patients with low IgM levels may not have undergone diagnostic procedures for X-HIGM. In summary, in this report and critical review of the literature, we described a new mutation of CD40L and highlighted the pitfalls of the diagnosis of X-HIGM.

Delayed ultraviolet erythema not suppressed by oral prednisolone: a randomized crossover study.

BACKGROUND: The anti-inflammatory potency of topical dermatological corticosteroids in suppressing ultraviolet (UV) erythema is routinely measured. No such model exists to assess the potency of systemically administered steroids. OBJECTIVE: To determine whether or not suppression of delayed UV erythema by a systemic corticosteroid could provide a useful model for assessing the anti-inflammatory potency of systemic corticosteroids. METHODS: We conducted a randomized, placebo-controlled, patient and assessor blinded, crossover study of oral prednisolone effects on the delayed UV-induced erythemal response in normal subjects. Six healthy volunteers were phototested with a xenon arc monochromator and then dosed with 30 mg of oral prednisolone or matching placebo daily for 4 days. Repeat phototesting was performed on the 4th day of dosing. The minimal erythema dose (MED) was assessed immediately after test UV doses were administered and 24 h later. After a 2-week washout period, the dosing and testing were repeated in a crossover fashion. RESULTS: A suppression index (SI) [1/(baseline MED value divided by on prednisolone/placebo value)] allowed comparison of the degree of suppression on and off prednisolone. Oral prednisolone did not significantly suppress the threshold UV erythema response (MED). We may have missed small effects in this study and possibly a larger dose or a longer duration of corticosteroid would have had an effect. Possibly, assessment of corticosteroid potency in suppressing established UV erythema rather than on the development of threshold erythema would have yielded different results. CONCLUSION: The threshold UV erythema suppression model assessed in this study could not distinguish between oral prednisolone and placebo. This UV-erythema suppression test system is not promising as a model to test the anti-inflammatory potency of systemic steroids.

Clinical application of MRI in children for the assessment of pulmonary diseases.

The standard examination technique for the chest in children is an X-ray examination - it is fast, cheap and provides a good overview of anatomy and pathology. In cases with an unclear pathology or if more details are needed (i. e. pre-therapeutically), computed tomography is most often performed with the well known drawbacks of limited soft tissue contrast and radiation. Radiation should be avoided in children, especially if follow-up examinations are needed. Recent magnetic resonance (MR) techniques allow for fast and reliable assessment of pulmonary diseases in children. Due to the inherent soft tissue contrast, diagnosis can be frequently performed without contrast media application. This review provides an exemplary MR examination protocol for routine application in pediatric patients. The diagnostic value of MRI is shown in patients with infectious diseases, patients with immunodeficiency, anatomic abnormalities, acquired chronic diseases, and pulmonary tumors. Since MRI is especially suitable for functional imaging, an MR protocol is provided for the examination of thoracic deformities. This review summarizes the use of thoracic MRI in the clinical pediatric setting with special focus on the clinical indications as a radiation-free method.

Necrolytic migratory erythema in an opiate-dependent patient.

An 18-year-old woman presented with severe features of seborrhoeic dermatitis involving her scalp. Subsequently, the toe webs and intertriginous areas became affected by an erythematous, slightly scaly and weepy rash. The groin area was most severely affected, and complicated by intermittent infections with staphylococci and herpes simplex. The patient admitted to smoking heroin and was subsequently enrolled in a methadone programme. A biopsy from the groin area showed a combination of parakeratosis and keratinocyte vacuolar changes, supporting a diagnosis of necrolytic migratory erythema (NME). On completion of methadadone withdrawal, the rash cleared. The rash returned upon recommencing methadone. NME consists of an irregular annular eruption with an erythematous crusted edge. It is often mistaken for intertrigo or seborrhoeic dermatitis. In this patient, a direct effect of heroin and methadone on the epidermal metabolism might be speculated. There could be a variant of the opiate recepter, which is especially sensitive to the effects of opiates. This is the second case occurring in association with opiate dependency and the first case where the patient was rechallenged, although the precise role of the opiates in the aetiology remains somewhat speculative.

Differential effects of the combination of caspofungin and terbinafine against Candida albicans, Candida dubliniensis and Candida kefyr.

The activity of caspofungin (CSP) combined with terbinafine (TRB) against Candida dubliniensis, Candida kefyr and azole-resistant Candida albicans was evaluated in vitro by checkerboard analysis. The combination of CSP with TRB resulted in positive interactive effects in vitro against C. albicans and C. kefyr but not against C. dubliniensis. Moreover, true synergism was observed only against TRB resistant strains which became susceptible to this drug in the presence of CSP. In contrast, indifference was observed against strains that were already sensitive to TRB indicating that CSP may inhibit resistance to TRB.

Combined surgical and antifungal treatment of a subcutaneous infection due to Paecilomyces lilacinus.

Paecilomyces lilacinus was the causal agent of a case of subcutaneous infection in a patient with liver cirrhosis. Surgical treatment in combination with systemic amphotericin B therapy led to complete recovery. Retrospectively performed microdilution testing revealed dose dependent in vitro susceptibility of the isolate to voriconazole (MIC = 2 g/ml) and terbinafine (MIC = 1 microg/ml).

Molecular typing for fungi--a critical review of the possibilities and limitations of currently and future methods.

Invasive fungal infections represent an increasing problem in patients with inherited and acquired immunodeficiencies. Molecular biotyping techniques, such as DNA fingerprinting, are useful tools to increase our knowledge of the pathogenic organisms that cause them, and thus to improve their treatment and develop prevention strategies. In the present review, we evaluate and discuss the possibilities and limitations of the methods currently used for biotyping strains of fungal species. These include techniques based on restriction fragment length polymorphism (RFLP) with or without hybridization to probes (Southern), PCR-based techniques, electrophoretic karyotyping (EK), and multilocus enzyme electrophoresis (MLEE). Additionally, we discuss newer techniques that are being developed for the fingerprinting of fungal strains. Among them, we review conformation-based polymorphism scanning methods, such as single-strand conformation polymorphism analysis (SSCP) and heteroduplex mobility assays, sequencing strategies such as multilocus sequence typing (MLST) and DNA microarrays.

Treatment of severe Candida infections in high-risk patients in Germany: consensus formed by a panel of interdisciplinary investigators.

Now that modern medicine can provide increasing chances of cure to patients with formerly incurable disorders, therapy-related complications play the key role in outcome. Thus, among opportunistic infections, severe candidiasis remains a challenge. A multidisciplinary panel of 20 investigators was formed to find a consensus on antifungal strategies for various underlying conditions in neutropenic and non-neutropenic patients. To record their preferences, the investigators used an anonymous voting system. Among antifungal agents, fluconazole emerged as the major alternative to the classic amphotericin B, being therapeutically at least equivalent but clearly less toxic. Factors that restrict the use of fluconazole include pretreatment with azoles, involvement of resistant species like Candida krusei, and an inability to exclude aspergillosis. Flucytosine can be reasonably combined with both amphotericin B and fluconazole. Within the limited antifungal armamentarium, amphotericin B lipid formulations and itraconazole also appear useful and require further investigation. The general consensus of the group is that antifungal agents should be administered at sufficient dosages, rather early, and often empirically.

Case Reports. Pulmonary cryptococcosis associated with cryptococcal meningitis in non-AIDS patients.

We report four cases of pulmonary cryptococcosis associated with cryptococcal meningitis in non-HIV infected patients. All four patients had no apparent symptoms and signs of focal lesions that necessitate evaluation for the pulmonary lesion. Two out of four patients had radiologic evidence of pulmonary cavitation and mass lesions simultaneously, an uncommon finding in non-AIDS patients. Diagnostic and therapeutic problems of pulmonary cryptococcosis associated with cryptococcal meningitis are discussed.

Fusariosis associated with pathogenic fusarium species colonization of a hospital water system: a new paradigm for the epidemiology of opportunistic mold infections.

We sought the reservoir of Fusarium species in a hospital with cases of known fusarial infections. Cultures of samples from patients and the environment were performed and evaluated for relatedness by use of molecular methods. Fusarium species was recovered from 162 (57%) of 283 water system samples. Of 92 sink drains tested, 72 (88%) yielded Fusarium solani; 12 (16%) of 71 sink faucet aerators and 2 (8%) of 26 shower heads yielded Fusarium oxysporum. Fusarium solani was isolated from the hospital water tank. Aerosolization of Fusarium species was documented after running the showers. Molecular biotyping revealed multiple distinct genotypes among the isolates from the environment and patients. Eight of 20 patients with F. solani infections had isolates with a molecular match with either an environmental isolate (n=2) or another patient isolate (n=6). The time interval between the 2 matched patient-environment isolates pairs was 5 and 11 months, and 2, 4, and 5.5 years for the 3 patient-patient isolate pairs. The water distribution system of a hospital was identified as a reservoir of Fusarium species.

Effect of the growth medium on the in vitro antifungal activity of micafungin (FK-463) against clinical isolates of Candida dubliniensis.

Micafungin (FK-463), a member of the new candin family of antifungal agents, was highly active against clinical isolates of Candida albicans and Candida dubliniensis. The in vitro activity of micafungin suggested that it was more potent than fluconazole, flucytosine, amphotericin B or voriconazole against C. albicans, and comparable or moderately less effective against C. dubliniensis isolates when high-resolution medium (HR) was used. Lower MICs of micafungin were recorded when RPMI 2% or AM3 2% media were used, indicating an influence of the growth medium on the MIC.

[Guidelines for Prevention of Pneumocystis carinii Pneumonitis in Children and Adolescents with Cancer]. / Empfehlungen zur Prävention der Pneumocystis-carinii-Pneumonie bei Kindern und Jugendlichen mit neoplastischen Erkrankungen.

Pneumocystis carinii pneumonitis (PCP) is one of the most important opportunistic infections in children and adolescents with cancer. Its high frequency and a considerable mortality have led to primary chemoprophylaxis in patients with hematological malignancies and following allogeneic hematopoietic stem cell transplantation. Although less well characterized, patients with autologous stem cell transplantation and patients with dose-intensive chemotherapy for pediatric solid tumors may have a similarly high risk for PCP based on their profound T-cell depletion. For more than two decades, effective chemoprophylaxis for PCP has been available. Trimethoprim and sulfamethoxazole (TMP/SMX) is the prophylactic modality of first choice. The combination has been shown to be almost 100 % efficacious in pediatric cancer patients at highest risk, and it is usually well tolerated in this setting. Secondary alternatives to TMP/SMX include oral dapsone, oral atovaquone, and aerosolized pentamidine-isethionate. These modalities are less effective than TMP/SMX, and have been evaluated predominantly in HIV-infected patients. This article reviews epidemiology and current approaches to chemoprophylaxis for PCP in children and adolescents with cancer and/or hematopoietic stem cell transplantation, and provides evidence-based guidelines for indications and modalities of PCP prophylaxis in this population.

[Prevention of fungal infections in children and adolescents with cancer]. / Prävention von Pilzinfektionen bei Kindern und Jugendlichen mit neoplastischen Erkrankungen.

Opportunistic mycoses have emerged as important causes for morbidity and mortality in pediatric cancer patients, particularly in those with intensively treated hematological malignancies, allogeneic hematopoetic stem cell transplantation, and aplastic anemia. The incidence of invasive fungal infections in these settings may range from 10 to 25 % despite empirical antifungal therapy with an overall case fatality rate of up to 50 and 75 % depending on the organism. Preventive interventions are thus warranted, including but not limited to chemoprophylaxis with antifungal agents. Effective chemoprophylaxis of invasive Candida infections with a long-term benefit for overall survival has been demonstrated in patients with allogeneic bone marrow transplantation. However, its benefit in other high-risk populations is less well established, and a clearly effective approach to chemoprophylaxis for invasive Aspergillus infections has not been documented in appropriately designed clinical trials. This article reviews epidemiology and current approaches to chemoprophylaxis of opportunistic invasive fungal infections in children and adolescents with cancer and/or stem cell transplantation, and provides evidence-based guidelines for indications and modalities of antifungal prophylaxis and antifungal infection control measures in this population.

Synergism of voriconazole and terbinafine against Candida albicans isolates from human immunodeficiency virus-infected patients with oropharyngeal candidiasis.

The synergism of voriconazole (VRC) and terbinafine was studied by using 39 genotypically defined clinical Candida albicans isolates that were cross-resistant to fluconazole and VRC and serial isolates that gradually developed azole resistance. Synergy was noticed in 100% (eight of eight) of the strains that were resistant to VRC. Antagonism was not observed.

[Adherence and invasion-two pathogenicity factors in bacterial and fungal pathogens]. / Adhärenz und Invasion: Zwei Pathogenitätsfaktoren bei pathogenen Bakterien und Pilzen.

Pathogenicity factors such as adhesins, toxins, capsules, and other microbial gene products are involved as causative agents for infectious diseases. Therefore, the pathogenicity of organisms is increasingly studied on a molecular level. In bacteriology, unspecific adherence mechanisms and receptor-specific adhesins have to be distinguished. An adhesin-mediated invasion of pathogenic organisms in eukaryotic host cells could be relevant for pathogenesis. In mycology, various specific adhesins are involved in colonization of the host. Aspartyl proteases and phospholipases are relevant for adherence and invasion of host structures by pathogenic yeasts. Resistance factors have a central function in the distribution of infectious organisms. Gene-transfer, point mutations and efflux mechanisms are involved in the development of antibiotic drug resistance. Antifungal drug resistance does occur predominantly in Candida albicans against azole drugs. As underlying mechanisms point mutations in the ERG11 gene, encoding for the target enzyme of azoles, as well as energy-dependent efflux mechanisms were identified. Whether these mycotic factors are specific virulence factors or "fitness-factors" for a better survival of these organisms in the host, and if a possible alternating effect exists between resistance and virulence mechanisms is currently under investigation.

Transmission of an azole-resistant isogenic strain of Candida albicans among human immunodeficiency virus-infected family members with oropharyngeal candidiasis.

We report transmission of an azole-resistant, isogenic strain of Candida albicans in a human immunodeficiency virus (HIV)-infected family of two children with symptomatic oropharyngeal candidiasis and a mother with asymptomatic colonization over a 5-year period. These findings were confirmed by three different molecular epidemiology methods: interrepeat PCR, Southern hybridization with a C. albicans repetitive element 2 probe, and electrophoretic karyotyping. This study contributes to an evolving understanding of the mode of transmission of C. albicans, particularly in children, and underscores the importance of monitoring specimens from family members of HIV-infected patients.

Current approaches to diagnosis and treatment of fungal infections in children infected with human immuno deficiency virus.

UNLABELLED: The prolonged survival of profoundly immunocompromised patients has revealed mucosal and invasive fungal infections to be major causes of morbidity and mortality in advanced HIV disease in children of all age groups. Antifungal resistance has become a clinically relevant problem. Paediatricians caring for HIV-infected children need to be aware of these increasingly frequent and often life-threatening infectious complications. This article reviews what is currently known about epidemiology, clinical presentation, diagnosis and treatment of mucosal and invasive fungal infections in children and adolescents with HIV disease. Candida spp. have become a leading bloodstream isolate in hospitalised patients; mucosal candidiasis is the most prevalent opportunistic infection in HIV-infected patients, and in both invasive and superficial infections, non Candida albicans spp. are on the increase. Invasive pulmonary aspergillosis has surfaced as an HIV-associated complication and previously uncommon fungi are more frequently encountered. HIV-infected individuals are particularly susceptible to Peumocystis carinii, Cryptococcus neoformans and infections by endemic fungi, such as Histoplasma capsulatum, Coccidioides immitis, Penicillium marneffei, and others. Newer immunological and molecular-based methods provide early and rapid diagnosis and monitoring. Potent and broad-spectrum third generation triazoles and novel fungicidal lipopeptides of the echinocandin class of antifungal antibiotics have entered clinical trials. Immunmodulation by recombinant cytokines and antifungal vaccines are very actively pursued inroads to adjunctive and preventive immunotherapy. CONCLUSION: Mucosal and invasive fungal infections will remain important complications in HIV-infected children of all age groups. Interventional studies and well documented case series are needed to improve the molecular diagnosis, treatment and prevention of invasive fungal infections in the paediatric HIV-infected population.