Cell-mediated Immunodeficiency Research Articles

18q Deletion Syndrome Presenting with Late-Onset Combined Immunodeficiency

Patients with chromosome 18q deletion syndrome generally experience hypogammaglobulinemia. Herein, we describe two patients with chromosome 18q deletion syndrome who presented with late-onset combined immune deficiency (LOCID), which has not been previously reported. Patient 1 was a 29-year-old male with 18q deletion syndrome, who was being managed for severe motor and intellectual disabilities at the Yamabiko Medical Welfare Center for 26 years. Although the patient had few infections, he developed Pneumocystis pneumonia at the age of 28. Patient 2, a 48-year-old female with intellectual disability and congenital malformations, was referred to Tokyo Medical and Dental University Hospital with abnormal bilateral lung shadows detected on her chest radiography. Computed tomography showed multiple lymphadenopathies and pneumonia. A lymph node biopsy of the inguinal region revealed granulomatous lymphadenitis, and a chromosomal examination revealed 18q deletion. Array-based genomic hybridization analysis revealed deletion at 18q21.32-q22.3 for patient 1 and at 18q21.33-qter for patient 2. Immune status work-up of the two patients revealed panhypogammaglobulinemia, decreased number of memory B cells and naïve CD4+ and/or CD8+ cells, reduced response on the carboxyfluorescein diacetate succinimidyl ester T-cell division test, and low levels of T-cell receptor recombination excision circles and Ig κ-deleting recombination excision circles. Consequently, both patients were diagnosed with LOCID. Although patients with 18q deletion syndrome generally experience humoral immunodeficiency, the disease can be further complicated by cell-mediated immunodeficiency, causing combined immunodeficiency. Therefore, patients with 18q deletion syndrome should be regularly tested for cellular/humoral immunocompetence.

Cytomegalovirus enteritis resistant to antiviral drugs improved following total colectomy

BackgroundCytomegalovirus (CMV) infection, often subclinical in childhood, is reactivated during a state of cell-mediated immunodeficiency. In cases of organ damage, patients can require medical treatment for an infectious disease, generally through the use of antiviral drugs. There are no reports of surgical treatment in cases, where infection was found, and medical treatment was difficult. We encountered a case of CMV enteritis that was difficult to treat because of resistance to antivirals but improved after total colectomy.Case presentationA previously healthy, 74-year-old woman visited a doctor with a chief complaint of watery diarrhea persisting for 2 weeks; she was transferred to our hospital because of hypoxemia and hypovolemic shock. Computed tomography scan indicated wall thickening over the entire colon and the patient was diagnosed with infectious colitis. Conservative and antibacterial therapies were started with fasting fluid replacement. Subsequently, bloody stools were observed 11 days after admission. Colonoscopy was then performed, which showed mucosal edema and longitudinal ulcer, while a histopathological examination of the colon mucosa revealed C7HRP positive on 22 days after admission. CMV enteritis was diagnosed, and the antiviral medication, ganciclovir, was started. Diseases causing immunosuppression and other possible causes of enteritis were also closely examined; however, all were negative. Furthermore, the patient’s symptoms and her endoscopic findings did not improve with ganciclovir administration; therefore, the antiviral drug was changed to foscarnet. Unfortunately, the patient did not improve despite the additional administration of gamma globulin and methylprednisolone, and she was determined to have enteritis resistant to medical therapy. A total colon resection was performed 88 days after the admission. Her condition gradually stabilized postoperatively, and oral intake was initiated and tolerated. The patient was transferred to another hospital for rehabilitation for home discharge. She is now at home and has had no recurrences.ConclusionsIn previous reports of surgical treatment for CMV enteritis, many cases were initially undiagnosed, emergency surgery was performed after perforation or stenosis was recognized, and then CMV was diagnosed and treated. In CMV enteritis without immunodeficiency, surgical treatment may be an option if medical treatment is ineffective.

Meningitis Caused by Cryptococcus neoformans in an Apparently Immunocompetent Patient.

Cryptococcal meningitis (CM), as a life-threatening opportunistic infection, often is among cases with cell-mediated immunodeficiencies, such as AIDS, hematologic malignancies, and solid organ transplant recipients. Cryptococcal meningitis in healthy individuals is uncommon, and its detection in immunocompetent cases may be tricky because the presentation is generally more indolent than the traditional meningitis presentation, leading to late diagnosis and potential sequels. We present a CM case in an immunocompetent Iranian male patient who was treated successfully.

M148 A CASE OF CUTANEOUS BOTRYOMYCOSIS IN A PATIENT WITH X-LINKED AGAMMAGLOBULINEMIA

Botryomycosis, a rare granulomatous inflammatory response to bacteria, commonly involves the skin. Botryomycosis is reported with various immunodeficiency states, particularly acquired cell-mediated immunodeficiency disorders. We describe, to our knowledge, the first case of cutaneous botryomycosis in a patient with X-linked agammaglobulinemia (XLA).

LISTERIA BACTEREMIA PRESENTING WITH CEREBRAL ABSCESS AND ENDOCARDITIS IN AN ELDERLY PATIENT WITH CHRONIC IMMUNE THROMBOCYTOPENIA

TOPIC: Cardiovascular Disease TYPE: Medical Student/Resident Case Reports INTRODUCTION: Listeria monocytogenes, an intracellular gram-positive bacillus, is a ubiquitous foodborne pathogen that causes Listeriosis. Its clinical spectrum ranges from mild, self-limiting gastroenteritis in immunocompetent individuals to severe, life-threatening, invasive disease affecting persons at the extremes of age, pregnant women, and individuals with cell-mediated immunodeficiencies. Central nervous system involvement by is common – presenting as meningitis, meningoencephalitis or, less frequently, rhombencephalitis. Listerial brain abscesses are rare. Moreover, only 5-8% of these infections are complicated by infective endocarditis (IE). CASE PRESENTATION: A 70-year-old Caucasian man with chronic immune thrombocytopenia (ITP) presented to the ED with acute onset of altered mental status and right-sided weakness. He was afebrile, with no heart murmurs or peripheral stigmata of IE. Neurologic exam findings included disorientation, expressive aphasia, and right-sided hemiparesis. Laboratory findings were unremarkable except for leukocytosis and hyponatremia. Brain MRI showed an irregular rim-enhancing lesion in the left frontal lobe with surrounding edema and midline shift. The lesion was excised with adjacent necrotic tissue and frozen sections were highly suspicious for a high-grade glial neoplasm. He was started empirically on vancomycin, ceftriaxone and metronidazole. Eventually, the organism was identified as Listeria monocytogenes from two sets of blood cultures; hence, antibiotics were de-escalated to ampicillin and gentamicin. Transesophageal echocardiography (TEE) showed mitral valve vegetation. The patient developed fever on day 4; by day 6, he began to defervesce and showed improvement in mental status. On day 9, he was discharged to the inpatient rehabilitation center to complete a total of 6 weeks on IV ampicillin and IV gentamicin. Pathology of the brain mass was subsequently reported as listerial brain abscess with no evidence of malignancy. DISCUSSION: Chronic treatment with high-dose oral glucocorticoids and pre-existing ITP have been independently implicated as predisposing factors in listerial brain abscess. There is a propensity to misdiagnose listerial brain abscess as an intracranial neoplasm due to similar clinical/imaging findings, especially when fever is absent at presentation. In addition, Listeria monocytogenes is an atypical cause of IE. Our patient had no pre-existing structural or valvular heart disease, but he satisfied two major diagnostic criteria for IE – two separate positive blood cultures of Listeria monocytogenes and a TEE demonstrating mitral valve vegetation. CONCLUSIONS: A high index of suspicion is necessary for early recognition and successful treatment of listerial brain abscess and listerial endocarditis in high-risk patients. REFERENCE #1: Tiri B, Priante G, Saraca LM, Martella LA, Cappanera S, Francisci D. Listeria monocytogenes brain abscess: controversial issues for the treatment—two cases and literature review. Case Rep Infect Dis. 2018;2018(6549496):1-9. REFERENCE #2: Hohmann EL, Portnoy DA. Listeria monocytogenes infections. In: Jameson JL, Kasper DL, Longo DL, Fauci AS, Hauser SL, Loscalzo J, eds. Harrison's Principles of Internal Medicine. 20th ed. New York, NY: McGraw-Hill Education; 2018:1100-1102. REFERENCE #3: Garcia-Granja PE, Lopez J, Vilacosta I, Olmos C, Sarria C, Roman JAS. Infective endocarditis due to Listeria monocytogenes: a report of 4 patients. Cardiol. 2016;69(7):699–709. DISCLOSURES: No relevant relationships by Nili Gujadhur, source=Web Response no disclosure on file for Vanessa Karimi; No relevant relationships by Olushola Ogunleye, source=Web Response

Nonavalent Human Papillomavirus Vaccine as a Treatment for Recalcitrant Warts in an Adult with HIV

To the Editor: Cutaneous warts are seen in as many as a quarter of immunosuppressed patients. 1 Cell-mediated immunodeficiency, as seen in HIV, is correlated with increased rates of palmoplantar warts. 2 These warts often cause discomfort, and can progress to verrucous carcinoma. As they can be resistant to traditional treatments like cryotherapy, patients must resort to more aggressive and invasive measures like intralesional bleomycin. In this case report, we present an immunocompromised patient with HIV successfully treated for his palmoplantar human papilloma virus (HPV) warts using the nonavalent HPV vaccine (Gardasil 9TM, Merck Inc, Kenilworth, NJ, USA) after only marginal improvement with six treatments of bleomycin.

Pneumonitis in patients with thymoma and Good's syndrome.

e20595 Background: The association between thymoma (T) and immunological dysregulations is well acknowledged. Good’s syndrome (GS), which occurs in approximately 6% to 11% of T patients, is characterized by hypogammaglobulinemia, few or absent B-cells (CD19+), CD4 T cells lymphopenia, abnormal CD4/CD8 T ratio and impaired T cell mitogenic response. Patients with GS have increased susceptibility to bacterial, opportunistic and viral infections related to both humoral and cell-mediated immunodeficiency. The recent Sars-Cov-2 pandemic drew attention to the clinical condition of fatal viral pneumonitis and cytokines storm. Here we reported our monocentric experience of pneumonitis in patients with T and GS before the Sars-Cov-2 pandemic. Methods: We conducted a retrospective analysis of T patients with associated GS referred to the Rare Tumours Reference Center of University Federico II of Naples over a 10-year period (from 2009 to 2019). All the patients with radiological and/or clinical pneumonitis diagnosis were evaluated for this report. Immunological features, histopathological diagnosis and clinical outcome were registered. Results: A total of 41 patients with T and GS were identified, including 17 patients with local disease (stage I-II according to Masaoka-Koga) and 24 with advanced disease (stage III-IV). The majority (56.3%) had B2 T diagnosis. Radiological and/or clinical pneumonitis diagnosis was assessed in 23 cases (56%). Viral pneumonitis was detected in 8 patients: 3 patients with H1N1 infection, 3 patients with CMV infection, 2 patients with EBV infection. Bacterial pneumonitis was diagnosed in 9 patients (3 patients with K. pneumoniae, 4 patients with S. aureus, 2 patients with H. influenza). Opportunistic pneumonitis was found in 2 patients with Aspergillosis infection. In 2 cases no pathogenic agent was identified. The immunophenotyping, assessed in 4 patients with viral pneumonitis, displayed very low/undetectable levels of B cells, with median % value of CD3+T cells and NKT of respectively 9.8% and 0.4% of the total leukocytes. The median % of Treg was 4.7%. CD4+/CD8+ ratio was variable, ranging from 1,2 to 0,6. Interestingly the number of B cells was extremely low, independent of CD4+/CD8+ ratio. Blood levels of cytokines, chemokines and growth factors revealed elevated IL-4, Eotaxin, CCL2 / MCP-1 and CCL5 / RANTES ad strong reduction of IL-10. PDGF-BB levels were also elevated. 15 patients required admission to intensive care Six patients died for fatal pneumonitis. Conclusions: The management of T patients with GS is extremely challenging. Clear diagnostic algorithms do not yet exist and immune-profiling and quantitative immunoglobulins should be considered a part of diagnostic search in these patients. The coexistence of cancer, infections and immunosuppression may trigger life-threatening conditions, such as fatal pneumonitis, which often require intensive care and multidisciplinary approach.

Oral candidiasis in HIV-uninfected pediatric population in areas with limited fungal diagnosis: A case study from a tertiary hospital, Tanzania.

Background:Oral candidiasis (OC) is an indirect indicator of cell-mediated immunodeficiency with a high predictive value of disseminated candidiasis. Here, we report the prevalence and factors associated with laboratory-confirmed OC in human immunodeficiency virus (HIV)-uninfected children with clinical OC attending the outpatient clinic or admitted in pediatric wards of the Bugando Medical Center (BMC).Methods:A cross-sectional study was conducted between January and June 2017. Social demographic and clinical data were collected using a pre-tested data collection tool. Oral swabs were collected using a sterile cotton swab and mycological culture was done to detect Candida spp. followed by susceptibility testing as per European Committee on Antimicrobial Testing (EUCAST) guidelines. Data were analyzed using STATA version 13 following study objectives.Results:A total of 325 non-repetitive oral swabs from HIV-uninfected children aged between 2 and 156 months were collected. Candida spp. were detected in 123 (37.8%) children. One (1.8%) C. albicans isolate was resistant to fluconazole, voriconazole, and posaconazole with minimum inhibitory concentrations (MIC) of 256 μg/ml, 32 μg/ml, and 0.31 μg/ml, respectively. Upon multivariate logistic regression analysis, being a male child (OR 2, 95% CI 1.2–3.2, p = 0.008) and having a history of antibiotic use (OR 1.8, 95% CI 1.1–2.8, p = 0.017) independently predicted laboratory-confirmed OC among HIV-uninfected children.Conclusion:Only a third of children with clinical OC were laboratory confirmed, and this was more likely in male children with a history of antibiotic use. Most of the isolates were highly susceptible to commonly used antifungal agents like fluconazole. Treatment of children at risk should be prioritized to reduce associated morbidity.

Thoracic Manifestations of Primary Immunodeficiency Disorders.

Primary immunodeficiency disorders (PIDD) are a group of disorders presenting with recurrent infections. The authors retrospectively reviewed the imaging records of 24 proven cases of PIDD and correlated the imaging findings with the type of defect. Final diagnoses were categorized in four groups; Group I (humoral immunodeficiency), Group 2 (cell mediated immunodeficiency), Group 3 (phagocytic disorders) and Group 4 (others). Group 3 was the commonest, followed by 1 and 2. Three most common disorders encountered were chronic granulomatous disease (CGD) (7/24), hyper IgE syndrome (5/24) and common variable immunodeficiency (CVID) (4/24). Consolidation (12/24), nodules (10/24), bronchiectasis (9/24) and lymphadenopathy (8/24) were the commonest imaging findings. Although not statistically significant, some definite imaging trends could be established. Presence of consolidation and nodules; with absence of bronchiectasis was the striking finding in Group 3. Group 2 disorders predominantly showed bronchiectasis, whereas presence of consolidation, nodules, bronchiectasis all were very common in Group 1.

Bendamustine and rituximab combination therapy for recurrent indolent B-cell lymphomas: a retrospective single-institution study

This retrospective study evaluated the outcomes of patients treated with combination of bendamustine and rituximab (BR) for recurrent indolent B-cell lymphoma from January 2011 to February 2018 in our department. The cohort included 36 males and 27 females, and majority of the patients (59%) were between 51 and 70 years of age. The disease types were follicular lymphoma (FL) and mantle-cell lymphoma in 42 (67%) and 15 (24%) patients, respectively. Median progression-free survival (PFS) was not reached in patients with FL who completed BR therapy. The analysis of patients who received BR therapy revealed that the number of CD4-positive lymphocytes remained around 200/µl even five years after the end of treatment. BR therapy was a useful treatment option for recurrent indolent B-cell lymphoma, especially in patients with FL, and completion of BR therapy appeared to be important for improved PFS. Furthermore, attention should be paid for potential infections for at least five years after BR therapy because cell-mediated immunodeficiency may become apparent after treatment.

Human cryptosporidiosis in immunodeficient patients in France (2015–2017)

Cryptosporidiosis is a common disease in children and immunodeficient individuals. In 2006, a national network was set up on the surveillance of human cryptosporidiosis in France. Since January 2015, the 41 tertiary care hospitals and the 3 private laboratories of the French National Network on the surveillance of human cryptosporidiosis have been able to declare confirmed cases of cryptosporidiosis online. Between 2015 and 2017, 210 cases of cryptosporidiosis were declared in immunodeficient patients in France; Cryptosporidium parvum and Cryptosporidium hominis represented 66% and 22% of cases, respectively. A peak was observed in autumn. Cryptosporidiosis occurred mainly in a context of solid organ transplantation (SOT) (49%) and of HIV infection (30%). In SOT recipients, cryptosporidiosis appeared more frequently in the first 6 months post transplantation. Regarding cases declared in SOT recipients, mycophenolate mofetil was used in 68%. A mortality rate of 6% was observed. Present results underline the importance of screening for cryptosporidiosis in immunocompromised patients suffering from diarrhea, especially in the course of major cell mediated immunodeficiency or even systematic screening before SOT. Exclusive Cryptosporidium free water feeding could be suggested during major cell mediated immunodeficiency.

Severe infections in sarcoidosis: Incidence, predictors and long-term outcome in a cohort of 585 patients.

Sarcoidosis is associated with cell-mediated immunodeficiency and treatment of symptomatic sarcoidosis usually includes systemic immunosuppressants. Data relative to incidence, prognosis factors, and outcome of infections are scarce.Retrospective cohort study of 585 patients with biopsy proven sarcoidosis in a tertiary referral specialist clinic, with a nested case-control analysis. Twenty nine patients (4.9%) with severe infections were compared to 116 controls subjects with sarcoidosis, matched according to their gender, ethnicity, age at diagnosis, and treatment with corticosteroids.After a median follow-up of 8 years [range; 1–46], 38 severe infections [mycobacterial infections (n = 14), fungal infections (n = 10), bacterial (n = 8), viral (n = 3) and parasitic (n = 1)] were observed in 30 patients. The incidence of severe infections was 0.71% persons-year (CI 95% 0.5–0.98) and 0.43% persons-year (CI 95% 0.27–0.66). Patients with severe infection were more frequently of male gender (60% vs 46%) and were more likely treated by ≥ 3 immunosuppressive agents (OR = 3.8, IC 95% [1.5–9.64], P = .005) and by cyclophosphamide (OR = 5.55, IC 95% [1.9–16.1], P = .002), and with neurological (OR = 3.36 CI 95% [1.37–8.25], P = .008), or cardiac (OR = 2.65 CI 95% [1.09–6.43], P = .031) involvement of the sarcoidosis, compared to the controls. Two patients died within the 6 months following infection, due to progressive multifocal leucoencephalopathy (n = 1), and of peritonitis (n = 1).Severe infections are observed in 5.1% of our patients with sarcoidosis after a median follow-up of 8 years. Risk factors for severe infections included neurological or cardiac involvement of sarcoidosis, the use of immunosuppressive agents and mainly cyclophosphamide.

Approach to a Child with Primary Immunodeficiency Made Simple.

Primary immunodeficiency disorders (PIDs) are a group of disorders affecting the capability to fight against infection. These include defects in T cells and B cells affecting cell-mediated and humoral immunity, respectively, combined humoral and cell-mediated immunodeficiency, defects in phagocytosis, complement defects, and defects in cytokine or cytokine signalling pathways which are detrimental for immune function. Depending upon the type and severity, age at onset of symptoms can vary from neonatal period to late childhood. Clinically, this group of disorders can involve any organ system of an individual such as respiratory system, gastrointestinal system, skin and mucous membrane, bone and joints, endocrine organs, and nervous system. Common dermatological manifestations include eczema, warts, molluscum contagiosum, mucocutaneous candidiasis, recurrent nonhealing ulcers, skin abscesses, erythroderma, petechiae, and nail changes. The common skin manifestations of various PIDs include eczema (seen in Wiskott–Aldrich syndrome and autosomal dominant hyper IgE syndrome); erythroderma (in Omen syndrome); viral warts or molluscum contagiosum (in autosomal recessive hyper IgE syndrome); chronic mucocutaneous candidiasis (in hyper IgE syndrome, autoimmune polyendocrinopathy candidiasis ectodermal dysplasia syndrome, Th17 cell defects); recurrent nonhealing ulcers (in leucocyte adhesion defect); skin abscesses (in antibody defects, hyper IgE syndrome, and chronic granulomatous disease); petechial or purpuric spots (in Wiskott–Aldrich syndrome).

Disseminated Cryptococcosis with Eosinophilia and Elevated IgE in a Non-HIV-infected Patient

In general, disseminated cryptococcosis usually occurs among immunocompromised patients, especially those with cell-mediated immunodeficiency, such as HIV-infected patients. We present herein a rare case of an apparently immunocompetent 33-year-old woman who developed disseminated cryptococcal diseases, which included meningitis and pneumonia with eosinophilia, and pulmonary tuberculosis during her disease course. Pneumonia with a diffuse micronodular pattern, immediately followed by meningitis, was diagnosed as disseminated cryptococcosis, because of the presence of yeast-like-fungi demonstrated by transbronchial lung biopsy and a positive cerebrospinal fluid (CSF) culture. In addition, the pneumonia exhibited eosinophilia in the peripheral blood and bronchoalveolar lavage fluid. Re-exacerbation of the pneumonia occurred approximately 3 weeks after onset, along with a sputum culture positive for Mycobacterium tuberculosis. Administration of anti-tuberculosis drugs resulted in recovery from the pulmonary tuberculosis. The treatment of cryptococcal meningitis was initiated using a standard induction regimen;however, an unrecovered status, highlighted by elevated CSF pressure, persisted. Finally, full recovery was induced by the addition of flucytosine treatment (100 mg/kg/day) and repeated daily via lumbar puncture. The allergic condition of this patient may have contributed to the onset of disseminated cryptococcosis.

Legionellosis in Patients With Cancer

Background Legionella species cause severe pneumonia in the immunocompromised population, especially those with cell-mediated immunodeficiency. However, the varied clinical and radiographic presentation of Legionnaires disease can make diagnosis very difficult, which can result in a delay of appropriate therapy. For that reason, we performed this study to review the characteristics of Legionella pneumonia in immunocompromised patients with underlying cancer. Methods The study was a retrospective chart review of 11 patients with Legionella pneumonia at the Moffitt Cancer Center diagnosed between March 2005 and February 2014. The patients were identified on the basis of a positive bronchoalveolar lavage culture for Legionella and/or a positive Legionella urine antigen. Summarized host characteristics included underlying malignancy, absolute neutrophil count, and absolute lymphocyte count at the time of diagnosis as well as the computed tomographic chest imaging findings. Results Of the 11 patients included, 10 had Legionella pneumophila and 1 had L. feeleii. Nine (81.8%) of the 11 patients had a hematologic malignancy and 2 (18.2%) of the 11 patients had a solid organ tumor. One (9.0%) of the 11 patients had an underlying lung disease. At the time of the diagnosis, 3 (27.2%) of the 11 patients were neutropenic (absolute neutrophil count, <500 cells/mm3) and 8 (72.7%) of the 11 patients were lymphopenic (absolute lymphocyte count, <1500 cells/mm3). Four (36.3%) of the 11 patients had bilateral pneumonia. Three (27.2%) of the 11 patients had nodular consolidation. However, only 2 (18%) of the 11 patients were found to have consolidation along with ground-glass opacity. All patients were treated with levofloxacin. Seven (63.6%) of the 11 patients adequately responded to the therapy, 1 (9.0%) patient died because of pneumonia, and 3 (27.3%) patients died because of the underlying cancer. Conclusions Legionnaire disease remains a life-threatening illness in patients with cancer. Our study found that most patients are lymphopenic, with multifocal consolidation in 2 of 3 patients. In addition, nodular opacities on computed tomographic imaging were described in more than one third of our patients, which resembles a mold pneumonia. All the cases that were thought to be a mold pneumonia were diagnosed as Legionella by bronchoalveolar lavage culture or the Legionella urine antigen, emphasizing the need for heightened awareness and testing for this pathogen.

Histoplasmosis in Patients With Cell-Mediated Immunodeficiency: Human Immunodeficiency Virus Infection, Organ Transplantation, and Tumor Necrosis Factor-α Inhibition.

Background. Histoplasmosis causes severe disease in patients with defects of cell-mediated immunity. It is not known whether outcomes vary related to the type of immunodeficiency or class of antifungal treatment.Methods. We reviewed cases of active histoplasmosis that occurred at Vanderbilt University Medical Center from July 1999 to June 2012 in patients with human immunodeficiency virus (HIV) infection, a history of transplantation, or tumor necrosis factor (TNF)-α inhibitor use. These groups were compared for differences in clinical presentation and outcomes. In addition, outcomes were related to the initial choice of treatment.Results. Ninety cases were identified (56 HIV, 23 transplant, 11 TNF-α inhibitor). Tumor necrosis factor-α patients had milder disease, shorter courses of therapy, and fewer relapses than HIV patients. Histoplasma antigenuria was highly prevalent in all groups (HIV 88%, transplant 95%, TNF-α 91%). Organ transplant recipients received amphotericin B formulation as initial therapy less often than other groups (22% vs 57% HIV vs 55% TNF-α; P = .006). Treatment failures only occurred in patients with severe disease. The failure rate was similar whether patients received initial amphotericin or triazole therapy. Ninety-day histoplasmosis-related mortality was 9% for all groups and did not vary significantly with choice of initial treatment.Conclusions. Histoplasmosis caused milder disease in patients receiving TNF-α inhibitors than patients with HIV or solid organ transplantation. Treatment failures and mortality only occurred in patients with severe disease and did not vary based on type of immunosuppression or choice of initial therapy.

Measurement of naive T cells for the diagnosis of severe combined immunodeficiency (SCID)

Aims SCID occurs as a result of mutations in genes that are required for the development and function of T lymphocytes, resulting in severe cell-mediated and humoral immunodeficiency. Patients with atypical SCID represent a diagnostic challenge as results of standard immune investigations may be normal. This study aimed to review the immune investigations required for the diagnosis of SCID at The Royal Children’s Hospital (RCH), Melbourne. Methods A retrospective audit of patients diagnosed with SCID at RCH over a 36 month period was undertaken. Results Of the 10 patients diagnosed with SCID, six had atypical presentations. Only two of six patients had low IgG at diagnosis. Four of six patients were lymphopenic, with total T cell numbers between 0.3 and 0.8 × 109/L; the remaining two of six patients had normal or elevated T cell numbers. Lymphocyte proliferation was markedly reduced in three of six patients but normal or moderately reduced in the remaining three patients. All six patients had absent or reduced naive T-cells (=13% of total T cells). Discussion SCID cannot be excluded on the basis of a normal lymphocyte count, normal T cell numbers or normal immunoglobulins. Identification of atypical SCID patients requires a high index of clinical suspicion and a thorough immunological workup, including the measurement of naive T cells.

Case report from the NIH Clinical Center: CNS nocardiosis

Case report from the NIH Clinical Center: CNS nocardiosis

Octamer-dependent transcription in T cells is mediated by NFAT and NF-κB

The transcriptional co-activator BOB.1/OBF.1 was originally identified in B cells and is constitutively expressed throughout B cell development. BOB.1/OBF.1 associates with the transcription factors Oct1 and Oct2, thereby enhancing octamer-dependent transcription. In contrast, in T cells, BOB.1/OBF.1 expression is inducible by treatment of cells with PMA/Ionomycin or by antigen receptor engagement, indicating a marked difference in the regulation of BOB.1/OBF.1 expression in B versus T cells. The molecular mechanisms underlying the differential expression of BOB.1/OBF.1 in T and B cells remain largely unknown. Therefore, the present study focuses on mechanisms controlling the transcriptional regulation of BOB.1/OBF.1 and Oct2 in T cells. We show that both calcineurin- and NF-κB-inhibitors efficiently attenuate the expression of BOB.1/OBF.1 and Oct2 in T cells. In silico analyses of the BOB.1/OBF.1 promoter revealed the presence of previously unappreciated combined NFAT/NF-κB sites. An array of genetic and biochemical analyses illustrates the involvement of the Ca2+/calmodulin-dependent phosphatase calcineurin as well as NFAT and NF-κB transcription factors in the transcriptional regulation of octamer-dependent transcription in T cells. Conclusively, impaired expression of BOB.1/OBF.1 and Oct2 and therefore a hampered octamer-dependent transcription may participate in T cell-mediated immunodeficiency caused by the deletion of NFAT or NF-κB transcription factors.

Does the presence of mediastinal adenopathy confer a risk for disseminated infection in immunocompetent persons with pulmonary coccidioidomycosis?

Pulmonary coccidioidomycosis is caused by inhaling airborne arthroconidia of Coccidioides, a soil-dwelling fungus endemic to the desert southwestern United States. Although uncommon, disseminated coccidioidal infection can be associated with well-defined risk factors, such as cell-mediated immunodeficiency, certain racial heritages (e.g. African or Filipino), male sex, or pregnancy. Before widespread use of computed tomography (CT), the presence or persistence of mediastinal lymphadenopathy was postulated to be a risk factor for disseminated coccidioidal infection. To investigate the use of CT scanning to identify the presence of mediastinal lymphadenopathy in patients with pulmonary coccidioidomycosis, and to correlate such lymphadenopathy with disseminated coccidioidal infection, we performed a retrospective review of patients with pulmonary coccidioidomycosis who were evaluated by chest CT. Two radiologists independently interpreted 150 CT scans from patients with pulmonary coccidioidomycosis. Forty-nine patients met CT criteria for mediastinal lymphadenopathy, whereas 101 patients did not. Disseminated coccidioidal infection was observed in 5 (10%) of the 49 patients with mediastinal lymphadenopathy and in 6 of the 101 (6%; P = .34) without such adenopathy. Among patients with coccidioidomycosis, patients with mediastinal lymphadenopathy, as assessed by CT, had a higher rate of disseminated infection, but the difference was not statistically significant.