History Of Recurrent Infections Research Articles

Homozygosity for c 6325T>G transition in the ATM gene causes an atypical, late-onset variant form of ataxia-telangiectasia

Dear Sirs,Ataxia-telangiectasia (A-T) is an inherited neurodegener-ative disorder caused by mutations in the ATM (A-TMutated) gene encoding the protein kinase ATM, a keyplayer in the cellular response to double-stranded DNAdamage [1, 2].Classical A-T patients manifest an early-onset of thedisease, severely disabling cerebellar ataxia, dysarthricspeech,oculocutaneoustelangiectasias,oculomotorapraxia,chorea and dystonia, endocrine dysfunctions, immunodefi-ciency and cancer. Brain MRI shows cerebellar atrophy.Laboratory tests reveal raised serum a-fetum protein (AFP)levels and chromosomal instability [1, 2]. Biochemicalstudies on cultured cells document a complete lack offunctional ATM protein. Accordingly, genetic studies usu-allyrevealhomozygousorheterozygous‘‘null’’mutationsinthe ATM gene [1–3].On the other hand, variant A-T forms show a relativelymild neurological phenotype, often normal brain MRI, andless frequently extra-neurological features. These forms areusually caused by missense mutations leaving somedetectable amount of functional ATM protein [2–4].We describe the peculiar clinical and biochemical fea-tures of two related variant A-T Italian patients carrying ahomozygous c.6325T[G transition in the ATM gene.Pt IV-1 (supplementary fig. 1), a 39 year-old woman,developed head and limb tremor and progressive gaitimbalance at around age 13. There was no history ofrecurrent infections or malignancies. Neurological exami-nation at age 28 showed resting and postural tremor, cer-ebellar dysarthria, severe gait ataxia, steppage with distallimb atrophy and areflexia. Eye movements were normal;ocular telangiectasias were noted. Brain MRI showedvermian atrophy. EMG studies documented an axonalsensory-motor polineuropathy. Laboratory tests showed amoderate increase of serum AFP levels (23 ng/ml, normalvalues \9), and normal Ig levels; a radiosensitivity assayon cultured lymphocytes was positive. She became wheel-chair bound at age 35.Pt IV-2 (supplementary fig. 1), a 44 year-old male, whois a third degree cousin of pt IV-1, from age 35 manifestedsome gait difficulties, progressive muscle weakness andcramps. At age 39 he presented a sensory-ataxic gait,weakness and atrophy of distal limb muscles and areflexia.Cerebellar and oculomotor signs were absent; mild con-junctival telangectasias were present. EMG studies docu-mented a sensory-motor axonal neuropathy. Two yearslater he manifested a mild cerebellar limb incoordination; abrain MRI showed cerebellar atrophy (Fig. 1). Serum AFPlevels were increased (82 ng/ml), while Ig levels werenormal and a radiosensitivity test was negative. He cur-rently walks using leg orthoses; until now, neither recurrentrespiratory infections nor malignancies occurred. An ocu-lographic study resulted normal.Immunoblotting [5] showed the absence of ATM proteinin both patients (Fig. 2a), confirmed by phosphorylationstudies (Fig. 2b), while the levels of Mre11, p95 and APTX

High Prevalence of Primary Immune Deficiencies in Children with Autoimmune Disorders

Objective Autoimmunity is a well-recognised manifestation of primary immunodeficiency disorders. However, the prevalence of primary immunodeficiency among children with autoimmune diseases is not well characterised. The objective of this retrospective study was to describe the prevalence of primary immunodeficiency disorders in a paediatric population with autoimmune diseases. Patients and methods We retrospectively analysed a cohort of patients investigated for diverse autoimmune conditions from June 1st 2005 to December 31st 2006 in the Rheumatology and Immunology service of a tertiary care paediatric hospital in Canada. The clinical data of patients were reported. Independently of their baseline characteristics, patients underwent a systematic immunologic workup, which was performed before treatment initiation. Results Thirty-three patients were included in this study. We identified 5 patients (15%) with a primary immunodeficiency disorder: common variable immunodeficiency (n=2), combined immunodeficiency (n=1) and complement component deficiency (n=2). Four other patients (12%) displayed decreased levels of immunoglobulins, B-cell lymphopenia and/or abnormal vaccinal response but did not fulfil the criteria of a defined primary immunodeficiency disorder at the time of the study. Importantly, none of these 9 patients had a particular familial history and none had a history of recurrent infections. Conclusion A significant proportion of patients presenting with an autoimmune condition have an underlying primary immunodeficiency disorder that may not be clinically obvious. Additional prospective investigations are needed to further define the role for routine immunologic testing in daily clinical rheumatologic practice.

Keratitis-ichthyosis-deafness (KID) syndrome

A 21-year-old man presented with a life-long history of diffusely thickened skin with a grainy-to-ridged surface, verrucous perioral plaques with radial fissures, and diffuse palmoplantar keratoderma with a stippled appearance. These skin findings were accompanied by sensorineural hearing loss and keratoconjunctivitis, a clinical triad diagnostic of keratitis-ichthyosis-deafness (KID) syndrome. The patient also had a history of recurrent infections and cysts on the scalp. This report draws attention to inflammatory nodules (representing ruptured folliculitis), cysts, and recurrent infections on the scalp as manifestations of KID syndrome and reviews the increasingly recognized risk of follicular tumors and squamous-cell carcinomas in patients with this conditions.

Limbic encephalitis associated with anti‐GAD antibody and common variable immune deficiency

A variety of autoantibodies have been identified with complex neurological disorders including limbic encephalitis. The underlying trigger for the immune-mediated process and the role of autoantibodies in the pathogenesis of limbic encephalitis remain to be clarified. Here, we report a 16-year-old female who was diagnosed with acute-onset non-neoplastic limbic encephalitis. The initial treatment with pulse doses of i.v. methylprednisolone improved the neurological symptoms. During the next 12 months, progressive decline was reported in her academic functioning and seizure control. Additional diagnostic evaluation revealed no evidence of malignancy or central nervous system infection but circulating anti-GAD antibodies were present in the serum and cerebrospinal fluid. Intravenous gammaglobulin infusion was initiated and continued monthly. Intravenous and oral steroids were added to the intravenous immunoglobulin treatment because of the worsening course and seizures, despite treatment with antiepileptic medications. Screening for quantitative immunoglobulins demonstrated hypogammaglobulinaemia with low immunoglobulin M and G in addition to low immunoglobulin A levels. There was a lack of protective pneumococcal antibody titers before and after immunization. Therefore, common variable immunodeficiency was suspected despite there being no history of recurrent infections. To our knowledge, this is the first report describing a possible link between immune-mediated limbic encephalitis and immune deficiency.

Extended-spectrum β-lactamase-producing pathogens in a children's hospital: A 5-year experience

Pediatric infection with bacteria producing extended-spectrum beta-lactamases (ESBLs) has not been well described. We sought to determine the proportion of isolates producing ESBLs and the incidence of infection or colonization with these organisms in our tertiary care pediatric facility over 5 years. In addition, we sought to evaluate the characteristics of children affected. We identified all Escherichia coli or Klebsiella spp cultured from children younger than 18 years of age at our facility between January 2003 and December 2007. Medical records were reviewed for affected children. Of 2697 E coli, K pneumoniae, and K oxytoca cultured, 26 ESBL producers were isolated from 16 children. Rates of ESBL production among cultured isolates significantly increased, from 0.53% in the first half of the study period to 1.4% in the second. Incidence of a primary ESBL infection also increased significantly, from 0.14/10,000 patient encounters to 0.31/10,000. The majority of children infected or colonized with ESBL-producing organisms were those with chronic medical conditions, frequent hospitalizations, or a history of recurrent infection. However, 4 affected children were less than 5 months old and evaluated in an outpatient setting. Rates and incidence of ESBL infection increased over the study period. Whereas most patients belonged to traditional risk groups for antibiotic-resistant infection, infants in the ambulatory setting were also affected, an at-risk population not previously described.

Primary IgA and IgG subclass deficiency in a 17-year-old Pakistani girl: a case report

Primary immunodeficiency disorders pose a diagnostic dilemma for physicians in the developing countries such as Pakistan because of lack of adequate diagnostic facilities. We present here the case of a 17-year-old girl who had a history of recurrent respiratory tract infections since childhood and had been treated with anti-tuberculous medications thrice; for a total of 24 months. She had also received multiple courses of antibiotics. Her initial presentation to our hospital was with acute bronchopneumonia. Her past medical history of recurrent infections also alerted the treating physician to the possibility of bronchiectasis secondary to a variety of underlying potential pathologies such as post-infection, immunodeficiency syndromes or ciliary dyskinesia disorders. Cystic fibrosis was also an important consideration. Direct enquiry revealed that there was no history of consanguineous marriage in her parents. Her sweat chloride test was within normal range (<40 mmol/L). Blood analysis was performed which showed IgA, IgG2 and IgG4 deficiency. She has been following up at our hospital for the past few years. In that course of time, she has had multiple episodes of pneumonia, gastroenteritis and maxillary sinusitis. She was successfully treated with intravenous immunoglobulins on four occasions when she presented with systemic crisis secondary to severe systemic infection. She also developed biopsy proven intermediate grade non-Hodgkin’s lymphoma five years after the diagnosis of immunoglobulin deficiency was first made. This appeared to be a complication of her immunodeficient state. She has been receiving chemotherapy for the lymphoma. Physicians should be cognizant of the morbidity that primary immunodeficiency syndromes such as immunoglobulin deficiency can have in the form of multiple infections and increased risk of malignancies as seen in our patient.

Nodular lymphoid hyperplasia in common variable immunodeficiency syndrome mimicking familial adenomatous polyposis on endoscopy

Common variable immunodeficiency syndrome (CVID) includes a heterogeneous disorder characterized by reduced levels of IgG, IgA or IgM, and recurrent bacterial infections with normal T-cell immunity in 60% of patients. It affects the gastrointestinal tract as the largest immune organ with a wide spectrum of symptoms and signs. We present a case of nodular lymphoid hyperplasia (NLH) of the small intestine in a 31-year-old man admitted for evaluation of chronic diarrhea. Upper and lower gastrointestinal endoscopy revealed multiple polyps in the stomach, duodenum, ileum, and large intestine mimicking familial adenomatous polyposis (FAP). Although he had no history of recurrent infection, immunological profiles were in favor of CVID. We emphasize the importance of considering CVID in any patient with gastrointestinal manifestations even in the absence of recurrent bacterial infections. Diagnostic delay results in more morbidity and complications in untreated patients.

Alterations In Immunity After Total vs Partial Tonsillectomy

Problem Palatine tonsils are secondary lymphoid organs active in sampling antigens entering the upper respiratory tract and in producing immunoglobulin (Ig) both locally and distally through migrating tonsillar B cells. Their size has been found to be directly proportional to the number of B and T cells. The aim of this study is to compare the change in serum and saliva Ig levels after total and partial tonsillectomy. Methods Children with obstructive tonsils and/or adenoid undergoing total or partial tonsillectomy were recruited in a pilot study. Patients with history of recurrent infections or immunodeficiency were excluded. Blood and saliva samples were obtained immediately preoperatively and at the 1st follow-up visit. Serum Ig's (G,M&amp;A) concentrations were determined using radial immunodiffusion. Saliva secretory IgA was measured using an Enzyme Immuoassay (EIA). Results Twenty five patients (13 partial and 12 total) were included. There were no statistically significant changes in serum Ig's levels after total or partial tonsillectomy, except for IgM which increased (1.317 to 1.632 g/L) after partial tonsillectomy, more significantly in males, in those aged 5 years and older, and when the postoperative samples were taken within a 2 month-period. Moreover, there was statistically non-significant decrease in secretory IgA level after both total and partial tonsillectomy. Conclusion The effect of partial or total tonsillectomy on immunoglobulin level seems reassuring. The increase in IgM and the non-significant decrease in SIgA may represent a kind of immunological readjustment after tonsillar surgery. Significance This is the first study (to our knowledge) that compares the changes in immunoglobulin levels (in serum &amp; saliva) after partial vs. total tonsillectomy. The obtained results are preliminary and are reassuring to the parents and physicians who have concerns regarding the immunological sequalae of tonsillectomy in children. A longer follow up will be done in a larger future study. Support This study was supported by Medtronic.

Safety of biologics – which lessons learned?

The safety profile of biologics depends on the type of antibody, dose, mode of administration, concurrent medications and host factors. Opportunistic infections, including tuberculosis, remain an important safety concern. Development of an infection is one of the most common adverse events reported following the use of TNF-alpha inhibitors. For example, with an average follow-up of 51 weeks, 36% of all patients receiving infliximab in clinical trials developed an infection vs 25% of placebo-treated patients after an average follow-up of 37 weeks. In adalimumab trials for rheumatoid arthritis (RA), 1 infection per patient per year was identified in adalimumab-treated patients, compared with 0.9 infections per patient per year in placebo-treated patients. For both agents, most of these infections were easily treated upper respiratory or urinary tract infections. However, more serious infections, including pneumonia, sepsis, disseminated tuberculosis (TB), invasive fungal infections, and other opportunistic infections have been reported after anti-TNF-alpha agent use. Although the risk for serious infections in Crohn’s disease or RA patients may be due in part to their underlying chronic disease (with or without concomitant use of corticosteroids and immunosuppressive agents), evidence is accumulating that the use of biologic agents may further heighten that risk. All of the TNF inhibitors carry warnings in their prescribing information about the potential risk for serious infection. These agents should not be administered to patients with a clinically important active infection, and caution should be exercised when considering their use in patients with a chronic infection or a history of recurrent infection. For patients with Crohn’s disease, one should proceed cautiously in treating patients with perianal or intra-abdominal infections or patients with a phlegmonous process in the abdomen. For abscesses, drainage should

Partial C4 Deficiency in Juvenile Idiopathic Arthritis Patients

C4 is encoded by 2 distinct but closely linked loci within the major histocompatibility complex locus on human chromosome 6. C4A deficiencies have been associated with autoimmune disease and C4B with increased frequency of infection. C4 deficiencies have rarely been associated with juvenile idiopathic arthritis (JIA). Our aim was to investigate the prevalence of deficiencies in C4 allotypes in JIA patients. We evaluated 61 patients [35 JIA patients, 15 systemic lupus erythematosus patients, 9 rheumatoid arthritis patients, and 2 mixed connective tissue disease (CTD) patients] for C4 deficiency. Genomic DNA was isolated from whole blood and subjected to polymerase chain reaction using sequence-specific primers for C4 allotypes. We found 5 JIA patients with C4 deficiencies. Two IgM rheumatoid factor-positive JIA polyarthritis patients had C4 deficiencies, one with complete C4A deficiency and another with partial C4A and complete C4B deficiency. Two oligoarthritis patients displayed partial C4B deficiencies, and complete C4B deficiency was revealed in 1 IgM rheumatoid factor-negative polyarthritis patient. Three patients had histories of recurrent infections and 2 demonstrated a more severe disease course. Disease controls showed 8 systemic lupus erythematosus patients had partial C4 deficiencies, whereas no deficiencies were revealed in the rheumatoid arthritis or mixed CTD patients. Defects in the complement system have been implicated in the pathogenesis of CTD. However, the specific role of C4 in JIA is not clear. We demonstrate partial C4 deficiencies in 5 JIA patients. Our findings suggest an association between C4 deficiency and another CTD, JIA, as well as with disease severity and recurrent infections.

Disseminated molluscum contagiosum in a patient with chronic plaque psoriasis taking methotrexate

Conflict of interest: none declared. A 69‐year‐old man with a 3‐year history of chronic plaque psoriasis presented with an itchy papular eruption over the trunk, progressing to involve the buttocks and limbs over a period of 3 months. He had been on oral methotrexate 7.5 mg/week for the previous 2 years (cumulative dose 1110 mg) for his psoriasis, and had not received phototherapy. He was otherwise well with no history of recurrent infections or recent ill health. Physical examination revealed smooth discrete yellowish papules, 2–5 mm in diameter, over the back, buttocks and limbs (Figs 1 and 2). Psoriasiform plaques were observed over the scalp. The rest of the examination was normal. Differential diagnoses considered were disseminated molluscum contagiosum, xanthogranulomas or eruptive xanthoma. Punch biopsy of a papule from the right thigh revealed a focal endophytic growth consisting of hyperplastic keratinocytes containing eosinophilic intracytoplasmic inclusions (Fig. 3). Laboratory findings revealed an unremarkable white cell count (5.4 × 109/L; normal range 4–10 × 109/L) with a normal differential count. The rest of the full blood count, and the renal and liver function tests were normal. An antibody assay for human immunodeficiency virus (HIV) was negative. A diagnosis of disseminated molluscum contagiosum was made and methotrexate was stopped. This resulted in a clear regression of the molluscum lesions within 3 months, although some papules still persisted. Cryotherapy for the residual lesions resulted in complete clearance. Fair control of his psoriasis was maintained with topical therapy with no further relapse of the molluscum contagiosum.

A 5-year PICU Experience of Disseminated Staphylococcal Disease, Part 1: Clinical and Microbial Profile

Staphylococcus aureus causes an impressive spectrum of disease in tropics and subtropics. Scanty data are available regarding disseminated staphylococcal disease (DSD) in children, especially on their critical care needs. It is important to recognize and prioritize patients who may benefit most from Pediatric Critical Care. The objective of this article is to review the demographic, clinical and microbial features, critical care needs, management and outcome of patients with DSD to identify clinical indicators for need of critical care. The study setting is a Pediatric Intensive Care Unit (PICU) of an urban tertiary care teaching hospital in a developing economy. The subjects were fifty-three patients (age, 1 month-12 years) with DSD admitted to PICU during June 1994-June 1999. DSD was defined as involvement of at least two distant organs with presence of Gram-positive cocci in clusters and/or growth of S. aureus from at least one normally sterile body fluid. Data regarding demographic and clinical picture, microbiological profile, indication for PICU admission, monitoring needs, medical and surgical management and outcome was retrieved from the case records. Patients had mean age of 5.1 years (+/- 3.4) (range, 1.5 months-12 years). Majority (34/53, 64%) were malnourished, however, none had history of recurrent infections. Two-thirds presented during hot and humid months (P < 0.001). Predisposing conditions were pustules (26%), blunt trauma (15%) and injections (8%). Fever (98%) and respiratory distress (81%) were commonest presentation followed by restriction of limb mobility and altered sensorium (21/53, 40% each). On an average, 3.25 sites were involved per patient (total, 171 sites). Twelve (9%) sites were detected after 7 days of hospitalization. Disease spectrum included necrotizing soft tissue disease (61%), pleuro-pulmonary disease (89%), pericardial effusion (40%), osteo-articular disease (30%) and meningitis (17%). Forty patients (76%) developed growth of methicillin sensitive S. aureus (MSSA) and four grew methicillin resistant S. aureus (MRSA). Hematological spread from benign skin lesions may lead to fulminant disseminated disease. Identifying metastatic foci by thorough clinical evaluation, appropriate and frequent imaging studies form an integral part of management.

X-Linked Neutropenia with a I294T Mutation of the Wiskott-Aldrich Syndrome Gene.

X-linked neutropenia (XLN, OMIM #300299) is a rare cause of severe congenital neutropenia and was first described in a three-generation Belgian family with 5 affected members. Reported features of XLN include severe congenital neutropenia and monocytopenia with recurrent bacterial infections, a decreased CD4/CD8 ratio and bone marrow maturation arrest at the promyelocyte/metamyelocyte stage. In the Belgian family, a L270P WAS mutation was identified, causing constitutive activity of the Wiskott-Aldrich-syndrome protein (WASP) toward actin polymerisation (Devriendt et al. Nat.Genet. 2001). Here, we report the clinical phenotype of a second large family with XLN and with a I294T WAS mutation. In this three-generation family, 10 affected males (7–45 y) and 8 female carriers were identified. Variable non-cyclic neutropenia is present in affected males (0.2–3.3*109/L in those not on G-CSF; 0.1–1.0*109/L on G-CSF). Five of 10 affected males in the I294T family have monocytopenia. A consistent feature in all cases is a reduced NK cell number. In fact, 3 of 3 tested L270P cases also had reduced NK cell counts. The severity of the clinical phenotype is variable without apparent correlation with the degree of neutropenia. Five of 10 affected males are receiving treatment with G-CSF because of recurrent infections. Four of 10 are reported healthy in the absence of G-CSF. One case with a borderline neutrophil count (2.4*109/L) is not on G-CSF, despite recurrent infections. In addition, two males with a history of recurrent infections, at least one of whom had neutropenia, died of infectious causes at age 5 and 18 years. Platelet counts are variably reduced in affected males, but with normal platelet volume. No consistent abnormalities in CD4/CD8 ratio are found. Available bone marrows have revealed no myelodysplastic features or cytogenetic abnormalities. Of note, female carriers show intermediate findings in neutrophil, platelet and NK cell counts. Only 1 female carrier is known with recurrent upper respiratory and ear infections and is treated with G-CSF. The T916C mutation we found in exon 9 of WAS, has recently been described (Ancliff et al. Blood online 2006) and results in a I294T mutation of the WASP GTPase-binding domain (GBD). The I294T GBD-VCA construct has a lower melting temperature (36°C) as measured by circular dichroism spectroscopy (78°C for wild-type). In the absence of Cdc42, I294T GBD-VCA is nearly completely active toward the Arp2/3 complex, contrary to wild-type GBD-VCA, but similar to the L270P construct. Thus, these data provide new and independent genetic evidence that mutations that disrupt the auto-inhibitory domain of WASP are the cause of XLN. In addition, based on this largest XLN kindred to date, reduced NK cell counts appear a consistent feature. None of the affected males presented with myelodysplasia. Finally, female carriers have moderately reduced neutrophil counts, mostly without clinical consequences. Thus, the presence of mild neutropenia in potential female carriers does not rule out the possibility of XLN in related males with neutropenia. Further investigation is needed to reveal how the L270P and the I294T WAS mutations lead to XLN.

Disappearance of immunoglobulins in acute phase of influenza A infection

In February, 2005, a 52-year-old previously healthy man was admitted to our hospital intensive care unit with progressive dyspnoea and diminished consciousness. He had been experiencing fatigue, headache, abdominal pain, and nausea for 4 days. During transport to the hospital the patient had a cardiac arrest and needed to be resuscitated. On admission, his temperature was 35·2°C, blood pressure was 80/40 mm Hg, and heart rate was 130 beats per min. The patient was comatose and had respiratory failure; septic shock, acute myocardial infarction, and haemorrhagic shock were considered as possible causes. Treatment with antibiotics (cefotaxime and levofl oxacin) was initiated after taking samples of blood, sputum, stool, and urine for culture. Simultaneously, supportive treatment, including fl uid resuscitation, mechanical ventilation, and vasopressor support, was instituted. Chest radiography showed some signs of interstitial oedema. ECG was normal. These fi ndings, combined with normal cardiac biomarker levels, made myocardial infarction an unlikely diagnosis. Laboratory test results showed a left-shifted leucocytosis (19·6×10/L), haemo concentration (haemoglobin 195 g/L; haematocrit 0·56), and evidence of tissue hypoxaemia (lactic acid 16 mmol/L; arterial pH 6·82). Despite vasopressors and fl uid resuscitation, the patient remained hypotensive. Low colloid osmotic pres sure as a result of capillary leak seemed to be partly responsible. Low albumin (16 g/L) and total protein (19 g/L) were indicative for this condition; hypogamma globulinaemia was present (IgA 0·23 g/L; IgM 0·12 g/L; IgG 1·0 g/L). Both high usage and impairment of liver synthesis function (the latter supported by hypo gammaglobulinaemia and an antithrombin of 0·20 U/mL) were possible explanations. Causes of hypogamma globulinaemia were considered. In this patient, without previous illnesses, medication, or recurring infections, a primary cause was unlikely. A viral infection as causal factor was considered. Serology for Epstein-Barr virus, cytomegalovirus, HIV, and parvovirus B19 was negative. Infl uenza A (H3N2) was isolated in sputum samples (2nd and 4th day in hospital). All other cultures remained negative. Although a diagnosis was established, the patient’s clinical condition had vastly improved, and, therefore, antiviral therapy was not initiated. Liver synthesis function recovered after a few days. After 9 days the patient was transferred to the ward and was discharged after another 5 days. Until fi nal followup in February, 2006, there had been no recurrence of illness and immunoglobulin concentrations remained normal (fi gure). Because of a remaining monoclonal IgG-λ in an otherwise normal protein γ-fraction, a fi rst episode of the rare systemic capillary leak syndrome has to be considered as well, although this is less likely. Reports of shock caused by viral infections are limited, and, in most cases, associated with underlying disease or occur in immune compromised patients. Although hypogamma globulinaemia indicated a state of immunodefi ciency, we have no reason to believe this was the case before admission because our patient did not have a history of recurrent infections and we could not identify a preexisting immune defi ciency in a plasma sample taken several weeks before admission (fi gure). Immunoglobulin concentrations returning to normal on recovery gave further evidence to support the hypothesis that the transient hypogammaglobulinaemia was caused by infl uenza A infection. In mice, depletion of B cells by infl uenza virus has been demonstrated. Alternatively, since anti-infl uenza antibodies can promote the resolution of primary infl uenza infection in animals, the severity of the clinical course in this case could have been caused by the lack of an antibody response. Common fl u-like diseases can have serious complications even in healthy persons who are not considered part of a high-risk population. Hypogammaglobulinaemia in a non-immunocompromised patient with sepsis syndrome should prompt the clinician to consider a viral cause and should allow for rapid institution of antiviral therapy.

Gastrointestinal manifestations of chronic granulomatous disease

Chronic granulomatous disease is a rare clinical entity characterized by recurrent infective and inflammatory complications. Patients are usually assigned to specialist centres, but nonspecialist clinicians may be required to treat these patients in the emergency setting. This review serves as a management guide to those clinicians who are faced with patients presenting with gastrointestinal manifestations of chronic granulomatous disease. This review is based on a literature search (Medline and NLM PubMed) with manual cross-referencing of all articles related to gastrointestinal chronic granulomatous disease. Gastrointestinal tract involvement is present in most affected patients. Clinical presentation can mimic common surgical complications such as colitis, perianal sepsis, gastric outlet obstruction and liver abscess. A history of recurrent infections during childhood is common. Management involves haematological, microbiological, endoscopic and radiological investigations. Treatment modalities include early aggressive empirical antimicrobial therapy for sepsis, immunomodulation for inflammatory complications and surgical drainage of abscesses. Early involvement of a centre with immunological expertise combined with aggressive management of complications significantly improves morbidity and mortality from this rare condition.

Immune function in autistic children

There have been reports that some children with autistic spectrum disorders have abnormal immune function. However, data in this area remain scarce and conflicting. To evaluate the immune function of a series of autistic children in the context of this proposed association. We prospectively collected data on 24 autistic children who, between January 1, 1996, and September 30, 1998, were referred unsolicited to an immunology clinic. We examined the clinical history and evaluated immunoglobulin levels; specific antibody titers to diphtheria, tetanus, and Haemophilus influenzae; T- + B-cell numbers; T-cell proliferation; and complement studies. Seven of the 24 children had a history of recurrent infections. Only 2 patients had immunoglobulin levels that were outside the age-adjusted reference ranges, 1 of whom was subsequently diagnosed as having common variable immune deficiency. All the patients had normal in vitro T-cell function and complement study results, and only 2 of 24 patients had subtle derangements in T-cell numbers. Elevated levels of IgE were found in 5 patients, which correlated with a clinical history of atopy. Low diphtheria or tetanus antibody levels were found in 12 patients, but in 11 of these, vaccination status was not up-to-date. Most of the autistic children studied had normal immune function, suggesting that routine immunologic investigation is unlikely to be of benefit in most autistic children and should be considered only when there is a history suggestive of recurrent infections.

Clinical and immunological features of 65 Iranian patients with common variable immunodeficiency.

Common variable immunodeficiency (CVID) is a primary immunodeficiency disease characterized by hypogammaglobulinemia and recurrent bacterial infections. The records of 65 patients with CVID (37 males and 28 females) in the age range of 24 to 537 months were reviewed. By the year 2003, 11 patients had died and seven patients could not be located. The total follow-up period was 221 patient-years. The median diagnostic delay (time between onset and diagnosis) in our patient group was 60 months. At the time of diagnosis, the baseline serum immunoglobulin G (IgG), IgM, and IgA levels were below the level normal for the patients' age; the medians for this group were 120, 10, and 0 mg/dl, respectively. All of the patients presented with infectious diseases at the time of onset, the most common of which were otitis media, diarrhea, pneumonia, and sinusitis. Acute and recurrent infections were also found in almost all of the patients, particularly involving respiratory and gastrointestinal systems. The most common infections, before diagnosis and during follow-up, were pneumonia, acute diarrhea, acute sinusitis, and otitis media. CVID should be considered in any patient with a history of recurrent infections and decreased levels of all serum immunoglobulin isotypes.

Identification of GRASP-1 as a novel 97 kDa autoantigen localized to endosomes

We have identified an autoantigen that is recognized by antibodies from an 18-year-old female with a history of recurrent infections who later in her clinical course developed Raynaud's phenomenon and telangiectasias. By indirect immunofluorescence (IIF), the index serum produced a unique cytoplasmic discrete speckled (CDS) staining pattern that partially colocalized with early endosome antigen 1 (EEA1) but not Golgi complex or other cytoplasmic organelles in HEp-2 cells. When HEp-2 cells were treated with 0.1 N HCl, the cytoplasmic speckled staining of the index serum was markedly decreased, suggesting that the reactive antigen was soluble. Western blot analysis showed a reactive ∼97 kDa protein in a saline soluble protein preparation from HeLa cells. Mass spectrometric analysis of the excised 97 kDa band that was immunoprecipitated from HeLa cell extracts identified GRASP-1 as a possible target. The index serum and anti-GRASP-1 antibodies colocalized to structures in the cytoplasm of HEp-2 cells. Synthetic peptides representing the full-length GRASP-1 protein were used to identify reactive epitopes. Like many other cytoplasmic autoantigens, GRASP-1 has numerous coiled-coil domains throughout the protein with the exception of short segments at the amino and carboxyl terminus.

Simultaneous Herpetic and Candidal Esophagitis in an Immunocompetent Teenager

Simultaneous Herpetic and Candidal Esophagitis in an Immunocompetent Teenager

Reading performance in children with otitis media

To examine whether middle ear diseases and the associated hearing loss in early childhood affect reading performance later at school. One hundred and sixty children, 6.5 to 8 years of age, were enrolled in this study: 80 children with a history of recurrent infections and/or prolonged periods of effusions of the middle ear before the age of 5 years, and 80 healthy children without any history of middle ear disease. Data were collected from the medical records of the children. Every child underwent a complete otological and audiological evaluation, followed by special reading tests. The study group performed more poorly, in all reading tests, as compared to the controls ( P < 0.001). Children with recurrent or prolonged middle ear diseases during the first five years of life tend to be at greater risk for delayed reading than aged-matched controls with no previous middle ear diseases.