7th International Immunoglobulin Conference: Immunodeficiencies.

Most primary immunodeficiency disorders (PID) are the result of single gene defects. Based on this fact, more than 240 different entities have been identified. Those PIDs with predominant antibody deficiency are treated with immunoglobulin (Ig) replacement therapy. This review focuses on the diagnosis, clinical characteristics and treatment of patients suffering from PID, or secondary immunodeficiency disorders (SID) caused, for instance, by irradiation, immunosuppressive drugs or thymectomy. Common variable immunodeficiency (CVID) is the most commonly diagnosed and least understood form of PID, with a heterogeneous range of symptoms and genotypes, requiring individualized treatment plans. This includes adjusting the dose and treatment interval, administrating Ig by intravenous or subcutaneous injection by either pump or push, and finally deciding which treatment options are best for a given patient. Ig therapy can also be used to treat immunodeficiencies resulting from lymphoproliferative and autoimmune diseases or immunosuppression following organ transplantation; however, there is an urgent need for research in this field. Accurate and early diagnosis of PID is important to ensure that optimal treatment is started early to maintain the patient's health. Detailed patient registries have been established to increase awareness of PID, as well as provide a valuable resource for further research.

7th International Immunoglobulin Conference: Immunodeficiencies.

Awareness of the challenges involved in diagnosing and treating a heterogeneous group of immunodeficiency disorders is growing. The improvements in neonatal screening offer new methods to ensure that primary immunodeficiencies (PIDs) are diagnosed as early as possible, enabling accurate treatment and the prevention of life-threatening infections and other complications. Additionally, the need to individualize patient therapy in order to optimize both clinical outcomes and quality-of-life is obvious and is exemplified by the ability to switch between intravenous and subcutaneous immunoglobulin administration offering flexible treatment regimens. However, further research is crucial in order to determine the optimal treatment for secondary immunodeficiencies, and to gain greater understanding of the underlying causes of PIDs, including common variable immunodeficiency. The information relating to the growth of patient registries is encouraging, with approximately 25 000 patients with PIDs included in the two registries discussed. Registries such as this are vital for future research, as well as providing an educational resource.

Efficacy and safety of home-based subcutaneous immunoglobulin replacement therapy in paediatric patients with primary immunodeficiencies.

Subcutaneous immunoglobulin infusions are effective, safe and well tolerated in the treatment of primary immunodeficiencies, but only limited data on the treatment of children are available. We investigated the efficacy, safety and pharmacokinetics of home therapy with a 16% liquid human immunoglobulin G preparation (Vivaglobin®) when administered subcutaneously in children with primary immunodeficiencies. Data were analysed from 22 children (2-<12 years) who participated in two prospective, open-label studies (one in Europe/Brazil, one in North America). All children had previously received intravenous immunoglobulins. They started weekly subcutaneous immunoglobulin infusions with an approximately 3-month wash-in/wash-out period, followed by a 6-month (Europe/Brazil) or 12-month (North America) efficacy evaluation period. In Europe/Brazil, subcutaneous doses generally equalled the previous weekly equivalent intravenous doses. In North America, subcutaneous doses during the efficacy evaluation period were 126% (median) of the previous weekly equivalent intravenous doses. Efficacy end-points in both studies included the occurrence of serious bacterial infections and any infections, and serum immunoglobulin G trough levels. Median serum immunoglobulin G trough levels exceeded those during previous intravenous therapy by 13% (North America) and 16% (Europe/Brazil). During the efficacy evaluation period of both studies, none of the children had a serious bacterial infection; the mean overall infection rate/patient year was 4·7 in Europe/Brazil and 5·6 in North America, concurring with previous reports in adults. The adverse event profile was comparable to previous reports in adults. Both studies confirmed the efficacy and safety of subcutaneous immunoglobulin therapy with Vivaglobin in children with primary immunodeficiencies.

Immunodeficiencies.

Primary immunodeficiencies (PIDs) are uncommon, chronic and severe disorders of the immune system in which patients cannot mount a sufficiently protective immune response, leading to an increased susceptibility to infections. The treatment of choice for PID patients with predominant antibody deficiency is intravenous immunoglobulin (Ig) replacement therapy. Despite major advances over the last 20 years in the molecular characterization of PIDs, many patients remain undiagnosed or are diagnosed too late, with severe consequences. Various strategies to ensure timely diagnosis of PIDs are in place, and novel approaches are being developed. In recent years, several patient registries have been established. Such registries shed light on the pathology and natural history of these varied disorders. Analyses of the registry data may also reveal which patients are likely to respond well to higher Ig infusion rates and may help to determine the optimal dosing of Ig products. Faster infusion rates may lead to improved convenience for patients and thus increase patient compliance, and may reduce nursing time and the need for hospital resources. Data from two recent studies suggest that Gamunex and Privigen are well tolerated at high infusion rates. Nevertheless, careful selection of patients for high infusion rates, based on co-morbid conditions and tolerance of the current infusion rate, is advisable. Based on the available data, intravenous Ig offers broad protection against encapsulated organisms. As vaccine trends change, careful monitoring of specific antibody levels in the general population, such as those against pneumococcal and meningococcal bacteria, should be implemented.

Subcutaneous immunoglobulin: opportunities and outlook.

Immunoglobulin (Ig) administration via the subcutaneous (s.c.) route has become increasingly popular in recent years. The method does not require venous access, is associated with few systemic side effects and has been reported to improve patients' quality of life. One current limitation to its use is the large volumes which need to be administered. Due to the inability of tissue to accept such large volumes, frequent administration at multiple sites is necessary. Most studies conducted to date have investigated the use of subcutaneous immunoglobulin (SCIg) in patients treated previously with the intravenous (i.v.) formulation. New data now support the use of s.c. administration in previously untreated patients with primary immunodeficiencies. SCIg treatment may further be beneficial in the treatment of autoimmune neurological conditions, such as multi-focal motor neuropathy; however, controlled trials directly comparing the s.c. and i.v. routes are still to be performed for this indication. New developments may further improve and facilitate the s.c. administration route. For example, hyaluronidase-facilitated administration increases the bioavailability of SCIg, and may allow for the administration of larger volumes at a single site. Alternatively, more concentrated formulations may reduce the volume required for administration, and a rapid-push technique may allow for shorter administration times. As these developments translate into clinical practice, more physicians and patients may choose the s.c. administration route in the future.

[Livestock owners with specifically increased disease awareness for Bluetongue: A new approach to disease surveillance]. / Tierhalter mit gezielt erhöhter "Disease Awareness" für die Blauzungenkrankheit: Ein neuer Ansatz in der Seuchenüberwachung.

For the first time in Switzerland, specifically trained livestock owners were included in a national disease surveillance program by the Federal Veterinary Office. A questionnaire on data about clinical and epidemiological aspects of Bluetongue Disease (BT) as well as on herd management was completed by 26 sheep owners three months after they had attended a training course about BT. The control group, consisted of 264 randomly selected sheep and cattle owners who had not visited a training course. Results showed that disease awareness for BT after attending the training course was considerably increased. This was especially evident in the better knowledge of the participants about the great number of possible symptoms. Training courses with the objective of increased disease awareness of livestock owners are an efficient, cost-effective instrument in control programs for exotic diseases.

Immunomodulatory effects of mixed hematopoietic chimerism: immune tolerance in canine model of lung transplantation.

Long-term survival after lung transplantation is limited by acute and chronic graft rejection. Induction of immune tolerance by first establishing mixed hematopoietic chimerism (MC) is a promising strategy to improve outcomes. In a preclinical canine model, stable MC was established in recipients after reduced-intensity conditioning and hematopoietic cell transplantation from a DLA-identical donor. Delayed lung transplantation was performed from the stem cell donor without pharmacological immunosuppression. Lung graft survival without loss of function was prolonged in chimeric (n = 5) vs. nonchimeric (n = 7) recipients (p < or = 0.05, Fisher's test). There were histological changes consistent with low-grade rejection in 3/5 of the lung grafts in chimeric recipients at > or =1 year. Chimeric recipients after lung transplantation had a normal immune response to a T-dependent antigen. Compared to normal dogs, there were significant increases of CD4+INFgamma+, CD4+IL-4+ and CD8+ INFgamma+ T-cell subsets in the blood (p < 0.0001 for each of the three T-cell subsets). Markers for regulatory T-cell subsets including foxP3, IL10 and TGFbeta were also increased in CD3+ T cells from the blood and peripheral tissues of chimeric recipients after lung transplantation. Establishing MC is immunomodulatory and observed changes were consistent with activation of both the effector and regulatory immune response.

Primary immune deficiency disorders presenting as autoimmune diseases: IPEX and APECED.

BACKGROUND: Several primary immune deficiency disorders are associated with autoimmunity and malignancy, suggesting a state of immune dysregulation. The concept of immune dysregulation as a direct cause of autoimmunity in primary immune deficiency disorders (PIDDs) has been strengthened by the recent discovery of distinct clinical entities linked to single-gene defects resulting in multiple autoimmune phenomena including immune dysregulation, polyendocrinopathy, enteropathy and X-linked (IPEX) syndrome, and autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy (APECED) syndrome. CONCLUSION: Reviewing recent advances in our understanding of the small subgroup of PIDD patients with defined causes for autoimmunity may lead to the development of more effective treatment strategies for idiopathic human autoimmune diseases.

Prognostic factors for health-related quality of life in adults and children with primary antibody deficiencies receiving SCIG home therapy.

The aims of the present study were to evaluate the health-related quality of life (HRQL) and treatment satisfaction (TS) of adults and children with primary antibody deficiencies (PAD) before and after the introduction of subcutaneous immunoglobulin G (SCIG) self-infusions at home and to identify prognostic factors (demographic/social, medical, patient/parent reported) for HRQL. 85 adults and 21 parents of children with PAD answered the SF-36 (adults), CHQ-PF50 (parents), and the LQI (adults and parents) at baseline and following 10 months of weekly self-administered SCIG infusions at home. The SCIG home therapy was associated with significant improvements in HRQL and TS, particularly in patients who had previously received IVIG therapy in hospital settings. Background factors that were found to be associated with HRQL changes in adults were age, serum IgG levels at month 10, concomitant joint/muscle/skeletal disorders, clinical study location and smoking status.

Intensive postgrafting immune suppression combined with nonmyeloablative conditioning for transplantation of HLA-identical hematopoietic cell grafts: results of a pilot study for treatment of primary immunodeficiency disorders.

This study was designed to determine the safety of a nonmyeloablative regimen in patients with primary immunodeficiency disorders (PID) who had infections, organ dysfunction or other risk factors that precluded conventional hematopoietic cell (HC) transplant. Fourteen patients received HLA-matched related (n=6) or unrelated (n=8) HC grafts from marrow (n=8), peripheral blood mononuclear cells (n=5) or umbilical cord blood (n=1), either without conditioning (n=1), or after 200 cGy total body irradiation alone (n=3) or with 90 mg/m2 fludarabine (n=10). All patients were given postgrafting immunosuppression with mycophenolate mofetil and cyclosporine. Mixed (n=5) or full (n=8) donor chimerism was established in 13 patients, and one patient rejected the graft. Eight patients developed acute grade III (n=1) and/or extensive chronic GVHD (n=8). With a median follow-up of 4.9 (range, 0.7-8.1) years, the 3-year overall survival, event-free survival and transplant-related mortality were 62, 62 and 23%, respectively. Correction of immune dysfunction was documented in 8 of 10 patients with stable donor engraftment. These preliminary results indicated that this approach was associated with stable donor engraftment and a low incidence of early mortality and, thus, can be considered for certain high-risk patients with PID. However, there was a risk of GVHD, which is an undesirable outcome for this group of patients.

A successful national control programme for enzootic respiratory diseases in pigs in Switzerland.

Before the start of systematic disease control, respiratory diseases in swine in Switzerland caused estimated losses of several million euros per year. In 1993, a national programme to control enzootic respiratory diseases in pigs was proposed, with the aim of reducing the incidence of clinical cases to less than 1%. Enzootic pneumonia (EP) caused by Mycoplasma hyopneumoniae and clinical cases of pleuropneumonia caused by any serotype of Actinobacillus pleuropneumoniae (APP) would be targeted, in addition to any cases with serological evidence of APP serotype 2. This control programme was initiated in 1996, region by region, and fully implemented by 2004. Clinical, epidemiological and laboratory test results were used to identify the appropriate disease control measures. Partial depopulation was used to control EP on breeding and breeding-finishing farms. Total depopulation was implemented on all farms affected with APP and finishing farms affected with EP Animal trade was strictly regulated during the programme and all suspected cases of respiratory disease in pigs were made notifiable. Continued monitoring is based on clinical suspicion of infection and/or the detection of gross pathological lesions at slaughter, followed by laboratory confirmation. In 2005, the incidence of clinical cases was less than 1%. Regulations have been introduced to control the international trade in live pigs and prevent the re-introduction of respiratory diseases into Switzerland.

A method for sheep scab control by applying selective treatment based on flock serology.

Sheep scab, caused by Psoroptes ovis, is a severe and debilitating disease that can be treated and controlled by the use of acaricidal dips or the use of broad-spectrum avermectins. In Switzerland, control measures are state regulated. In particular, sheep should be routinely treated with ectocide dips or avermectin injections before they are moved onto common alpine pasture in late spring. However, a substantial part of the sheep population remains untreated and represents a potential reservoir for the mite population. Untreated sheep that are not moved to alpine pasture may infest treated sheep when flocks are reassembled in autumn. In an attempt to identify infested sheep, all flocks in the Canton of Schwyz (Switzerland) were serologically tested in 2001 and in 2002 (587 and 565 flocks, respectively). In 2003, a representative number (182 of the 531 flocks) was again investigated. Seropositive flocks were treated with doramectin (0.3 mg kg(-1) body weight, intramuscularly) from 2001 to 2003. In spring 2002, no chemo-methaphylaxis was given to seronegative flocks before movement onto common alpine pastures. Of the 587 flocks surveyed in spring 2001, 34 were seropositive (5.8%). These consisted of 21 infested with P. ovis, 1 with P. cuniculi, 4 with Chorioptes spp. and 8 of seropositivity of unknown origin; there was a decrease of seropositive flocks in spring 2002 (4.4%) with 15, 0, 2 and 8, respectively. Of the 182 flocks surveyed in spring 2003, just 4 flocks (2.2%) were seropositive. All the seropositive reactions in these flocks were the result of Chorioptes spp. infestations. There was a corresponding decrease in the proportion of seropositive animals from 6.3% in spring 2001 to 2.1% in spring 2003. These results corroborate the concept that it may be possible to target chemo-metaphylaxis and hence decrease the use of endectocides as well as of ectocides to control sheep scab. This would be of great benefit in reducing the likelihood of development of anthelmintic resistance against avermectins, decreasing the extent of environmental and human contamination with potentially toxic products and diminishing potential drug residues in meat and milk.

[Autochthonous infections with Angiostrongylus vasorum in dogs in Switzerland and Germany]. / Autochthone Infektionen mit Angiostrongylus vasorum bei Hunden in der Schweiz und Deutschland.

Angiostrongylus vasorum is endemic in foxes an other carnivores in the South and south East of France, Denmark and Great Britain. The reddish nematode is present in the Arteria pulmonalis and the right side of the heart and causes respiratory and cardiovascular symptoms. From 1999 to 2004, A. vasorum was diagnosed in 5 dogs from northern Switzerland, in 1 dog from southern Germany and in 3 dogs from south Ticino. Clinical signs in the affected dogs varied and ranged from cough, tachypnoea and dyspnoea to neurological symptoms in 2 of the dogs. Four dogs died and in 3 of the 4 dogs adults and larvae were found after digestion of formalin-fixed tissue. Diagnosis in the other 5 dogs was achieved by detecting the larvae coproscopically. Based on anamnestic data, these 9 dogs are probably autochthonous cases.

Cognitive and motor deficits associated with HIV-2(287) infection in infant pigtailed macaques: a nonhuman primate model of pediatric neuro-AIDS.

Lentivirus-infected nonhuman primates exhibit behavioral and neurological pathology similar to human immunodeficiency virus (HIV)-infected humans and offer a means to examine the effects of lentivirus infection while controlling for confounding factors inherent in human populations. The purpose of this study was to examine cognitive and motor development in infant macaques vertically infected with HIV-2287. Subjects were 20 infant pigtail macaques (Macaca nemestrina); 8 controls born to uninfected dams, and 12 infants whose dams had been inoculated and infected with HIV-2287 in the third trimester of pregnancy. Eight of these pregnancies had undergone surgical procedures in the form of maternal amniotic catheters or maternal amniotic and fetal carotid artery and jugular vein catheters. Data indicated that catheterization had little or no impact on behavioral development. Seven infants were vertically infected (as measured by polymerase chain reaction (PCR) at birth) and five were not infected (as measured by PCR and coculture on repeated testing). Infected infants attained cognitive and motor milestones at significantly later ages than controls. Uninfected infants, born to infected dams, attained developmental milestones at later ages than controls on all tasks, but this reached statistical significance only for the Fine Motor Task. Attainment of milestones was not correlated with viral dose, maternal CD4+ levels at parturition or infant viral RNA levels at birth. Attainment of milestones was negatively correlated with infants' proportions of CD4+ lymphocytes at birth and significantly correlated with proportions of CD4+ lymphocytes 2 weeks after birth, indicating poorer performance in those infants with a more rapid CD4+ depletion. These cognitive and motor deficits closely resemble those observed in human infants and children infected with HIV and indicate that HIV-2287-infected infant macaques represent an excellent model of pediatric neuro-acquired immunodeficiency syndrome (neuroAIDS).

Inhaled IFN-gamma for persistent nontuberculous mycobacterial pulmonary disease due to functional IFN-gamma deficiency.

Pulmonary infection with nontuberculous mycobacteria (NTM) in previously healthy human immunodeficiency virus-seronegative individuals is difficult to treat. Recently, functional interferon (IFN)-gamma deficiency has been identified in individuals susceptible to this disease. Treatment with inhaled IFN-gamma for NTM pulmonary disease associated with functional IFN-gamma deficiency has not been previously described. In this study, the IFN-gamma pathway was characterised in an individual who had progressive NTM pulmonary infection, despite appropriate multidrug antibiotic therapy, and 10 healthy controls. Levels of IFN-gamma and tumour necrosis factor-alpha in whole blood were assessed before and after incubation with lipopolysaccharide, heat-killed Escherichia coli, heat-killed Staphylococcus aureus and phorbol myristate acetate/ionomycin. The coding regions of interleukin (IL)-12, IL-18 and the IL-12 receptor were sequenced using nested primers. IFN-gamma1b (100 microg.dose(-1)) was administered to the affected individual by ultrasonic nebuliser 3 days.week(-1) for 3 months. In vitro whole blood production of IFN-gamma with and without physiological stimuli was consistent with functional IFN-gamma deficiency in the affected individual. There was no evidence of mutation in the coding regions of IL-12p35, IL-12p40, IL-12Rbeta1 and IL-18 in the affected individual. Treatment with inhaled IFN-gamma resulted in rapid and sustained clearance of the organism from the airways and stabilisation of lung function. In conclusion, inhaled interferon-gamma can be effective for the treatment of nontuberculous mycobacteria pulmonary disease associated with functional interferon-gamma deficiency.

Clinical development and serological antibody responses in sheep and rabbits experimentally infested with Psoroptes ovis and Psoroptes cuniculi.

Psoroptes ovis of sheep origin, and Psoroptes cuniculi of rabbit origin were used in experimental infestations. In experiment I, groups of four rabbits and four sheep were infested with 50-100 mites of each isolate on the skin of the back (skin infestation, SI) or in the external auditory canal (aural infestation, AI). In rabbits, SI and AI with P. cuniculi and AI with P. ovis induced in all animals typical ear lesions and pronounced antibody reactions to P. cuniculi antigens in ELISA. After SI of rabbits with P. ovis no clinical signs were detected, no mites could be reisolated and no specific antibodies were detected. In sheep, P. ovis SI induced mange whereas AI did not induce typical clinical signs and mites could not be reisolated. In both these animal groups, ELISA revealed pronounced and comparable specific antibody reactions. After SI and AI with P. cuniculi no clinical symptoms were observed and no mites could be reisolated. Nevertheless, low levels of specific antibody were detected. In experiment II, clinical progression and antibody reactions to P. ovis SI in naive sheep were compared with sheep previously exposed to P. ovis or P. cuniculi. In both pre-exposed groups of animals, clinical signs appeared within 2 days after challenge infestation and three days earlier than in primarily infested sheep. Subsequently, no obvious difference in the clinical progression was observed between the three groups of animals. The results of this study document antigenetic crossreactivity of the two morphologically and genetically distinguishable Psoroptes species but differences in their biological behaviour and virulence which both are of epidemiological and taxonomic relevance.

[Outbreak of sheep scab on two adjacent common alpine pastures in the canton of Schwyz (Switzerland)]. / Ausbrüche von Schafräude auf zwei benachbarten Grossalpen im Kanton Schwyz.

Sheep scab, which is caused by the mite Psoroptes ovis, is a notifiable disease in Switzerland. In the framework of an epidemiological study in the canton of Schwyz, a sheep scab outbreak on 2 adjacent alpine pastures with 62 flocks (1770 sheep) was followed up clinically, parasitologically and serologically. No mass treatment of the flocks with organophosphates or avermectins had been undertaken before the flocks were taken up to the alpine pastures, but they were treated according to their serological status. Supervised treatment of seropositive judged flocks (at least one seropositive or at least 2 serologically equivocal animals per flock) with Doramectin was undertaken, whilst seronegative judged flocks remained untreated. Sheep returned from the summer pastures in early September 2001 and within three months scab infestation was diagnosed in 53 flocks (85.5%). These infested flocks were scattered all over the canton. Furthermore, the transfer of sheep from 6 infested flocks resulted in the transmission of the disease to 10 new flocks. Infested flocks were kept in quarantine and sanitized. The complexity of the traditional use of shared alpine pastures and the intense, uncontrolled trading with animals render the control of sheep scab difficult.

Regional differences in risk factors and clinical presentation of diabetic foot lesions.

BACKGROUND: Problems associated with the diabetic foot are worldwide. However, there may be regional variation among risk factors and clinical presentation. Prospective comparative data concerning this topic are rare. AIM: To determine differences in underlying risk factors and clinical presentation of foot problems among people with diabetes in different regions. PATIENTS AND METHODS: Six hundred and thirteen consecutive patients with diabetic foot lesions from three centres [Soest-Germany (GER), Dar-es-Salaam, Tanzania (TAN) and Chennai, India (IND)] were included during the period June 1998 through December 1999. Diabetes-related data, risk-factor profiles, and lesion-related data were collected for each patient. Due to varying proportions of recurrent lesions among the centres, only data from patients with newly presenting diabetic foot lesion were analysed. RESULTS: Of the 613 patients sampled, 368 (60%) were treated for newly presenting diabetic foot lesion. In all three centres, patients were predominately male and had Type 2 diabetes. The average diabetes duration until the onset of the initial foot lesion was 14 years in GER and 12 years in IND, but only 5 years in TAN. The corresponding patient ages were 71, 56 and 51 years. Neuropathy was common to patients in all three centres. Peripheral vascular disease (PVD) was a frequent risk factor in GER (48%). In TAN and IND it was far less common (12 and 13%), probably due to younger patient populations, shorter diabetes duration and lower proportions of smokers. Inadequate footwear was the most common cause of foot lesions in GER (19%), while lack of footwear, irregular foot care and burns were the primary precipitating factors among patients in TAN and IND. CONCLUSION: Similarities in different regions of the world among people with diabetes suffering newly presenting foot lesions include a predominance of males and patients with Type 2 diabetes, as well as a high frequency of diabetic neuropathy. However, differences concerning age, diabetes duration, peripheral vascular disease, and precipitating factors contributing to injury are also observed.