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The clinical outcomes of primary immunodeficiencies (PIDs) are greatly improved by accurate diagnosis early in life. However, it is not common to consider PIDs before the manifestation of severe clinical symptoms. Including PIDs in the nation-wide newborn screening programs will potentially improve survival and provide better disease management and preventive care in PID patients. This calls for the detection of disease biomarkers in blood and the use of dried blood spot samples, which is a part of routine newborn screening programs worldwide. Here, we developed a newborn screening method based on multiplex protein profiling for parallel diagnosis of 22 innate immunodeficiencies affecting the complement system and respiratory burst function in phagocytosis. The proposed method uses a small fraction of eluted blood from dried blood spots and is applicable for population-scale performance. The diagnosis method is validated through a retrospective screening of immunodeficient patient samples. This diagnostic approach can pave the way for an earlier, more comprehensive and accurate diagnosis of complement and phagocytic disorders, which ultimately lead to a healthy and active life for the PID patients., (Copyright © 2020 Dezfouli, Bergström, Skattum, Abolhassani, Neiman, Torabi-Rahvar, Franco Jarava, Martin-Nalda, Ferrer Balaguer, Slade, Roos, Fernandez Pereira, López-Trascasa, Gonzalez-Granado, Allende-Martinez, Mizuno, Yoshida, Friman, Lundgren, Aghamohammadi, Rezaei, Hernández-Gonzalez, von Döbeln, Truedsson, Hara, Nonoyama, Schwenk, Nilsson and Hammarström.)

The Swiss National Registry for Primary Immunodeficiency Disorders (PID) was established in 2008, constituting a nationwide network of paediatric and adult departments involved in the care of patients with PID at university medical centres, affiliated teaching hospitals and medical institutions. The registry collects anonymized clinical and genetic information on PID patients and is set up within the framework of the European database for PID, run by the European Society of Immunodeficiency Diseases. To date, a total of 348 patients are registered in Switzerland, indicating an estimated minimal prevalence of 4·2 patients per 100 000 inhabitants. Distribution of different PID categories, age and gender are similar to the European cohort of currently 19 091 registered patients: 'predominantly antibody disorders' are the most common diseases observed (n = 217/348, 62%), followed by 'phagocytic disorders' (n = 31/348, 9%). As expected, 'predominantly antibody disorders' are more prevalent in adults than in children (78 versus 31%). Within this category, 'common variable immunodeficiency disorder' (CVID) is the most prevalent PID (n = 98/217, 45%), followed by 'other hypogammaglobulinaemias' (i.e. a group of non-classified hypogammaglobulinaemias) (n = 54/217, 25%). Among 'phagocytic disorders', 'chronic granulomatous disease' is the most prevalent PID (n = 27/31, 87%). The diagnostic delay between onset of symptoms and diagnosis is high, with a median of 6 years for CVID and more than 3 years for 'other hypogammaglobulinaemias'., (© 2015 British Society for Immunology.)

There are few reports about congenital indifference to pain or Hereditary and Sensory Autonomic Neuropathy (HSAN). Several investigations for pathophysiology of this syndrome have been performed and different classifications about it. In this report we present a case of HSAN type II with general absence of pain and self amputations and leprosy-like damage of extremities which was suspected to be phagocytic immunodeficiency due to past history of repeated ulcer and abscess formation.

The field of phagocytic disorders has attained major biologic and clinical significance in the past 40 years. The development of exciting new techniques in molecular biology and the cellular physiology of signal transduction have made it possible to identify the genetic defects involved in many of these disorders. Moreover through immunopharmacologic intervention, bone marrow or peripheral or cord blood stem cell transplantation along with the prospect of gene therapy, we have begun attempts to at least partially correct genetic defects in cell development and activation pathways in the entire spectrum of phagocyte disorders. Carrier detection and prenatal diagnosis employing with chain reaction techniques or direct nucleotide sequencing in fetal blood have made these diseases potentially preventable or treatable in utero or shortly after birth.

Neutrophils have a crucial function in the defense against bacteria and fungi. Indeed, during chronic, severe neutropenia and in case of severe neutrophil dysfunctions, the patients may suffer recurrent and sometimes life-threatening infections. This article describes the clinical symptoms, the theory behind the antimicrobial systems of neutrophils, the methods to diagnose the various aberrations, and the possibilities for treating these patients. A few of the most common causes of neutropenia and neutrophil dysfunctions are described in detail, including recent genetic information regarding the cause of these diseases.

The evaluation of phagocytic and microbicidal activities of the blood neutrophils has been recognized as one of the important tools for investigating phagocytic dysfunctions in patients with recurrent infections. In the present study, these activities were examined in neutrophils and monocytes from healthy adults and patients affected by primary phagocytic dysfunctions by using a modified fluorochromic microbicidal assay, discriminating simultaneously the extracellular adherence, ingestion and intracellular killing of Staphylococcus aureus Cowan I. The assay employs acridine orange staining, as described in Bellinati-Pires et al. (1989) (AO assay), but was modified by the addition of an alternative leukocyte treatment with 0.5 U/ml of lysostaphin (LS) for 5 min at 37 degrees C, after phagocytosis (AO-LS assay). The LS treatment was standardized to eliminate staphylococci adhered to the outer surface of the phagocytes without affecting the determination of intracellular live or dead bacteria, as demonstrated in normal neutrophils and monocytes. Our purpose in this study was to compare AO and AO-LS assays in order to evaluate the effect of LS on the determination of actually ingested staphylococci and to provide a means for improving the fluorochromic assay for detecting phagocytic defects, as well as bactericidal disturbances. By using the AO-LS assay, decreased ingestion of staphylococci by neutrophils in Chediak-Higashi Syndrome (CHS) was demonstrated. However, increased staphylococci adherence, as well as ingestion, was observed in neutrophils or monocytes from chronic granulomatous disease (CGD) patients, comparing AO and AO-LS assays. Bactericidal defect, which is a common feature in CHS and CGD, was detected in neutrophils or monocytes in both assays. We emphasize that such alterations were deduced by comparing the patients' results with those obtained from their respective normal controls and with the normal range of values previously established for 160 healthy adults. No alteration was observed in hyper IgE syndrome phagocytes. Despite the possible penetration of LS into the leukocytes, as stated in other studies, we concluded that a short period of phagocyte incubation with this enzyme increased the sensitivity of the fluorochromic assay to detect phagocytic defect without affecting the determination of the bactericidal activity. Moreover, comparations between AO and AO-LS assays may be important in the study of the initial pathways of staphylococci phagocyte interaction, including adherence by non-phagocytic receptors.

The functional activity of polymorphonuclear leukocytes (PMNL) was studied in the test of biochemical luminescence (BCL) in 43 patients including 31 patients with systemic lupus erythematosus (SLE) and 12 with nodular periarteritis (NP). Generation of the active forms of oxygen depended on the activity of the pathological process and the level of the circulating immune complexes (CIC). As established, under the conditions of hyperproductions IC PMNL in patients with SLE and NP preserve a rather high capacity to generate active forms of oxygen into intracellular space that allows one to speak about the role of oxygen radicals in the development of vascular lesions in patients with rheumatic diseases.

A study was made of the mechanisms of leucocyte phagocytic and bactericidal activity with relation to Staph, aureus and the NBT-test in simple and simulated variants in 71 patients with diabetes mellitus. A compensatory elevation of the phagocytic index and the phagocytic number was found in all the patients with a decrease in phagocytosis completion which testified to the internal defects of bactericidal activity which, according to the NBT-test results, consisted in insufficient activity of oxidation enzymes. The stimulated NBT-test showed a decrease in phagocytic potentialities in patients with diabetes mellitus. Phagocytosis defects in type I and type II diabetes mellitus were more noticeable in a severe and labile course of the disease.

This article presents an outline of a rational approach to the patient with recurrent infections. The different categories of phagocytic defects are reviewed, and a brief discussion of the various tests of phagocyte function is presented.

A case of necrotizing granulomatous vasculitis limited to the gallbladder and manifesting as acute cholecystitis is presented. The different types of vasculitis are discussed and the characteristics of necrotizing granulomatous vasculitis (allergic granulomatosis) are described.

Job's syndrome is characterized by the clinical features of fair skin, red hair, recurrent cold staphylococcal skin abscesses with concurrent other bacterial infections and skin lesions. This case report chronicles a classic presentation of Job's syndrome. A brief review of the otolaryngological presentations of immune deficiencies is presented. Other than its relationship to the manifestations of other immunological defects, Job's syndrome is of interest to the otolaryngologist because of the head and neck infections represented in its clinical expression. Familiarity with phenotypic and laboratory manifestations of such diseases will enable earlier recognition and treatment of this syndrome.

Report on a boy, now 3 years old, who presented the typical clinical picture of a BCG generalization during infancy. The BCG agents were verified in the lymph node. Intensive tuberculostatic therapy in combination with the transfer factor failed. The negative NBT test revealed a progressive septic granulomatosis.

Although inherited forms of phagocyte defects affect a small proportion of the general population, their clinical course can be altered dramatically by a physician's awareness of these diseases and modifications of the approach to and treatment of affected patients. The most common syndromes are chronic granulomatous disease of childhood (CGD), the Chediak-Higashi syndrome (CHS), the hyperimmunoglobulin-E-recurrent infection (Job's) syndrome (HIE), and myeloperoxidase (MPO) deficiency. CGD patients have defects in the oxidative metabolism involved in killing catalase-positive organisms. CHS patients have giant granules defective in fusing with phagosomes and subsequent killing of ingested organisms. HIE patients have abnormal chemotaxis and elevated IgE levels and are susceptible to skin infections with Staphylococcus aureus and recurrent sinopulmonary infections. MPO-deficient patients often go undetected since they rarely have recurrent infections unless they have a concomitant disease such as diabetes mellitus. Patients with a recently described syndrome, C3bi receptor deficiency, have recurrent bacterial infections and persistent leukocytosis, and their neutrophils have abnormal adherence and phagocytosis. The absence of specific granules is a more rare entity but these patients also have recurrent infections thought to be secondary to a chemotactic defect and a minor abnormality of microbial killing exhibited by their neutrophils. This review will focus on the clinical presentation and management of these patients.

The so-called Job's syndrome belongs to the group of diseases designated "chronic granulomatous disease", characterized by recurrent suppurative infections of the skin, eczema, nail dystrophy, conjunctivitis, lymphadenitis and pulmonary infections. Leucocyte function is defective; the nature of the defect has not yet been elucidated. High immunoglobulin E levels are characteristic. The historical background to this syndrome is outlined.

The available literature on the nitroblue tetrazolium reduction test is reviewed. The mechanism of this test is poorly understood. There are two basic methods of performing the test, namely, the stimulated and the spontaneous methods. However, the test procedure has not been standardized, and numerous modifications have ensued resulting in a number of technics. The stimulated test has proved to be valuable for screening patients or carriers with chronic granulomatous disease of childhood. It is one of the useful tests in studying neutrophil dysfunction. On the other hand, extensive accumulated data indicate that this test, be it stimulted or spontaneous, cannot be relied upon as an absolute test to differentiate bacterial from nonbacterial infectious disease as there have been numerous false-positive and false-negative results. When this test is used, the result should be interpreted in the context of other laboratory test results and the clinical picture of the patient. Preliminary data indicate that in certain diseases, if the initial test is positive in a particular patient, it may be useful as one of the follow-up tests to ascertain the activity of the disease process.

When patients suffer from recurrent infections with bacteria or fungi that react poorly with the commonly prescribed antibiotics, phagocyte dysfunctions should be considered. In this article, a survey is given of the mechanism of action of these cells, the dysfunctions that may occur, the resulting clinical symptoms, the laboratory diagnostics and some therapeutical approaches.

CD11/CD18 leukocyte glycoprotein deficiency is a rare, inherited disorder of leukocyte function, manifested by recurrent severe bacterial infections. A deficiency in the expression of a family of leukocyte membrane glycoproteins (the CD11/CD18 glycoproteins) represents the molecular basis for this disease.

In the child with recurrent infection, early recognition of defects in host defenses is critical for appropriate treatment and for patient survival and well-being. Familiarity on the physician's part with the clinical clues of an anatomic or functional defect can save time, money, and patient discomfort. When no such defect is apparent, the problem may be in the child's immunologic system and more specific testing is necessary to identify whether the defect is in cell-mediated immunity or is in the functioning of the phagocytic, complement, or humoral system. Treatments for these problems are available, but their success depends on early diagnosis before recurrent infection and malnutrition result in irreversible tissue damage.

The various "in vitro" tests for evaluating polymorphonuclear leucocyte function in children with recurrent infections are described and the different clinical conditions caused or accompanied by defects in polymorphonuclear function are summarized briefly. The necessity of correct interpretation of the results of the laboratory tests used in the diagnostic evaluation of patients with suspected immunodeficiency is stressed.