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Background Malacoplakia is a rare acquired, infection-related granulomatous disorder, that may affect many systems, but typically occurs in the urinary tract. Cutaneous involvement is less prevalent, and most commonly presents with a perianal or genital region localization. Cutaneous malacoplakia is believed to be caused by an acquired bactericidal defect of macrophages in the setting of chronic infections and immunocompromised states. A diagnosis of cutaneous malacoplakia should be considered when encountering non-specific granulomatous lesions that are refractory to treatment. Histologic findings are marked by the presence of foamy macrophages containing the pathognomonic Michaelis-Gutman bodies. Objectives The aim of this review is to discuss the current perspectives on the pathophysiology, clinical features, diagnosis, and treatment of this disease. We would also like to emphasize that the integration of clinical information, microscopic findings, and exclusion of other cutaneous granulomatous processes is necessary to accurately diagnose this exceedingly rare disease and provide opportunity for therapeutic intervention. Patients/methods Data for this work were collected from the published literature and textbooks. Results Combined surgical excision and protracted antibiotic courses appear to have the highest success rate. Antibiotics should be culture specific, but drugs that easily permeate the macrophages appear to be the best choice.

Summary 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’.

Maintaining an airway clear of inhaled particles, pathogens, and cellular debris is paramount for lung homeostasis. In healthy individuals, the phagocytes of the innate immune system act as sentinels to patrol the airway and ensure sterility. However, in airways diseases, including asthma, COPD, and cystic fibrosis, there is a propensity for bacterial colonization that may contribute to disease worsening. Evidence suggests that this may be due to dysfunctional phagocytosis. In patients with COPD, phagocytosis of several bacterial species and removal of apoptotic cells (efferocytosis) by alveolar macrophages are significantly reduced; however, these cells can remove inert beads normally. Attenuated phagocytosis is also apparent in monocyte-derived macrophages from the same patients, suggesting an inherent defect in these cells. Reduced expression of cell surface recognition receptors has been suggested as one mechanism for these observations; however, the literature is currently contradictory and requires further clarification. In cystic fibrosis, a similar defect is also observed in both airway neutrophils and macrophages, leading to ineffective bacterial uptake and subsequent killing. In asthma and other airways diseases, there are also reports of defective phagocytosis of bacterial pathogens, although the relevance to disease pathophysiology is not understood. Oxidative stress is emerging as a common mechanism that may be altering both macrophage and neutrophil functions that can be reversed by various antioxidant strategies. The identification of this and other mechanisms underlying phagocyte dysfunction may present novel therapeutic opportunities for the treatment of many of these intractable diseases and improve patient morbidity and mortality.

An important task for both dentists and pediatricians dealing with patients manifesting different oral lesions is to be able to differentiate changes signaling systemic disease from those appearing without any concomitant serious health problem. In this article, symptomatology of selected primary immune deficiency diseases are discussed with particular emphasis on oral manifestations reported in this group of disorders. Facial, dental, and oral findings compose a constellation of symptoms observed in immunodeficiency diseases. Predisposition to bacterial invasion, cytokine dysregulation, tissue inflammatory process, and necrosis lead to early-onset oral lesions and periodontitis. Developmental abnormalities, periodontal disease, and oral lesions may accompany immunodeficiency and require particular awareness directed toward diagnosis of an underlying disease of the immune system.

A 13-year-old girl with no previously known predisposing disease developed phycomycosis involving the left lung, pleura and shoulder, the left side of the neck, the left thigh, the kidney sand the brain. Prolonged amphotericin B therapy resulted in clinical improvement, but the disease was wide-spread when the patient died 5 months after debut of symptoms from a subarachnoid haemorrhage due to fungal destruction of the basilar artery. During hospitalization, a marked reduction in the bactericidal activity of circulating neutrophil granulocytes was repeatedly demonstrated and the endotoxin stimulated nitroblue tetrazolium test was negative. Together with the demonstration of granuloma formation and the accumulation of lipid-laden histiocytes in the spleen, lymph nodes, bone marrow and the thymus, these findings indicate that the patient had a less severe form of chronic granulomatous disease.

Carriers for chronic granulomatous disease (CGD) and patients with lupus erythematosus (LE) share several characteristics: They are mostly females, they reduce nitroblue tetra-zolium (NBT) poorly in their neutrophils, and, in some cases, they have similar skin lesions. We thus investigated 19 female LE patients for the presence of laboratory findings characteristic of the carrier state for CGD. None of these patients turned out to have the combined abnormality of neutrophil bactericidal activity and neutrophil NBT-reduction that is diagnostic of CGD carrier state in the X-linked form. An increased frequency of CGD carriers among female LE patients thus appears to be unlikely. Why some CGD carriers develop skin lesions typical of LE remains unexplained.

TABLE OF CONTENTS I. Preface S1 II. Executive Summary S2 III. Algorithms S7 IV. Summary Statements S14 V. General Considerations S20 VI. Humoral Immunodeficiencies S24 VII. Cellular Immunodeficiencies S30 VIII. Combined Immunodeficiencies S33 IX. Phagocytic Cell Disorders S40 X. Complement Deficiencies S43 XI. Acknowledgments S45 XII. References S45 XIII. Appendix S61

One hundred sixty-six cases of primary immunodeficiency diseases (PID) (95 males, 71 females), diagnosed according to WHO criteria, have been registered at the Children's Hospital, University of Sao Paulo, Brazil. The following frequencies were found: predominantly humoral defects, 60.8% (n = 101); T cell defects, 4.9% (n = 8); combined ID, 9.6% (n = 16); phagocyte disorders, 18.7% (n = 31); and complement deficiencies, 6% (n = 10). IgA deficiency was the most frequent disorder (n = 60), followed by transient hypogammaglobulinemia (n = 14), chronic granulomatous disease (n = 14), and X-linked agammaglobulinemia (n = 9). In comparison to other (national) reports, we observed higher relative frequencies of phagocyte and complement deficiencies. Recurrent infections were the cause of death in 12.7%. Allergic symptoms were observed in 41%, mainly in IgA-deficient, hypogammaglobulinemic, or hyper-IgE patients, and autoimmune disorders in 5%, predominantly in IgA and complement deficiencies. Five patients suffered from BCG dissemination; two of them died. This is the first Brazilian report on PID over an observation time of 15 years.

The differential diagnosis for a patient presenting with recurrent infections is formidable, given the complexity of the immune system. The clinical presentation of a patient who has a qualitative neutrophil abnormality may be similar to that of one who has an antibody or complement disorder. In general, evaluation for phagocytic cell disorders (Table) should be initiated among those patients who have at least one of the following clinical features: 1) Two or more systemic bacterial infections; 2) Frequent, serious respiratory infections, such as pneumonia or sinusitis, or frequent bacterial infection, such as cellulitis, draining otitis media, or lymphadenitis; 3) Infections presenting at unusual sites (hepatic or brain abscess); and 4) Infections associated with unusual pathogens (ie, Aspergillus pneumonia, disseminated candidiasis, or infections with Serratia marcescens, Nocardia sp, and Pseudomonas cepacia). Disorders of Neutrophil Function HYPERIMMUNOGLOBULIN E SYNDROME (JOB SYNDROME) Hyperimmunoglobulin E (hyper-IgE) syndrome is an autosomal dominant disorder with incomplete penetrance that is characterized by elevated levels of serum IgE and recurrent staphylococcal abscesses (Table). Neutrophils in these children exhibit impaired chemotaxis, although phagocytic function is normal. Clinically, hyper-IgE syndrome must be distinguished from severe atopic dermatitis. Both disorders are characterized by the development of severe dermatitis in the presence of elevated IgE levels.

A five-and-a-half-month-old male weimaraner with severe recurrent bacterial infections was assessed for immunocompetence. Results revealed a low serum immunoglobulin G concentration and defective neutrophil phagocytosis.

Patients with phagocyte defects frequently develop bacterial or fungal pneumonias, but they are not considered to be at increased risk for viral infections. We describe 3 patients with known phagocyte immunodeficiencies who developed lower respiratory tract infections (LRTI) caused by respiratory syncytial virus (RSV). All 3 patients had dense pneumonias as indicated by computed tomography scan of the lungs and RSV was recovered. We conclude that RSV can present as a dense pneumonia in patients with phagocyte defects. Along with common pathogens causing LRTI, RSV should be considered in the differential diagnosis. Viral cultures as well as rapid antigen detection assays for respiratory viruses should be included in the evaluation of LRTI in patients with phagocyte defects.respiratory syncytial virus, phagocyte, immunodeficiency, pneumonia.

The aims of the present study are: first, to assess the toxic role of serum from thalassemic patients in phagocytosis of PMN from healthy controls, and second, to seek to determine whether serum and cellular disturbances of polymorphonuclear neutrophils (PMN) phagocytosis, observed in thalassemic patients, can be prevented and/or corrected by use of desferrioxamine (DFX). Two kinds of in vitro incubations--without or with DFX--were performed. PMN or serum from thalassemic patients or from healthy controls was used. First, a phagocytosis defect of 3 different bacteria species was induced in PMN from healthy controls by incubation in thalassemic serum. Second, DFX could prevent, already at 1 microM, the phagocytic defect induced in normal PMN by the incubation with thalassemic serum, with disappearance of the toxic role of thalassemic serum at higher concentrations. Third, improvement of the phagocytosis defect of PMN from thalassemic patients was also observed at 1 microM of DFX for the 3 bacteria species. Normalization was obtained at higher concentrations for gram-negative bacteria. In vivo studies revealed, after a 3 hr subcutaneous infusion of DFX into 3 thalassemic patients, an improvement of the phagocytosis results and a decrease of the Prussian Blue reactivity of the PMN. It is concluded first that an iron-mediated defect in phagocytosis can be induced in normal neutrophils by incubation in serum from thalassemic patients, and second that a precautious and intensive chelation therapy seems to be advantageous for increasing PMN defense against infectious agents. Special care must nevertheless be taken in order to detect rapidly opportunistic (such as Yersinia) infections.

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.

There is evidence that acquired dysfunction of neutrophils, monocytes, or macrophages is an important cause of infection in patients with diabetes mellitus, renal or hepatic failure, alcoholism, autoimmune diseases, influenza or human immunodeficiency virus infection, burns, and trauma. Distinguishable mechanisms of acquired phagocyte dysfunction include inhibitory effects of metabolic disturbances (e.g., hyperglycemia, uremia), chemical toxins (e.g., ethanol), viral proteins on phagocyte activation, and pathologic activation of phagocytes in the circulation (e.g., after hemodialysis, burns, or cardiopulmonary bypass). Although the burden of morbidity and mortality resulting from acquired phagocyte dysfunction appears to be vast, research in this area has been hampered by the complexity of the underlying illnesses and by limitations of laboratory assays and clinical study methodology. Given the advent of improved assays of phagocyte functions and treatments that can enhance these functions, there is a pressing need for more prospective studies of acquired phagocyte dysfunction.

We tested peripheral blood from 60 patients with definite multiple sclerosis (MS) and 60 healthy controls for polymorphonuclear leukocyte (PMNL) functions and found significant disorders in adherence (9.07% +/- 8.18% for patients versus 28.97% +/- 5.76% for controls), chemotaxis (18.32 +/- 3.1 for patients versus 30.49 +/- 4.52 for controls), phagocytosis (73.6 +/- 25.25 for patients versus 111.2 +/- 25.7 for controls), and bactericidal action (10.35% +/- 5% for patients versus 25.09% +/- 4.82% for controls). All differences were significant (p0.001). We confirmed the results by retesting 3 to 8 months later. The depressed PMNL functions in MS patients may explain their increased susceptibility to infections of the respiratory, digestive, and urinary tracts.

We examined whether or not preoperative impaired bactericidal activities of polymorphonuclear neutrophils (PMN) are associated with infections following surgery for esophageal cancer. Intracellular killing (KI), superoxide anion-producing capacity (SOP), and myeloperoxidase (MPO) activity were measured in 22 patients with esophageal cancer, 27 with gastric cancer, and 13 age-matched controls. The average level of KI was significantly depressed in patients with esophageal cancer or with gastric cancer, to a similar extent, compared to findings in controls, but SOP was not. In esophageal cancer patients, the SOP level was significantly higher in those with postoperative septic complications than in those without such problems, whereas the KI level was depressed to a similar extent in both. Therefore, a depression of KI with elevation of SOP of PMN may serve to predict complications of infection following surgery in patients with esophageal cancer. © 1992 Wiley-Liss, Inc.

Neutrophils are the host's first line of defense against many pathogenic bacteria and fungi. Disorders of neutrophil function are often suggested by recurrent cutaneous, periodontal, respiratory, or soft tissue infections. In this review, we summarize the current understanding of neutrophil function, provide an update of recent developments in the field, and outline an approach to diagnosis and management of the major congenital disorders of neutrophils.

We present a case of acute bowel obstruction in an immunocompromised child, who also had lobar pneumonia and a giant unilateral pneumatocele. She was successfully managed with subarachnoid anaesthesia for exploratory laparotomy to relieve a colonic obstruction. This proved to be a safe alternative to general anaesthesia with tracheal intubation in this patient and should be considered in infants and children in selected cases whenever a contraindication to general anaesthesia exists.

A second case of symptomatic renal involvement of chronic granulomatous disease of childhood is reported, and all previous cases of documented genitourinary lesions in this disease are reviewed. Although frequent infections of other organ systems are a well recognized part of chronic granulomatous disease, involvement of the urinary tract has been rarely reported. The nature of the few cases described suggests that extensive insidious destruction occurs before urinary tract involvement is clinically suspected.

The ability of macrophages of phagocytize particulate matter is largely dependent on fibronectin, a nonspecific opsonin found in plasma. Fibronectin depletion, resulting in reticuloendothelial system (RES) depression, occurs following a variety of physical insults. RES depression may contribute to postinjury sequelae such as respiratory distress syndrome and septicemia. Fibronectin concentration was measured in the plasma of sheep with chronic lung lymph fistulas subjected to controlled thermal injury. Fibronectin levels were significantly (p < 0.05) decreased at 4, 24, 48, and 72 hours following burning. Fibronectin concentration decreased in parallel with serum albumin concentration; serum globulin concentrations did not decrease. Fibronectin concentration had an inverse relationship to lung lymph flow, a reflection of pulmonary transvascular fluid filtration rate. The role of fibronectin in the pathogenesis of postinjury respiratory distress syndrome deserves further exploration.

The enhancement of antimicrobial resistance and immunomodulatory action, and the anabolic effect caused by the consumption of live lactobacteria as a dietary adjunct are proposed by the author as sufficient reasons to test lactobacterial preparations in patients with AIDS. The problem of dosage is discussed and a practical solution presented.

Infants, children, and young adults who suffer chronic and recurrent bacterial or fungal infection despite adequate numbers of circulating granulocytes and normal or elevated levels of immunoglobulins should be suspected of having fundamental defects in granulocyte functioning. This article considers clinical disorders for which there is evidence for associated defects of polymorphonuclear leukocytes.

NADPH oxidase activity was examined in paired 27,000×g granule fractions isolated from normal polymorphonuclear leukocytes and leukocytes from patients with chronic granulomatous disease. At 0.17 mM NADPH, the oxidase activity was not measurable in normal resting cells but was activated by phagocytosis. This activation was absent in CGD cells. At higher levels of NADPH, activity was present in cells from patients with CGD, although it was lower than normal, and no difference in activity was found between resting and phagocytizing cells. Granule fractions from phagocytizing normal cells exhibited higher activity than granule fractions from resting normal cells at all levels of NADPH. These results suggest that NADPH oxidase activity is defective in chronic granulomatous disease, and further that the defect is not the absence of the enzyme but rather a failure to activate it.

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.

The kinetics of phagocytosis by monocytes isolated from cord blood and from the blood of adult volunteers was studied. Monocytes attached to glass coverslips were incubated with polystyrene spheres (1.1 µ diameter) for up to 120 minutes. In this system, the rate of phagocytosis was considerably slower in newborn monocytes than in those from adults. By the time phagocytosis had occurred in virtually all of the adult cells, only 38% of the neonatal monocytes had engulfed particles. However, this defect was not absolute, since ultimately all of the newborn cells contained engulfed spheres. Levamisole had no effect on normal adult monocytes but accelerated phagocytosis of newborn cells to a rate identical with that of adult cells. These data demonstrate that newborn monocytes are less efficient in the early stages of phagocytosis than are comparable cells from adults, raising the question of the impact of phagocytic kinetics in the development of neonatal sepsis. The correction of this defect by levamisole suggests that the differences in neonatal and adult monocytes may be evaluated more thoroughly by similar pharmacologic probes.

A 16-years-old male with a history of Job's syndrome and a recent diagnosis of Crohn's disease was admitted to the hospital because of abdominal pain, nonbloody diarrhea, weakness, and fever. Due to failure to respond to medical therapy it was decided that an operation was indicated, and resection of the terminal ileum and right colon was performed. Cecum and ileum were inflamed, and pathologic studies revealed the presence of budding yeasts which on special stain were diagnostic of Histoplasma species. Successful management was accomplished with oral ketoconazole.

Summary Three patients with the lazy phagocyte syndrome suffered from recurrent infections in the orofacial region which persisted despite treatment with antibiotics. All had neutrophil counts at the lower normal limits which did not increase after strenuous exercise or rise during infections. Tests of chemotaxis, random mobility and the skin window were abnormal. Ingestion and intracellular killing, however, were normal in one patient and abnormal in two. The findings are compatible with the lazy leucocyte syndrome but the symptoms were not manifest in early childhood as originally described by Miller et al. (1971), and the neutrophil counts were not as low as in his patients. Two of our patients also differed in showing a defective intracellular killing for Candida albicans. The lazy leucocyte syndrome should now be recognized to include different variants, some with late onset, a range in the degree of neutropenia, and some with defective ingestion and killing, though all possess a basic intrinsic defect of movement.

Summary The functions of neutrophils obtained from 3 calves affected with chronic and recurrent pneumonia, with marked neutrophilia, were examined. Their functions were compared with those of normal calves. Neutrophils from the three calves showed a markedly decreased phagocytosis, bacterial killing activity, NBT reduction activity, luminol-dependent chemiluminescence and chemotactic response. These findings show that the 3 calves had defective neutrophils; the disorder was diagnosed as bovine granulocytopathy syndrome. Zusammenfassung Bovines Granulozytopathie-Syndrom: Dysfunktion der neutrophilen Granulozyten bei Holstein-Friesian-Kalbern: Es wurde die Funktion von neutrophilen Granulozyten gepruft, die von 3 Kalbern mit chronischer recurrenter Pneumonie und ausgepragter Neutrophilie stammten. Zum Vergleich wurde auch die Funktion neutrophiler Granulozyten von normalen Kalbern untersucht. Die von den drei kranken Kalbern stammenden neutrophilen Granulozyten zeigten eine herabgesetzte Phagozytose, eine verringerte Bakterien-Abtotungs-Aktivitat, eine verringerte NBT-Reduktions-Aktivitat, eine herabgesetzte Luminol-abhangige Chemohumineszenz sowie eine reduzierte chemotaktische Antwort. Nach diesen Befunden hatten die 3 Kalber defekte neutrophile Granulozyten; die Storung wurde als bovines Granulozytopathie-Syndrom diagnostiziert.

A. Correction of the Defect 108 B. Protective Isolation 108 C. Elimination of Potentially Pathogenic M icroorganisms 108 D. Physiotherapy 109 E. Nutritional Status 109 F. Avoidance of Drugs Interfering with Phagocyte Function 109 G. Immunization 109

Superoxide-dependent cytochrome c reduction was used to measure Superoxide production by granulocytes from two patients with chronic granulomatous disease, from children of similar age wit...

I N HIS INTRODUCTION to this Seminar, Roberts has indicated the place in the immunologic scheme of things of so-called type III responses: antigen-antibody reactions that form immune complexes that activate complement, causing a variety of types of tissue damage, but especially vasculitis, interstitial pneumonitis, and sometimes granu1omatosis.s Fraser has discussed type III responses to known extrinsic antigens elsewhere in this symposium. This section will cover several related type IIIlike diseases in which the antigen either is unknown or is a tissue component of the body that has become offensive to the immune system. Some of the features that justify this classification are: (1) similarities in the interstitial pneumonitis of extrinsic allergic alveolitis and idiopathic interstitial fibrosis that suggest possible analogous immunologic mechanisms; (2) the prominence of vasculitis in many collagen diseases and in Wegener’s granulomatosis, raising the possibility of a mechanism related to serum sickness or an Arthus reaction; and (3) evidence that antigenantibody complexes of particular proportions result in granulomatous reactions even without delayed hypersensitivity (although proof of the relevance of this observation to the present group of diseases is lacking).

Of 32 patients (19 females and 13 males, ranging in age from 2 to 44 years), nine had ocular problems related to neutrophil dysfunction. Four patients had blepharokeratoconjunctivitis and pannus formation. In one of these, severe visual loss secondary to corneal thinning and scarring occurred. Five patients had inactive chorioretinal scars without visual loss. Although some of the other 23 patients had minor ocular abnormalities, we could not demonstrate that they were related to the neutrophil dysfunction. However, none of the control subjects (20 patients with systemic lupus erythematosus and 20 randomly selected eye clinic patients) had lesions resembling those of the patients with neutrophil dysfunction. Fisher's exact test (one-tailed) gave the following values: P less than .03 for keratitis; P less than .01 for chorioretinal scars; and P less than .001 for keratitis and chorioretinal scars. Abnormal neutrophil function probably interferes with the control of normal eyelid flora and predisposes the eye to the development of marginal keratitis. Eyelid hygiene and topical administration of antibiotics and corticosteroids during inflammatory episodes may prevent the progression of corneal vascularization. The chorioretinal scars do not appear to be progressive.

SummaryThe concentration of ascorbic: acid was determined in guinea pig peritoneal PMNL, normal rabbit alveolar macrophages, BCG-induced rabbit alveolar macrophages, rabbit peritoneal PMNL, and human circulating PMNL. The high levels of ascorbate seen in all cell types examined are consistent with a role for this compound in the bactericidal activity of the phagocytes. No significant differences from normal were observed in leukocytes from patients with chronic granulocytic leukemia, polycythemia vera, or in one patient with chronic granulomatous disease.

Patients with chronic granulomatous disease of childhood have an inherited defect in polymorphonuclear neutrophil (PMN) bactericidal activity and suffer from recurrent severe infections. The onset is usually in infancy with a fatal outcome nearly always by adolescence. Four adult male siblings, aged 28, 30, 32 and 40 years, had the onset at age six of serious bacterial infections involving the lungs and lymph nodes followed by a marked decrease in the frequency of infections by their mid-twenties. Sequelae include pulmonary fibrosis, ill-defined polyarthritis and glomerulonephritis. The diagnosis of chronic granulomatous disease (CGD) of childhood was made by showing the characteristic defects in PMN function. Despite normal morphology and the ability to ingest microbes, postphagocytic PMN failed to (1) reduce nitroblue tetrazolium (NBT) dye, (2) consume oxygen and produce hydrogen peroxide and (3) stimulate the hexose monophosphate shunt. Family studies demonstrated X-linked recessive inheritance. PMN glucose-6-phosphate dehydrogenase (G-6-PD) levels were normal. Although these oxidative abnormalities of the patients' PMNs were marked and typical of "classic" CGD, patients' PMNs killed and iodinated bacteria slightly better than cells from previously studied patients with CGD. Additional bactericidal mechanisms which might explain the longevity of the patients were searched for in phagocytic cells. To see if nonoxidative bactericidal factors were important, the patients' PMNs were studied anaerobically. However, like normal PMNs, the patients' cells showed impaired bacterial killing anaerobically. In contrast to normal monocytes and cultured macrophages which reduced NBT, patients' cells failed to reduce the dye. CGD should be considered in adults with a history of severe infections and unexplained pulmonary fibrosis.

Cachectic patients infused with hypertonic amino acids and dextrose ("parenteral hyperalimentation") are subject to severe hypophosphatemia and recurrent fungal and bacterial septicemia. We observed a relation between the two. Severe hypophosphatemia, induced in a total of 18 mongrel dogs, resulted in a 50 per cent depression of chemotactic, phagocytic and bactericidal activity of their granulocytes. There was a concomitant reduction in leukocyte ATP content. The motility defect was corrected if cellular ATP was repleted by phosphate supplementation of animals in vivo or by incubation of leukocytes with adenosine and phosphate in vitro. Analogously, severe hypophosphatemia in a hyperalimented patient was associated with a 45 per cent impairment of chemotactic responsiveness and was reversed by similar in vivo and in vitro manipulations. The studies provide an additional explanation for the high rate of sepsis in patients undergoing hyperalimentation therapy, secondary to an acquired granulocyte d...

The hyperimmunoglobulin E and recurrent infection syndrome is difficult to diagnose in children with markedly elevated IgE and recurrent superficial Staphylococcus aureus infections who have not presented with a severe infection. The patient, the child of a woman with HIE, had elevated cord blood IgE. In early infancy, she had cutaneous colonization with S. aureus followed by frank impetiginous lesions. Anti-S. aureus IgE was easily detected with a highly specific ELISA assay at 2 years of age (2 years before her presentation with a S. aureus subcutaneous abscess). Thus, the measurement of anti-S. aureus IgE by this technique may be a useful laboratory test for the diagnosis of HIE before the appearance of a severe infection.

KX, an antigen related to the Kell blood group system, is present in trace amounts on normal red cells and is strongly active on the neutrophils of all of 50 persons thus far tested. Normal circulating monocytes are now shown to also bear KX determinants. Absence of neutrophil KX has been associated with all of three previously tested patients with chronic granulomatous disease. In this study two male siblings with CGD also have been shown to have KX negative leukocytes, and white blood cells from their heterozygous mother were found to have a reduced competency to absorb anti-KX. Five CGD boys are known to lack KX; the probability of this occurring by chance is greater 10(-6).

The rate of degranulation by neutrophils from three male patients with X-linked chronic granulomatous disease was studied with use of non-ingestable heat-aggregated human IgG as the phagocytic stimulus. Both the spontaneous and the stimulated release of two lysosomal enzymes (acid phosphatase and β-glucuronidase) was measured at various times. The difference between these two measurements, called the net release, was compared to that from 25 control subjects. For the first 15 minutes after phagocytic stimulation the net release of lysosomal enzymes was significantly reduced in neutrophils from the patients and their mothers in comparison to controls. By 30 minutes, the net release became normal. The total content of acid phosphatase and β-glucuronidase in polymorphonuclear leukocytes from patients was normal. These data suggest impaired lysosomal degranulation during the early stages of phagocytosis in X-linked chronic granulomatous disease. (N Engl J Med 291:332–337, 1974)

To test the hypothesis that IgE-mediated release of histamine may be, in part, responsible for the abnormal inflammatory response observed in the hyperimmunoglobulin E (HIE) and recurrent infection syndrome, urine and plasma histamine levels were measured. Twenty-four-hour urinary histamine concentrations from 15 patients with HIE (23.7 +/- 6.9 micrograms/24 hr) were significantly elevated (p less than 0.001) compared to a large historical control population (10.5 +/- 0.7 micrograms/24 hr; n = 97). However, urinary histamine levels in HIE were much less abnormal (p less than 0.01) than in five patients with biopsy-proven systemic mastocytosis (159 +/- 62 micrograms/24 hr) and were not significantly elevated when levels were compared to 13 concurrently studied normal subjects (10.1 +/- 1.7 micrograms/24 hr) and nine patients with chronic granulomatous disease (8.1 +/- 1.2 micrograms/24 hr). Overall, there was no clear relationship between urine histamine values and the presence of infection as well as no significant correlation between urine histamine and total IgE or anti-Staphylococcus aureus IgE. However, urine histamine levels in a subgroup of six patients with HIE with chronic eczematoid dermatitis (42.4 +/- 12.5 micrograms/24 hr) were elevated compared with values from the historical control subjects (p less than 0.001), the concurrent control subjects (p less than 0.01), the patients with chronic granulomatous disease (p less than 0.01), and five patients with HIE who did not have skin manifestations (4.6 +/- 1.1 micrograms/24 hr; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The hyperimmunoglobulin E recurrent-infection syndrome (HIE) entails a disorder of recurrent bacterial infections of the skin and sinopulmonary tract commencing in infancy or early childhood in the presence of serum levels of IgE which are at least 10 times normal (greater than 2,000 IU/ml). Variable concomitants of HIE are coarse facies, chronic eczematoid rashes, cold cutaneous abscesses, mild eosinophilia, mucocutaneous candidiasis, and a neutrophil chemotactic defect. The bacteria which commonly infect these patients are Staphylococcus aureus and Haemophilus influenzae although Streptococcus pneumoniae and enteric gram-negative rods are seen in some cases. Other than pneumonias, deep-seated infections are unusual, although osteomyelitis, arthritis, and visceral abscesses are seen. Bacteremia and sepsis are rare. Therapy should involve prolonged intravenous antibiotics and early surgery to treat infections which usually seem deceptively benign. HIE patients' neutrophils display a variable chemotactic defect, and their mononuclear cells variably produce an inhibitor of neutrophil chemotaxis. The production of the inhibitor correlates with the in vitro chemotactic defect. The basis of the propensity for recurrent infections is still speculative, and the further study of this syndrome should add new dimensions to our understanding of host defenses against bacterial invaders.

Since 1971, significant deviations from the classic pattern of chronic granulomatous disease have been recognized, and the disease appears to be more common that it did formerly. Knowledge of the basic underlying molecular defect has been broadened, and some new concepts of diagnosis and management have been formed. This report summarizes new knowledge of this important disorder.

A 9-year-old girl with lifelong susceptibility to infection and thrombocytopenia subsequently developed an unusual form of histiocytic leukemia and died six months later. The abnormal histiocyte had been identified in bone marrow aspirates for four years prior to the onset of leukemia. Splenectomy hastened the progression of the disease that shared clinical and pathologic features of histiocytic medullary reticulosis and leukemic reticuloendotheliosis. Histologic, metabolic, and bactericidal studies of the patient's phagocytes indicated that the abnormal histiocytes could phagocytize and sequester bacteria, lacked lysosomes and peroxidase, and were likely responsible for the ineffective in vitro killing of three species of bacteria.