Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disorder caused by defects in the lysosomal trafficking regulator gene that lead to disregulated lysosomal fusion. Clinical manifestations include oculocutaneous albinism, immunodeficiency with frequent pyogenic infections, and neurologic impairment.1,2 Without bone marrow transplantation (BMT), considered the definitive treatment, this condition is often fatal during childhood, with death due to infection, bleeding, or the so-called accelerated phase, a lymphoma-like syndrome that occurs in up to 80% of patients.

HES is a myeloproliferative disorder characterized by persistent eosinophilia leading to end-organ damage. Scleroderma has been reported following eosinophilic fasciitis(EF). We present a patient with no history of EF developing scleroderma with cardiac fibrosis leading to arrhythmia requiring implantable cardioverter-defibrillator(ICD) years after HES remission. Biopsies: liver, bone marrow(BM), lymph node(LN), GI, skin, endomyocardium. Ten-month old infant presented with fevers, hepatomegaly, pericardial and pleural effusions. Severe peripheral eosinophilia: initially 14,259cells/μL increasing to 26,316cells/μL. Liver biopsy: marked eosinophilia without fibrosis/cirrhosis. BM biopsy: 15% eosinophils, no malignancy. LN biopsy: no malignancy. Negative infectious work-up. Prednisone resulted in downtrend of eosinophilia, but she developed vomiting/diarrhea episodes with small-bowel obstruction. GI biopsy: esophageal and colonic fibrosis with eosinophilic infiltration. GI symptoms required treatment with azathioprine, methotrexate and total parenteral nutrition. At age 3, she developed scalp scarring, thigh dimpling, and chest lesions concerning for scleroderma versus EF. Skin biopsy: morphea scleroderma without eosinophils. Intestinal biopsy: consistent with scleroderma. Hydroxychloroquine and D-penicillamine resulted in skin improvement. At age 6, apneic episode led to cardiac evaluation: right bundle-branch block, intermittent ventricular tachycardia(VT). Echocardiogram: pericarditis with effusion. Endomyocardial biopsy: myocarditis-- lymphocytic infiltrate and endocardial fibrosis. At age 9, she presented with VT prompting ICD placement. Ten years following ICD she did reasonably well with occasional gastrointestinal symptoms, and currently not on medications. HES presentation during infancy is rare and later development of scleroderma in absence of eosinophilic fasciitis is rarer. Patient's clinical course may be instructional for better understanding of natural history of these disease entities.

Abstract The majority of patients with primary immunodeficiency have a defect in their ability to make sufficient quantities of specific antibodies. This lack of specific antibodies is due to the lack of B lymphocytes, defects in B‐lymphocyte function, or inability of B lymphocytes to interact with T lymphocytes. Patients born with only antibody deficiency usually appear normal at birth due to maternal antibodies that crossed the placenta. They usually start developing more infections at around six months of age when maternal antibodies have been depleted, and they cannot make their own antibodies. Treatment may include prophylactic antibodies until diagnosis is confirmed or infusion of immunoglobulin, either by intravenous route or subcutaneously. When patients have antibody deficiency plus defects in T lymphocytes, the disease is usually more severe and will be further discussed in other articles. Key Concepts: The most severe form of antibody deficiency, Bruton's, requires regular infusions of IVIG starting in infancy. Common variable immunodeficiency (CVID) is often associated with autoimmune disease as well as malignancies. Less severe forms of B‐cell deficiency may be managed with prophylactic antibiotics. Severe combined immunodeficiency (SCID) requires stem cell transplantation for treatment. Early diagnosis is essential in preventing long‐term disability or early death

Common variable immunodeficiency is the most common severe primary immunodeficiency. Most common variable immunodeficiency patients have progressive hypogammaglobulinemia involving all immunoglobulin classes, poor or absent antibody responses, and recurrent bacterial infections, usually of the sino-respiratory tract. Some may present with complicated cutaneous infections like furunculosis (J Allergy Clin Immunol; 109: 581) or recurrent cutaneous warts. Here, we report the case of an 18-year-old male diagnosed with common variable immunodeficiency who had extensive cutaneous warts that resolved within 2 months of starting weekly infusions of subcutaneous immunoglobulin.

The potential for morbidity and mortality in an ill child with primary immune deficiency (PID) is extremely high. It is estimated that there are more than 500,000 cases of PID in the United States and an incidence of up to 1 in 2000 live births. Although the increased outpatient care of these patients necessitates a standardized approach to maximize emergent treatment, the diversity of these rare diseases and their potential infectious, autoimmune, and malignant sequelae complicate treatment guidelines. We present an overview of the clinical characteristics of primary immune deficiencies and then describe unique aspects of emergent care for these complex patients. Conservative management with empiric antimicrobials, early and aggressive surgical debridement of abscesses, and admission at a tertiary pediatric care center are often indicated. Familiarity with the clinical manifestations of PID and collaboration with a pediatric immunologist are prerequisites for optimal emergent care of these complex patients.

Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by hypogammaglobulinemia, poor antibody responses, and recurrent bacterial infections, usually of the sinorespiratory tract. A not uncommon complication is granuloma of the lungs, spleen, liver, and/or skin. We report the case of an 18-year-old boy with CVID and chronic granulomas of the left arm (since 13 years of age) refractory to treatment with antibiotics, intravenous immunoglobulin, antifungal agents, systemic and intralesional steroids, IFN-gamma, cyclosporine, methotrexate, hydroxychloroquine, localized radiation therapy, and surgical excision. The lesions improved after treatment with the systemic administration of the TNF-alpha inhibitor etanercept for 1 year. Etanercept prevents soluble TNF from binding to its cell membrane receptor, leading to inhibition of its inflammatory cascade. We recommend further trials of etanercept in patients with CVID with noninfectious recalcitrant granulomas.

RATIONALE: We report on 7 individuals between 4 and 12 months of age with severe atopic dermatitis and markedly depressed serum IgG and serum albumin.METHODS: This was a retrospective chart review of 7 infants who initially presented for treatment of severe, diffuse atopic dermatitis refractory to standard topical treatment.RESULTS: All infants presented with diffuse excoriations, weeping lesions, and moderate to severe impetigo. They had markedly depressed serum IgG, ranging from 70 to 225 mg/dL, which was far below the average physiologic nadir of 427 ± 186 mg/dL in infancy. Serum albumin was also below normal (2 to 3 mg/dL). Investigations for protein loss in the urinary and the gastrointestinal tracts were negative. Presence of IgE and IgM indicated the patients were able to produce immunoglobulins and so were likely losing proteins through skin breakdown. The infants were each placed on standard treatment for atopic dermatitis and started on monthly intravenous immunoglobulin (IVIG) infusions. Three of the infants have had improved skin symptoms after 10 months of IVIG, and their serum IgG has normalized. The other four infants are still receiving IVIG infusions but have also had improvement in their symptoms.CONCLUSIONS: These findings suggest that significant protein loss, particularly IgG, can be found in young infants with severe atopic dermatitis. This protein loss likely occurs through skin barrier breakdown, much like the protein loss in patients who have second and third degree burns. Further investigations regarding the associations between low serum protein, IVIG treatment, and atopic dermatitis in young children are warranted. RATIONALE: We report on 7 individuals between 4 and 12 months of age with severe atopic dermatitis and markedly depressed serum IgG and serum albumin. METHODS: This was a retrospective chart review of 7 infants who initially presented for treatment of severe, diffuse atopic dermatitis refractory to standard topical treatment. RESULTS: All infants presented with diffuse excoriations, weeping lesions, and moderate to severe impetigo. They had markedly depressed serum IgG, ranging from 70 to 225 mg/dL, which was far below the average physiologic nadir of 427 ± 186 mg/dL in infancy. Serum albumin was also below normal (2 to 3 mg/dL). Investigations for protein loss in the urinary and the gastrointestinal tracts were negative. Presence of IgE and IgM indicated the patients were able to produce immunoglobulins and so were likely losing proteins through skin breakdown. The infants were each placed on standard treatment for atopic dermatitis and started on monthly intravenous immunoglobulin (IVIG) infusions. Three of the infants have had improved skin symptoms after 10 months of IVIG, and their serum IgG has normalized. The other four infants are still receiving IVIG infusions but have also had improvement in their symptoms. CONCLUSIONS: These findings suggest that significant protein loss, particularly IgG, can be found in young infants with severe atopic dermatitis. This protein loss likely occurs through skin barrier breakdown, much like the protein loss in patients who have second and third degree burns. Further investigations regarding the associations between low serum protein, IVIG treatment, and atopic dermatitis in young children are warranted.

The interaction between neutrophils and viruses is complex, and the clinical significance is not well established. It is known that neutrophils can inhibit or kill viruses by various mechanisms, including production of oxygen intermediates and phagocytosis in the laboratory. Viruses may activate neutrophils by binding to the surface and by the production of cytokines which occurs in upper respiratory tract infections. Neutrophils may be inhibited viruses such as CMV by direct interaction by suppression of the bone marrow. These interactions between neutrophils and viruses will be discussed in this chapter.

RATIONALE: Protein-losing enteropathy has been associated with severe immunodeficiency due to loss of immunoglobulins and lymphocytes through the gastrointestinal tract.We examined the effectiveness of weekly subcutaneous immunoglobulin infusions in a six-year-old male with primary intestinal lymphangiectasia, a rare disease characterized by edema, diarrhea, hypoproteinemia, and hypogammaglobulinemia.Immunoglobulin G (IgG) levels were as low as 93 mg/dL, and there was also a selective loss of CD4+ cells, dropping to 10% with an absolute cell count of 63/cmm.METHODS: Weekly infusions of subcutaneous immunoglobulin were given to the patient at 2.5 gm a week over 4 weeks and serum IgG levels were checked prior to each infusion.RESULTS: Over four weeks, the patient's IgG went from 185 mg/dL to 205 mg/dL, 215 mg/dL, and 214 mg/dL.He tolerated the procedures well with no complications.He did not develop any new infections during this time period.CONCLUSIONS: These results suggest that subcutaneous infusions of immunoglobulin resulted in more stable levels of IgG.Weekly administration of subcutaneous immunoglobulin may allow for a more steady state of serum IgG than monthly intravenous bolus doses of immunoglobulin.There is also the potential for self-administration of subcutaneous immunoglobulin, which may be a preferable and effective alternative for patients with protein-losing enteropathy.Further studies and longer treatment periods are needed to establish its usefulness.

C -at-scratch disease (CSD) is an infection with Bartonella henselae (B. henselae), a fastidious gram-negative bacterium.' A skin papule may occur at the presumed site of bacterial inoculation, usually occuring 1-2 weeks after the scratch of a kitten, followed by the development of lymphadenopathy in 1 to 2 weeks. Lymphadenopathy usually involves nodes that drain the site of inoculation including cervical, axillary, epitrochlear, or inguinal nodes. The area around the affected lymph nodes may become tender, warm, erythematous, and indurated. Fever greater than 101°F and systemic symptoms, including malaise, fatigue, headache, and anorexia, occur in 30% of patients. The affected nodes suppurate spontaneously in about 30% of cases The treatment is primarily symptomatic since the disease is usually self-limited, resolving spontaneously in 2-4 months. Antibiotic treatment has been suggested for immunocompromised

Chronic wounds are associated with considerable morbidity and prolonged hospitalizations. The availability of recombinant growth factors and cytokines provides a new modality for treatment of recalcitrant wounds. Granulocyte-macrophage colony-stimulating factor (GM-CSF), a growth protein for hematopietic cells, also enhances neutrophil and monocyte function and promotes keratinocyte proliferation. In three patients with inherited disorders associated with leukocyte dysfunction and non-healing wounds, topical application of GM-CSF resulted in complete wound closure within 1 to 4 weeks. A subcutaneous (s.c.) infusion pump for the local s.c. delivery of GM-CSF was also found to enhance healing. Local application of GM-CSF may thus promote wound closure in patients with impaired wound healing.

The ability of IL-12 and IL-15 to enhance natural killer (NK) activity and antibody-dependent cellular cytotoxicity (ADCC) of mononuclear cells (MNCs) from HIV+ children and their mothers was investigated. MNCs from HIV+ patients were deficient in NK and ADCC activity compared to control MNCs against several target cells. Overnight incubation with IL-15 or IL-12 augmented NK activity of MNCs from both patients and controls, and the combination of IL-12 and IL-15 resulted in the greatest enhancement. ADCC in HIV+ patients against gp120-coated CEM.NKR cells or chicken erythrocytes could also be enhanced by IL-2 or IL-15 in overnight cultures. Culturing MNCs with either IL-2 or IL-15 for 1 week increased the NK activity in patients to levels of controls treated with these cytokines. However, the response to the combination of IL-12 and IL-15 was less than that to IL-15 alone in 1-week cultures. Culturing MNCs with IL-2 and IL-15 for 1 week also increased the percentage of CD16+/CD56+ cells in both patients and controls. Thus, IL-15 can restore the deficient NK activity in patients and may be a candidate for immunomodulative therapy in HIV+ patients.

J Allergy Clin Immunol 1998;101:848-9.

Subcutaneous Human Intravenous Immunoglobulin (IVIG) in the Treatment of Antibody Deficiency. ♦ 60

Cellular cytotoxicity may be an important defense in the control of HIV progression. In the present study antibodies were attached to peripheral blood mononuclear cells (PBMC) by exposing them to polyethylene glycol and phthalate oil in the presence of HIV human hyperimmune IVIG (HIVIG). The attachment procedure is known as “franking” and the resultant cytotoxicity is termed “antibody-directed.” The majority of the cells that are franked with attached HIVIG are CD16+(Fcγ RIII), placing them in the natural killer cell population. Franking increased the cytotoxicity of PBMC from both healthy controls and HIV-seropositive patients approximately fourfold compared to conventional antibody-dependent cellular cytotoxicity using CEM cells coated with HIV gp120 antigen as targets. Use of anti-HIV monoclonal antibodies for franking was less efficient than polyclonal HIVIG. The HIVIG-franked PBMC suppressed p24 production ofin vitroHIVIIIb-infected human PBMC. The ability of HIVIG to enhance and direct cytotoxicity to HIV targets may suggest a new therapeutic approach to HIV control.

Chronic recurrent multifocal osteomyelitis is characterized by recurrent episodes of painful swollen lesions of the bone and overlying skin with radiographic changes and an elevated sedimentation rate. It resembles infectious osteomyelitis but with negative findings on bacterial culture and no response to antibiotics. We treated a 13-year-old girl with interferon gamma for 3 months. She had 11 episodes of chronic recurrent multifocal osteomyelitis in 2 1/2 years before therapy and has had none in the 15 months since therapy, an outcome suggesting a favorable therapeutic response.

INTERLEUKIN-2 (IL-2) AND IL-12 ENHANCE HIV GP120-SPECIFIC CELL-MEDIATED CYTOTOXICITY (CMC) OF MONONUCLEAR CELLS FROM HIV-INFECTED(HIV+) PATIENTS.† 58

ENHANCEMENT OF GP120-SPECIFIC CELL-MEDIATED CYTOTOXICITY (CMC) BY HIV HYPERIMMUNE INTRAVENOUS IMMUNOGLOBULIN (HIVIG)-ARMED EFFECTOR CELLS. † 1049