A 27-year-old man with recurrent sinopulmonary and cutaneous infections.

The increasing availability of genetic testing for modern immunologists in the evaluation of immune diseases could provide a definite diagnosis in elusive cases. A 27-year-old white male patient presented to the clinic with recurrent sinopulmonary and cutaneous infections since childhood. The patient's mother had seronegative polyarthritis, and one of two sisters of the patient had chronic sinopulmonary infections. Serum immunoglobulins, immunoglobulin G (IgG) subclasses, lymphocyte subset markers, mannose-binding lectin, mitogen and antigen stimulation, bacteriophage study, and Streptococcus pneumoniae titers to 23 serotypes were all normal. B-cell phenotyping revealed a decrease in both nonswitched memory B cells (CD19+CD27+IgD+) and switched memory B-cells (CD19+CD27+IgD-). Genetic testing and the improvement of clinical symptoms after IgG replacement led to the final diagnosis.

A 72-Year-Old Man With a Violaceous Rash and Sepsis.

CASE PRESENTATION: A 72-year-old man presented to our ED less than 24 hours following the acute onset of nausea, vomiting, and diarrhea. Within 12 hours of symptom onset, he noted bilateral lower extremity pain and swelling. His pain was associated with a new violaceous irregular rash on the anterior aspect of both feet and legs. There was no history of inciting trauma or recent wounds. In addition, there was no history of consumption of raw or undercooked food (including seafood) or recent change in food source. There was accompanying fever and chills for the same duration and painful swelling of his left thumb. His comorbidities included stage IIIb classical Hodgkin lymphoma diagnosed 4 months prior. His last dose of doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapy was 4 days before presentation. He had previously failed anti-CD30 monoclonal therapy resulting from attributed pancolitis.

Eosinophilic dermatoses.

Eosinophilic dermatoses are a heterogeneous group of diseases, characterized by an eosinophil-rich infiltrate and/or degranulation of eosinophils. Blood eosinophilia may be an associated feature. Typical, albeit not specific histological findings include 'flame figures', which are caused by the accumulation of cationic proteins released by eosinophils and subsequent collagen denaturation. "Classic" eosinophilic dermatoses include eosinophilic cellulitis (Wells syndrome), granuloma faciale, eosinophilic fasciitis (Shulman syndrome) and eosinophilic folliculitis (Ofuji disease). In addition, there is a multitude of skin diseases that present with varying degrees of eosinophilic infiltration. These include atopic dermatitis, bullous pemphigoid, urticaria, allergic contact dermatitis, prurigo nodularis, arthropod bite reaction, parasitic infections, and drug hypersensitivity. Even though these disorders share a common characteristic (tissue eosinophilia), they differ greatly in their clinical presentation.

Perifolliculitis capitis abscedens et suffodiens treatment with tumor necrosis factor inhibitors: A case report and review of published cases.

Perifolliculitis capitis abscedens et suffodiens (PCAS) or dissecting cellulitis is a rare condition presenting deep follicular occlusions, follicular ruptures and follicular infections in the scalp area with unknown etiology, which consequently cause primary neutrophilic cicatricial alopecia by the repeated follicular inflammation. PCAS is categorized as one of the "follicular occlusion tetrad" along with hidradenitis suppurativa, acne conglobata and pilonidal cyst. In the pathogenesis of the follicular occlusion tetrad, the involvement of neutrophils and its activator tumor necrosis factor (TNF) have been discussed. Here, we report a case of PCAS that was successfully treated with adalimumab, a human anti-TNF monoclonal antibody. This is the first Asian case of PCAS that was improved by a TNF inhibitor.

Clostridioides difficile-related toxic megacolon after Cryptococcus neoformans cellulitis: A complex of two rare infections in an immunocompromised host.

A 76-year-old Japanese woman was admitted due to uncontrolled cellulitis of the right lower leg. She had deep vein thrombosis on the right limb. Moreover, she had a long history of rheumatoid arthritis treated with corticosteroids. Skin biopsy and lumbar puncture were performed to diagnose disseminated cryptococcosis. She was administered antifungal agents (liposomal amphotericin B and 5-fluorocytosine). On treatment day 14, debridement was performed, and cryptococcosis was controlled. However, she developed toxic megacolon due to Clostridioides difficile infection (CDI). On day 32, she was transferred to the intensive care unit due to severe acidosis and acute kidney injury secondary to CDI-related toxic megacolon. Vancomycin, metronidazole, and tigecycline were administered for treatment of CDI. After several weeks of intensive care, toxic megacolon was improved, but renal replacement therapy was discontinued according to the patient's will. On day 73, she died of renal failure. We experienced a complex of rare diseases, Cryptococcus neoformans cellulitis and Clostridioides difficile-related toxic megacolon. Both diseases were presumed to be the result of corticosteroid and methotrexate use. Hence, careful monitoring is required when treating immunocompromised hosts to reduce the risk of developing complications.

INDEXES OF CYTOKINE PROFILE OF BLOOD IN PATIENTS WITH COMPLICATED ERYSIPELAS.

The cytokine blood profile in patients with complicated erysipelas was investigated. It was found that in patients with complications of erysipelas (gangrene, phlegmon, abscess, thrombophlebitis of the subcutaneous veins of the shin) levels of pro-inflammatory cytokines IL-1ß, TNF-α, IL-2, IL-6 in serum significantly increase and level of anti-inflammatory cytokine IL-4 increases slightly, as well as was found a significant increase in coefficients reflecting the ratio of pro-inflammatory and anti-inflammatory cytokines, which indicates the prevalence in the blood of examined patients with complications of erysipelas an anti-inflammatory properties. A more significant increase in pro-inflammatory cytokines serum levels is typical for patients with destructive forms of erysipelas - phlegmonous and gangrenous, a slight increase - for patients without purulent-necrotic component of complication (thrombophlebitis of the subcutaneous veins of the shin). In the future we plan to study pharmacological correction of shifts in cytokine blood profile with drugs with immunomodulating properties in patients with complicated erysipelas.

Predilection to Dermato-Lymphangio-Adenitis in Obstructive Lymphedema of Lower Limbs Depending on Genetic Polymorphisms at TNFα-308G>A, CCR2-190G>A, CD14-159C>T, TLR2 2029C>T, TLR4 1063A>G, TLR4 1363C>T, TGFß 74G>C, and TGFß 29T>C.

BACKGROUND: Infection is the most common type of complication observed in lymphedema and is promoted by lymphatic system dysfunction, which causes locoregional immune disorders. Infectious complications are primarily bacterial and most commonly cellulitis (dermato-lymphangio-adenitis, DLA) caused by patients' own skin Staphylococci epidermidis and aureus. The clinical course and outcomes in the immune response to infection have been shown to be associated with genetic polymorphisms. AIM: To investigate polymorphism of TNFα-308G>A, CCR2-190G>A, CD14-159C>T, TLR2 2029C>T, TLR4 1063A>G, TLR4 1363C>T, TGFß 74G>C, and TGFß 29T>C. The second part of study was the correlation of levels of TNFα and TGFß with their genes polymorphism in one hundred patients with lower limb postdermatitis lymphedema. RESULTS: (a) High percentage of TNFα homozygotes, no differences in genotypes of CD14-159C>T, CCR2-190G>A, TGFß 74G>C, TGFß 29T>C, and TLR4 1063A>G, low percentage of TLR2 2029C>T heterozygotes and homozygotes TT, and a high percentage of TLR4 1363C>T homozygotes TT, (b) low serum levels of TGFß and TNFα in 19% and 43% of patients, respectively, however, lack of correlation between low levels of these cytokines and frequency of homozygotes CC and AA, respectively. CONCLUSIONS: The practical implications of finding high frequency of genotype TT of TLR4 1363C>T are indications for testing this gene in patients with obstructive lymphedema of lower limbs and early antibiotic prophylaxis of recurrent attacks of DLA, and during elective surgery of lymphedema. The obtained data are also important as a contribution to mapping of genetic variations in acquired lymphedema of lower limbs.

Cryptococcal cellulitis: A rare entity histologically mimicking a neutrophilic dermatosis.

Cutaneous Cryptococcus infection presents classically with granulomatous and gelatinous reactive patterns. Cases mimicking neutrophilic dermatoses have not been described. Conversely, neutrophilic dermatoses with degrading cells mimicking cryptococcal organisms have been reported. We report a case of cryptococcal cellulitis in an immunocompromised male with a robust neutrophilic infiltrate raising histologic consideration for a neutrophilic dermatosis.

Clinical Course of Eosinophilic Cellulitis.

The patient was a previously healthy 23-year-old woman who made an outpatient visit to our hospital's Department of General Internal Medicine after developing pain and edema of the lower legs a week earlier. The patient was diagnosed with eosinophilic cellulitis (EC) based on an increased eosinophil count of 5,418/mm3 and the results of a skin biopsy of the lower leg that showed eosinophilic infiltration of the dermal tissue. Her condition improved after oral prednisone therapy. EC presents clinically as edema and eosinophilia. Therefore, in many cases, patients make an outpatient visit to the internal medicine department. In the present study, the clinical course of nine patients diagnosed with EC as outpatients at our Department of General Internal Medicine over the past 10 years was examined.

Current Status of Dedicator of Cytokinesis-Associated Immunodeficiency: DOCK8 and DOCK2.

DOCK8 deficiency is an autosomal recessive combined immunodeficiency disease associated with elevated IgE, atopy, recurrent sinopulmonary and cutaneous viral infections, and malignancy. The DOCK8 protein is critical for cytoskeletal organization, and deficiency impairs dendritic cell transmigration, T-cell survival, and NK cell cytotoxicity. Early hematopoietic stem cell transplantation is gaining prominence as a definitive treatment given the potential for severe complications and mortality in this disease. Recently, DOCK2 deficiency has been identified in several patients with early-onset invasive bacterial and viral infections.

Clinical categories of exaggerated skin reactions to mosquito bites and their pathophysiology.

Mosquito bites are skin irritating reactions, which usually resolve spontaneously without intensive medical care. However, in certain situations, mosquito bites may form a more vicious reaction, sometimes accompanying fever and systemic symptoms. In such cases, the presence of rare hematological disorders, abnormalities in eosinophils and/or association with Epstein-Barr virus (EBV) may underlie. Importantly, hypersensitivity to mosquito bites (HMB), which is characterized by necrotic skin reactions to mosquito bites with various systemic symptoms, is often observed in association with EBV infection and natural killer (NK) cell lymphoproliferative disorder. Exaggerated skin reaction to mosquito bites is also seen in Wells' syndrome. While strong Th2-skewing immune dysregulation is apparent in the patients, they also show robust CD4(+) T cell proliferation in response to mosquito salivary gland extracts, indicating close association between Wells' syndrome and mosquito bites. Similar skin reaction to mosquito bites is also noticed in certain types of B cell neoplasm, although the role of B cells in this peculiar reaction to mosquito bites is yet to be elucidated. In this review, we will discuss the current knowledge of exaggerated reaction toward mosquito bites seen in conjunction with these unique hematological disorders, and examine the scientific studies and observations reported in previous literatures to organize our current understanding of the pathogenesis of this distinct disorder.

IgG4-related disease of the paratestis in a patient with Wells syndrome: a case report.

BACKGROUND: We report a case of a 33-year-old man who presented with immunoglobulin (Ig)G4-related disease (IgG4-RD) forming a pseudotumor in the left paratesticular region during oral administration of corticosteroid for Wells syndrome, which involves cellulitis with eosinophilia. CASE PRESENTATION: The patient was introduced to our institution from a private hospital with a 3-month history of asymptomatic left scrotal mass. A 5-cm diameter nodule was palpable in the left scrotum. Tumor lesion in the left paratestis involving the epididymis and spermatic cord was observed on computed tomography and magnetic resonance imaging. Blood testing showed no abnormalities other than a minimal increase in C-reactive protein levels. Urine examination likewise revealed no significant findings. Left radical orchidectomy was performed under a diagnosis of left paratesticular neoplasm suspected as malignant tumor. The tumor was pathologically identified as IgG4-RD of the left paratestis involving the epididymis and spermatic cord. CONCLUSIONS: We present a first description of IgG4-RD in a patient with Wells syndrome and the ninth case of IgG4-RD in a scrotal organ, and discuss this very rare entity with reference to the literature. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_225.

A possible mechanism in the recruitment of eosinophils and Th2 cells through CD163(+) M2 macrophages in the lesional skin of eosinophilic cellulitis.

BACKGROUND: M2 macrophages play a critical role in the recruitment of T helper 2 (Th2) regulatory T cells (Treg). OBJECTIVES: To study the role of M2 macrophages and Treg cells in eosinophilic celulitis. MATERIAL AND METHODS: We employed immunohistochemical staining for CD163( )and CD206 (macrophages) as well as FoxP3 (Treg), in lesional skin of four cases of eosinophilic cellulitis. RESULTS: CD163(+) CD206(+) M2 macrophages, which were previously reported to produce CCL17 to induce Th2 cells and Treg cells, were predominantly infiltrating the subcutaneous tissues and interstitial area of the dermis. M2 macrophages derived from PBMC showed significantly increased expression of CCL11, CCL17, CCL24 and CCL26 mRNA and production of CCL17 and CCL24, when stimulated by IL-4 or IL- 13. In addition, CCL17-producing cells and CCL24-producing cells were prominent in the lesional skin of EC. CONCLUSION: Our study sheds light on one of the possible immunological mechanisms of eosinophilic cellulitis.

New developments in clinical aspects of lymphatic disease.

The lymphatic system is fundamentally important to cardiovascular disease, infection and immunity, cancer, and probably obesity--the four major challenges in healthcare in the 21st century. This Review will consider the manner in which new knowledge of lymphatic genes and molecular mechanisms has demonstrated that lymphatic dysfunction should no longer be considered a passive bystander in disease but rather an active player in many pathological processes and, therefore, a genuine target for future therapeutic developments. The specific roles of the lymphatic system in edema, genetic aspects of primary lymphedema, infection (cellulitis/erysipelas), Crohn's disease, obesity, cancer, and cancer-related lymphedema are highlighted.

HMGB1 in severe soft tissue infections caused by Streptococcus pyogenes.

Extracellular High Mobility Group Box 1 (HMGB1) has been associated with acute and chronic inflammatory conditions. However, little is known about HMGB1 in necrotizing bacterial infections. We hypothesized that the local HMGB1 response is excessive in severe soft tissue infections (STIs), which are characterized by necrosis and hyperinflammation. To explore this, tissue biopsies were collected from patients with varying severity of Streptococcus pyogenes skin and STIs, including erysipelas, cellulitis, and necrotizing fasciitis. Tissue sections were immunostained for HMGB1, S. pyogenes, and inflammatory cell infiltrates and results quantified by acquired computerized image analysis (ACIA). HMGB1 expression increased in parallel to disease severity and was significantly higher in necrotizing fasciitis than in erysipelas (p = 0.0023). Confocal microscopy of sections co-stained for HMGB1 and cell markers revealed both extracellular and cytoplasmic HMGB1, the latter of which was found predominantly in macrophages. To further verify macrophages as main source of activation triggered HMGB1 release, human macrophages were infected with clinical S. pyogenes isolates. The results demonstrated infection triggered release of HMGB1. Dual staining's visualized HMGB1 in areas close to, but not overlapping, with neutrophils, indicating a potential chemotactic role. In vitro transmigration experiments showed a chemotactic effect of HMGB1 on neutrophils. The data furthermore provided in vivo support that HGMB1 may form immunostimulatory complexes with IL-1ß. Taken together, the findings provide the first in vivo evidence that HMGB1 is abundant at the local site of severe bacterial STIs and its levels correlated to severity of infections; hence, indicating its potential value as a biomarker for tissue pathology.