Serum IgG Levels Research Articles

Safety and Efficacy of Hizentra® Following Pediatric Hematopoietic Cell Transplant for Treatment of Primary Immunodeficiencies

Primary immunodeficiency disease (PIDD) comprises a group of disorders of immune function. Some of the most severe PIDD can be treated with hematopoietic cell transplant (HCT). Hizentra® is a 20% liquid IgG product approved for subcutaneous administration in adults and children greater than 2 years of age with PIDD-associated antibody deficiency. Limited information is available on the use of Hizentra® in children following HCT for PIDD. A multicenter retrospective chart review demonstrated 37 infants and children (median age 70.1 [range 12.0 to 176.4] months) with PIDD treated by HCT who received Hizentra® infusions over a median duration of 31 (range 4–96) months post-transplant. The most common indication for HCT was IL2RG SCID (n = 16). Thirty-two patients switched from IVIG to SCIG administration, due to one or more of the following reasons: patient/caregiver (n = 17) or physician (n = 12) preference, discontinuation of central venous catheter (n = 16), desire for home infusion (n = 12), improved IgG serum levels following lower levels on IVIG (n = 10), and loss of venous access (n = 8). Serious bacterial infections occurred at a rate of 0.041 per patient-year while on therapy. Weight percentile increased by a mean of 16% during the observation period, with females demonstrating the largest gains. Mild local reactions were observed in 24%; 76% had no local reactions. One serious adverse event (death from sepsis) was reported. Hizentra® was discontinued in 15 (41%) patients, most commonly due to recovery of B cell function (n = 11). These data demonstrate that Hizentra® is a safe and effective option in children who have received HCT for PIDD.

PM2.5 exposure regulates Th1/Th2/Th17 cytokine production through NF-κB signaling in combined allergic rhinitis and asthma syndrome

Particulate matter (PM) is a major component of air pollution from emissions from anthropogenic and natural sources and is a serious problem worldwide due to its adverse effects on human health. Increased particulate air pollution increases respiratory disease-related mortality and morbidity. However, the impact of PM with an aerodynamic diameter of≤2.5μm (PM2.5) on combined allergic rhinitis and asthma syndrome (CARAS) remains to be elucidated. Accordingly, in the present study, we investigated the effect of PM2.5 in an ovalbumin (OVA)-induced CARAS mouse model with a focus on NF-κB signaling. We established an OVA-induced mouse model of CARAS to determine the effects of exposure to PM2.5. BALB/c mice were randomly divided into four groups: (1) naive, (2) PM2.5, (3) CARAS, and (4) CARAS/PM2.5. Mice were systemically sensitized with OVA and challenged with inhalation of ultrasonically nebulized 5% OVA three times by intranasal instillation of OVA in each nostril for 7 consecutive days. Mice in the PM2.5 and CARAS/PM2.5 groups were then exposed to PM2.5 by intranasal instillation of PM2.5 for several days. We then examined the impacts of PM2.5 exposure on histopathology and NF-κB signaling in our OVA-induced CARAS mouse model. PM2.5 increased infiltration of eosinophils in bronchoalveolar lavage fluid (BALF) samples and inflammatory cells in lung tissue. It also increased production of GATA3, RORγ, IL-4, IL-5, IL-13, and IL-17 in nasal lavage fluid (NALF) and BALF samples in the CARAS mouse model, but secretion of IL-12 and IFN-γ was suppressed. Exposure to PM2.5 increased OVA-specific IgE and IgG1 levels in serum, inflammatory cell infiltration in the airways, and fibrosis in lung tissue. It also activated the NF-κB signaling pathway, increasing Th2/Th17 cytokine levels while decreasing Th1 cytokine expression, thereby inducing an inflammatory response and promoting inflammatory cell infiltration in nasal and lung tissue. Our results demonstrate that PM2.5 can aggravate OVA-induced CARAS.

Anti- SARS-CoV-2 IgG and IgM Levels in Iraqi General Population.

Acquired immunity plays an important role in the prevention of viral infections. SARS-CoV-2 is an infection that leads to a pandemic. The development of specific anti-SARSCoV- 2 antibodies may play a vital role in disease prevention and control. Thus IgG antibody screening in the general population provides information on the immunological status of the community. To clarify the SARS-CoV-2 immune status in the general population. A cross-sectional study was conducted in Kirkuk province during the period from 15 May 2022 to 11 September 2022. The samples were collected from voluntary subjects and informed consent was taken from each participant before their enrolment in the study. SARS-CoV-2 IgG, SARSCoV- 2 IgM, 25-OH Vitamin D, Vitamin B12, and Folate were determined using the Electrochemiluminescence Immunoassay (eCLIA) technique with the instrument NIPIGON-Robot R1Automated ECL Analyzer (Canada). The overall IgG mean concentration was 37.75 ± 23.18 COI, with a median of 39.99 COI and a range of 0.25 - 87.23 COI. Additionally, 93% of tested samples were with concentrations of more than 1 COI. The highest frequency (18.2%) was for the IgG concentration of 51 to 60 COI, while the lowest frequency (1.3%) was for the concentration of 81 - 90 COI. The IgG was significantly higher (P = 0.046) in males (39.87 ± 24.04 COI) than that in females (35.12 ± 21.89 COI). The IgM overall concentration was 0.569 ± 0.456 COI, with a median of 0.489 COI and a range of 0.17 - 6.40 COI. The mean serum level of folic acid concentration was 9.03 ± 5.72 ng/ml, with a median of 7.476 ng/ml and a range of 0.60 - 20.00 ng/ml. The mean serum concentration of vitamin B12 was 462.65 ± 349.18 pg/ml, with a median of 353 pg/ml and a range of 13.05 - 2000 pg/ml. The mean serum concentration of vitamin D was 18.29 ± 18.42 ng/ml with a median of 12.44 ng/ml and a range of 3 - 100 ng/ml. IgG and IgM serum levels did not show a significant correlation with serum levels of folic acid, vitamin D, and vitamin B12. However, there was a significant correlation between folic acid and vitamin D (r = 0.197; P = 0.012); vitamin B12 and vitamin D (r = 0.253, P = 0.001). While there was a non-significant correlation between folic acid and vitamin D serum levels (r = 0.129, P = 0.10). General population IgG antibody concentration reflects a high rate of herd immunity. Folic acid was with a mean value of about half of the upper normal limit and only 17.7% were with low values. Vitamin B12, only 6.3% of the population had values lower than normal. However, the range of vitamin B12 was wide. While vitamin D values were lower than the normal limit at 82.6%. However, a large scale well designed was warranted to evaluate COVID-19 national immune response.

Subcutaneous immunoglobulin therapy for adult patients with primary immunodeficiency disease: Qatar experience.

Subcutaneous immunoglobulin (SCIG) and intravenous immunoglobulin (IVIG) are used for the treatment of primary immunodeficiency (PIDD). SCIG is as effective as IVIG in preventing infections.1 However, SCIG has advantages over IVIG as it causes fewer systemic reactions and can be infused at home by the patient leading to improved quality of life.2 Methods: We retrospectively analyzed adult patients with PIDD who received SCIG in an Adult Allergy Clinic in Qatar. Patients who received IVIG before SCIG and are naïve to IgG replacement were included. We compared Serum IgG levels, the number of antibiotic courses received, and the number of hospital admissions one year before and one year after starting SCIG. SF36 score was used to compare health-related quality of life scores before SCIG and after one year of SCIG. Twenty patients were included in the study, of which 17 were on prior IVIG replacement, and three were naive to replacement. SCIG replacement resulted in the maintenance of serum IgG levels in those who received IVIG prior. SCIG resulted in a statistically significant reduction in the number of antibiotics prescribed and hospitalization in the naïve subgroup but no substantial change in the prior IVIG group. 6/20 patients developed side effects like injection site pain, swelling, and headache. No patients developed significant systemic side effects. 10/20 patients discontinued the SCIG therapy, four patients due to side effects, and others due to noncompliance and financial reasons. SF36 Score was compared for the five patients in IVIG prior group and showed no significant improvement in individual score but improvement in the overall score (p=0.003) Conclusions: In our experience, SCIG therapy effectively prevents recurrent infection in PIDD patients, and patients did not experience any significant systemic side effects. There is a substantial improvement in the quality of life. However, compliance continues to be a problem.

Long-term mepolizumab treatment reduces relapse rates in super-responders with eosinophilic granulomatosis with polyangiitis

BackgroundThe mainstay of treatment for eosinophilic granulomatosis with polyangiitis (EGPA) is systemic corticosteroid therapy; some patients also receive intravenous immunoglobulins, other immunosuppressive agents, and biologics. Mepolizumab, an anti-interleukin-5 monoclonal antibody, induces remission and decreases the daily corticosteroid dose; however, the clinical efficacy of mepolizumab in EGPA and the prognosis with long-term treatment with this drug are unknown.MethodsSeventy-one EGPA patients were treated at Hiratsuka City Hospital, Japan, between April 2018 and March 2022. We administered mepolizumab for a mean of 2.8 ± 1.7 years to 43 patients in whom remission could not be induced by conventional treatment. After excluding 18 patients who had received mepolizumab for less than 3 years, we classified 15 patients into a “super-responder group” (the daily dose of corticosteroids or other immunosuppressant could be decreased, or the interval between IVIG treatments could be prolonged) and 10 patients into a “responder group” (neither of these changes was achievable). Eosinophil numbers, serum IgG levels, daily doses of corticosteroids and other immunosuppressants, Birmingham Vasculitis Activity Score (BVAS), and relapse frequency before and after mepolizumab initiation were determined.ResultsBlood eosinophil count at diagnosis and the lowest serum IgG level before mepolizumab treatment were significantly higher in super-responders than in responders (p < 0.05). In super-responders, the prednisolone dose at last visit on mepolizumab treatment was lower than that before treatment (p < 0.01) and lower than that at last visit in the responders (p < 0.01). In both groups, peripheral blood eosinophil numbers and BVAS were lower after starting mepolizumab than before (p < 0.01). BVAS before mepolizumab (p < 0.05) and at last visit (p < 0.01) were lower in super-responders than in responders. Relapse rates every year after the start of mepolizumab were lower in super-responders than in responder groups (p < 0.01). In super-responders, relapse rates were lower during the 3 years following mepolizumab initiation (p < 0.01) and at last visit (p < 0.01) were significantly lower than after 1 year of treatment.ConclusionMepolizumab treatment of super-responders sustainably reduced the relapse rate.

Mucosal immunization with Lactiplantibacillus plantarum-displaying recombinant SARS-CoV-2 epitopes on the surface induces humoral and mucosal immune responses in mice

BackgroundThe use of probiotic lactic acid bacteria as a mucosal vaccine vector is considered a promising alternative compared to the use of other microorganisms because of its “Generally Regarded as Safe” status, its potential adjuvant properties, and its tolerogenicity to the host. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease (COVID-19), is highly transmissible and pathogenic. This study aimed to determine the potential of Lactiplantibacillus plantarum expressing SARS-CoV-2 epitopes as a mucosal vaccine against SARS-CoV-2.ResultsIn this study, the possible antigenic determinants of the spike (S1–1, S1–2, S1–3, and S1–4), membrane (ME1 and ME2), and envelope (E) proteins of SARS-CoV-2 were predicted, and recombinant L. plantarum strains surface-displaying these epitopes were constructed. Subsequently, the immune responses induced by these recombinant strains were compared in vitro and in vivo. Most surface-displayed epitopes induced pro-inflammatory cytokines [tumor necrosis factor alpha (TNF-α and interleukin (IL)-6] and anti-inflammatory cytokines (IL-10) in lipopolysaccharide-induced RAW 264.7, with the highest anti-inflammatory to pro-inflammatory cytokine ratio in the S1–1 and S1–2 groups, followed by that in the S1–3 group. When orally administered of recombinant L. plantarum expressing SARS-CoV-2 epitopes in mice, all epitopes most increased the expression of IL-4, along with induced levels of TNF-α, interferon-gamma, and IL-10, specifically in spike protein groups. Thus, the surface expression of epitopes from the spike S1 protein in L. plantarum showed potential immunoregulatory effects, suggesting its ability to potentially circumvent hyperinflammatory states relevant to monocyte/macrophage cell activation. At 35 days post immunization (dpi), serum IgG levels showed a marked increase in the S1–1, S1–2, and S1–3 groups. Fecal IgA levels increased significantly from 21 dpi in all the antigen groups, but the boosting effect after 35 dpi was explicitly observed in the S1–1, S1–2, and S1–3 groups. Thus, the oral administration of SARS-CoV-2 antigens into mice induced significant humoral and mucosal immune responses.ConclusionThis study suggests that L. plantarum is a potential vector that can effectively deliver SARS-CoV-2 epitopes to intestinal mucosal sites and could serve as a novel approach for SARS-CoV-2 mucosal vaccine development.

The effect of combined dietary supplementation of herbal additives on carcass traits, meat quality, immunity and cecal microbiota composition in Hungarian white geese.

The present study was performed to investigate the effects of dietary supplementation with herbal additives on meat quality, slaughter performance and the cecal microbial community in Hungarian white geese. A total of 60 newborn geese were assigned equally into the control group (CON) and the herbal complex supplemented group (HS). The dietary supplementations consisted of Compound Herbal Additive A (CHAA) including Pulsatilla, Gentian and Rhizoma coptidis, and Compound Herbal Additive B (CHAB) containing Codonopsis pilosula, Atractylodes, Poria cocos and Licorice. The geese in the HS group received a basal diet supplemented with 0.2% CHAA from day 0 to day 42 at the postnatal stage. Then from day 43 to day 70, the geese in HS group were provide a basal diet with 0.15% CHAB. The geese in the CON group were only provided with the basal diet. The results showed that the slaughter rate (SR), half chamber rates (HCR), eviscerated rate (ER) and breast muscle rate (BMR) in the HS group tended to increase slightly compared with the CON group (ns). In addition, the shear force, filtration rate and pH value of breast muscle and thigh muscle in the HS group were slightly enhanced compared to the CON group (ns). Significant increased levels in carbohydrate content, fat content and energy (P<0.01) and significant decreased levels in cholesterol content (P<0.01) were observed in the muscle of the HS group. The total amino acid (Glu, Lys, Thr and Asp) content in the muscle increased in HS group than in the CON group (P<0.01). Dietary herb supplementations significantly increased the levels of IgG in serum (P<0.05) on day 43 and higher levels of IgM, IgA and IgG (P<0.01) were also observed in the HS group on day 70. Furthermore, 16S rRNA sequencing results indicated that herbal additives increased the growth of beneficial bacteria and inhibited the proliferation of harmful bacteria in the geese caecum. Altogether, these results offer crucial insights into the potential benefits of incorporating CHAA and CHAB into the diets of Hungarian white goose. The findings indicate that such supplementations could significantly improve meat quality, regulate the immune system and shape the intestinal microbiota composition.

Isolated variant of IgG4-sclerosing cholangitis masquerading as hilar cholangiocarcinoma — an enigmatic entity

BackgroundIgG4-mediated sclerosing cholangitis (IgG4-SC) is an autoimmune disease that generally occurs in association with type 1 autoimmune pancreatitis (AIP). However, an isolated variant of IgG4-SC is a rare disease that can occur without concurrent AIP and closely mimics extrahepatic cholangiocarcinoma both clinically and radiologically.Case presentationHere, we report a case of an isolated variant of IgG4-SC, which was pre-operatively diagnosed as hilar cholangiocarcinoma. Pathological and immunohistochemical examination revealed features suggestive of IgG4-SC, which was confirmed by elevated serum IgG4 levels measured postoperatively.ConclusionTherefore, IgG4-SC should be carefully ruled out in patients presenting with isolated bile duct obstruction, before performing morbid surgical procedures.

A meta-analysis of the effects of colostrum heat treatment on colostral viscosity, immunoglobulin G concentration, and the transfer of passive immunity in newborn dairy calves

Newborn ruminants depend on colostrum intake immediately after birth to obtain immunoglobulins for effective transfer of passive immunity (TPI). As colostrum may also be a vehicle of infectious agents, heat treatment of raw colostrum is a practice aimed at eliminating or reducing its pathogen load. Despite the usefulness of heat treatment in preventing the transmission of infectious colostrum-borne diseases, heat treatment of colostrum may have some side effects. A systematic review and meta-analysis were conducted to summarize the effects of colostrum heat treatment on colostral viscosity and IgG concentration, and serum IgG concentration as a proxy for TPI in newborn calves fed raw versus heat-treated colostrum. Moderators were studied to identify sources of heterogeneity. Literature databases were searched for peer-reviewed articles published between 1946 and 2022. A Master of Science thesis was also included. Five, 21, and 19 original publications were quantitatively evaluated in 3 separate meta-analyses, based on predefined selection criteria. Two-level and 3-level random-effects meta-analysis revealed a significant overall effect of heat treatment on colostral viscosity and IgG concentration, and serum IgG concentration in newborns. Heat-treated colostrum had significantly higher viscosity (21.0 cP, 95% CI: 3.8 to 38.2) and lower IgG concentration (-7.4 g/L, 95% CI: -11.1 to -3.7) compared with raw colostrum. Overall, newborn calves fed heat-treated colostrum had higher serum IgG concentrations (2.8 g/L, 95% CI: 1.4 to 4.0) 24-48 h after birth than those fed with raw colostrum. Particularly, this positive effect on the serum IgG concentrations was seen when colostrum was heat-treated at ≤60°C (2.9 g/L, 95% CI: 0.9 to 4.2) and when the standard low-temperature low-time (LTLT) method was used for heat treatment (2.6 g/L, 95% CI: 0.1 to 5.1). Colostrum treated at >60-63.5°C tended to have higher viscosity (275.6 cP, 95% CI: -37.9 to 589.3) and had lower IgG concentration (-21.7 g/L, 95% CI: -27.3 to -16.1). Calves fed colostrum treated at this temperature range had significantly lower serum IgG (-4.2 g/L, 95% CI: -7.9 to -0.4) compared with those fed raw colostrum. Heat treatment of colostrum at 72-76°C was not associated with a significant increase in colostral viscosity (6.3 cP, 95% CI: -324.3 to 336.9) nor a reduction in IgG colostral concentration (-13.1 g/L, 95% CI: -26.5 to 0.2), but calves fed colostrum treated at this temperature range had a significant reduction in serum IgG (-11.3 g/L, 95% CI: -17.1 to -5.4). Feeding newborn calves with colostrum heat-treated at ≤60°C by the standard LTLT method, particularly within 2 h after birth, resulted in increased serum IgG concentration at 24-48 h of age. Importantly, delaying feeding of heat-treated colostrum to newborns beyond 2 h of age resulted in no significant difference in IgG serum levels compared with feeding raw colostrum, highlighting the importance of early administration of heat-treated colostrum to favor TPI. On-farm colostrum heat treating should achieve an equilibrium between pathogen elimination and the preservation of colostral immunoglobulins while minimizing undesired increases in viscosity. The beneficial effects of colostrum heat treatment on TPI can be negligible if colostrum feeding is not performed within 2 h after birth.

Quality of Life Evaluation in Saudi Arabian Pediatric Patients with Primary Immunodeficiency Diseases Receiving 20% Subcutaneous IgG Infusions at Home.

Subcutaneous immunoglobulin (SCIG) home infusion is widely used as an alternative to intravenous immunoglobulin (IVIG). This study aimed to determine the quality of life (QoL) of patients with primary immunodeficiency (PID) after switching to home-based SCIG. In this prospective open-label single-center study, QoL was determined using the validated Arabic version of the Child Health Questionnaire at baseline and 3 and 6 months after switching from IVIG to SCIG. Twenty-four patients were recruited from July 2018 to August 2021, including 14 females and 10 males. The median age of the patients was 5 years (range, 0-14 years). The patients' diagnoses included severe combined immunodeficiency, combined immunodeficiency, agammaglobulinemia, Omenn syndrome, immunodysregulation, hyper-IgE syndrome, common variable immunodeficiency, and bare lymphocyte syndrome. The median duration on IVIG before inclusion was 40 months (range, 5-125 months). The QoL score showed a significant improvement in the patients' global health at 3 and 6 months compared with those at baseline and a significant improvement in the patients' general health at 3 and 6 months compared with that at baseline. The mean baseline serum IgG trough level was 8.8 ± 2.1 g/L. The mean serum IgG level was significantly higher on SCIG at both 3 and 6 months (11.7 ± 2.3 and 11.7 ± 2.5 g/L, respectively). This is the first study involving an Arab population to show improvement in the QoL of patients with PID after switching from hospital-based IVIG to home-based 20% SCIG.

Cost-minimization analysis of HYQVIA® in the treatment of primary immunodeficiency disease (PID) and secondary immunodeficiency disease (SID) in Italy

Background: Primary (PID) or secondary (SID) immunodeficiencies are diseases caused by quantitative and/or functional alterations of the different mechanisms involved in the innate and adaptive immune response. This economic evaluation was conducted to compare the cost of treatment of HYQVIA® (hyaluronidase-facilitated subcutaneous infusion of immunoglobulin, fSCIG) compared to intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin (SCIG), currently reimbursed in Italy, in the treatment of PIDs or SIDs. Methods: A cost-minimisation analysis was carried out, considering the hospital’s perspective. The direct medical costs (cost of immunoglobulins and cost of administration) were assessed. The analysis was conducted considering one year (52 weeks) time horizon. The reference population included adult patients with PID with impaired antibody production or adult patients with SID with severe or recurrent infections, ineffective antimicrobial treatment and documented specific antibody defect (PSAF) or serum IgG level &lt; 4 g/L. Results: In the maintenance treatment of PID, HYQVIA® (€ 20,020.00) was the therapeutic alternative with the lowest mean annual cost compared to HIZENTRA® (€ 22,165.19) and VENITAL® (€ 24,967.68). Moreover, in the maintenance treatment of SIDs, HYQVIA® (€ 17,160.00) was the cost-saving therapeutic alternative compared to VENITAL® (€ 22,107.68). A sensitivity analysis confirmed the base case results. Conclusion: Due to lower costs of administration and different scheme of administration, HYQVIA® was a cost-saving alternative to SCIG e IVIG in the treatment of PID and to IVIG in the treatment of SID

A Case of Demyelinating Neuropathy with Markedly Elevated Serum IgG4 Levels and Anti-Contactin 1 IgG4 Antibody.

We herein report a 77-year-old man with a 4-month history of progressive gait and sensory disturbances of the extremities. A nerve conduction study indicated demyelinating polyneuropathy. Serum IgG4 levels and anti-contactin 1 IgG4 antibodies were markedly increased. The sural nerve biopsy specimen showed IgG4-positive plasma cell infiltration in the epineurium. Treatment with steroids resulted in an amelioration of functional status, improvement of nerve conduction parameters, decreased serum IgG4 levels, and negative conversion of anti-contactin1 antibody. Further studies are needed to clarify the significance of IgG4-positive plasma cell infiltration in anti-contactin 1 antibody-positive neuropathies.

IgG4 related disease: a novel association with hypertrophic osteoarthropathy

IgG4 related disease (IgG4-RD) is a recently recognized disease that has several associated clinical phenotypes including autoimmune pancreatitis, sclerosing cholangitis, major salivary gland enlargement (Mikulicz disease), orbital pseudotumor, retroperitoneal fibrosis, and inflammatory vascular disease manifesting as aortitis or coronary artery calcification. Histopathology of affected organs shows lymphoplasmacytic infiltrations with a predominance of IgG4-positive plasma cells in the affected tissue and an increased number of eosinophils. Serum IgG4 levels are elevated in two-thirds of patients, and IgE is also often elevated. We report here the first known associated case of presumed IgG4-RD with hypertrophic osteoarthropathy. Hypertrophic osteoarthropathy (HOA) is frequently a paraneoplastic disease of bone, but HOA can be associated with chronic infection, chronic pulmonary disease, cardiac shunts, and cirrhosis. HOA is a clinical diagnosis consisting of arthralgia, digital clubbing, and periostosis of tubular bones seen on imaging with or without synovial effusion. Our 35 yo male LatinX patient presented with typical clinical symptoms of HOA that were confirmed on imaging. During the negative work up for malignancy, disproportionate-for-age coronary artery calcification was identified, which prompted an evaluation for IgG4-RD. The patient also had lung disease (peribronchial thickening), atopic dermatitis, subtle clubbing, elevated IgE, elevated IgG4 (9× normal), and eosinophilia. The patient's symptoms and inflammatory markers improved on prednisone and methotrexate, but a decision to treat with rituximab was made after having to discontinue methotrexate for transaminitis. Rituximab has been used in patients with IgG4-RD with some success, and our patient continues to improve in his skin, respiratory, and bone symptoms with reduction in IgG4, inflammatory markers, and bone turnover markers (alkaline phosphatase).

Abstract #1411935: A Radiographic Diagnosis: IgG4-Related Hypophysitis Presenting with Hypopituitarism and Central Diabetes Insipidus

Hypophysitis is defined as inflammation of the pituitary gland. IgG4-related hypophysitis is a rare form and isolated IgG4-related hypophysitis is even more rare. Here, we discuss an interesting patient who presented with symptoms of diabetes insipidus and was found to have panhypopituitarism with suspicious MRI findings of a suprasellar mass and a thickened pituitary stalk, suggestive of IgG4-related hypophysitis. A 69-year-old male with past medical history of lung adenocarcinoma status-post right pneumonectomy, chronic obstructive pulmonary disease, orthostatic hypotension, and poor oral intake due to esophageal compression presented with acute encephalopathy and sepsis secondary to pneumonia. CT head scan done for encephalopathy showed a 1.2 cm suprasellar mass. On consultation, the patient was found to be hypernatremic. Upon further questioning, the patient reported experiencing polydipsia, nocturia, chronic cold intolerance, fatigue, and impotence for several weeks to months. He denied any vision changes, breast tenderness, or galactorrhea. Laboratory testing revealed a sodium level of 157 mmol/L (n.135-145 mmol/L) with plasma osmolality elevated at 332 mOsm/kg (n.275-295 mosm/kg). Urine sodium was low at < 20 mmol/L. Desmopressin (DDAVP) 0.1mg nightly was started given concern for diabetes insipidus. Peak cortisol after performed Cosyntropin stimulation test resulted at 13.5mcg/dL with an ACTH 6 pg/mL (n.6-50 pg/mL). TSH was < 0.01 mU/L, free T4 1.79 ng/dL, and free T3 4.9 nmol/L. The elevated free T3 was felt to be from heparin displacement. Total testosterone was 84 ng/dL with suppressed FSH and LH. Elevated prolactin of 39 ng/mL was thought to be from stalk-effect. MRI of the pituitary gland revealed a 1.3cm enhancing suprasellar mass in the region of the optic chiasm and a smaller 9mm intra-sellar mass, with a thickened pituitary stalk. Given these radiologic findings and the patient's age and gender, the possibility of IgG4 hypophysitis was suspected. CT chest, abdomen, and pelvis were unremarkable. In addition to the DDAVP, he was started on high-dose hydrocortisone, thyroxine replacement, and testosterone replacement. Serum IgG4 level was 23.6 mg/dL (n. 4-86 mg/dL). A six week repeat pituitary MRI is pending; however, the patient is clinically improving and doing well. Specific radiologic findings, such as thickened pituitary stalk and pituitary enlargement with suprasellar mass, led us to strongly consider IgG4-related hypophysitis in our differential for this patient. Clinical presentation of panhypopituitarism, along with patient age and gender, also supported the diagnosis of IgG4-related hypophysitis. Although this patient does not meet all Leporati diagnostic criteria for IgG4-related hypophysitis, the high degree of suspicion led to prompt treatment with high dose steroids. High dose steroids have been shown to revert symptoms and prevent irreversible fibrosis. This case highlights the need for radiologists and endocrinologists to work together in the early recognition of the diagnosis and treatment of IgG4-related hypophysitis.

Adjuvanted quaternized chitosan composite aluminum nanoparticles-based vaccine formulation promotes immune responses in chickens.

Aluminum adjuvant is a typical adjuvant that can promote humoral immune response, but it lacks the ability to effectively induce cellular immune response. The water-soluble N-2-Hydroxypropyl trimethyl ammonium chloride chitosan nanoparticles (N-2-HACC NPs) can enhance humoral and cellular immune responses of vaccines. To enable aluminum adjuvant to induce cellular immunity, the composite nano adjuvant N-2-HACC-Al NPs were synthesized by the N-2-HACC and aluminum sulfate (Al2(SO4)3). The particle size and zeta potential of the N-2-HACC-Al NPs were 300.70±24.90nm and 32.28±0.52mV, respectively. The N-2-HACC-Al NPs have good thermal stability and biodegradability and lower cytotoxicity. In addition, to investigate the immunogenicity of the composite nano adjuvant, the combined inactivated vaccine against Newcastle disease (ND) and H9N2 avian influenza (AI) was prepared with the N-2-HACC-Al NPs as a vaccine adjuvant. The immune effect of the vaccine (N-2-HACC-Al/NDV-AIV) was evaluated by chicken in vivo immunization. The vaccine induced higher levels of serum IgG, IL-4, and IFN-γ than those of the commercial combined inactivated vaccine against ND and H9N2 AI. The levels of IFN-γ were more than twice those of the commercial vaccine at 7days post the immunization. The N-2-HACC-Al NPs could be used as an efficient nano adjuvant to enhance the effectiveness of vaccine and have immense application potential.

Utility of Class-Switched B-Cells in Diagnosing Common Variable Immunodeficiency

Measuring the relative quantity of peripheral blood class-switched CD27 +IgD- B-cells (CSBs) has previously been proposed as useful in the subclassification of CVID diagnoses. Perhaps incautiously, this practice has been adopted widely among clinical immunologists and has even been included as supportive diagnostic criteria for CVID. Existing research has also shown lower numbers of CSBs in CVID than in IgG deficiency; however, the diagnostic utility of CSBs was not evaluated and additional cohorts have not been studied. This study aimed to determine if low peripheral blood CSB numbers accurately differentiate CVID from other forms of humoral immunodeficiency.We performed a retrospective chart review of all patients at Children's Hospital of Colorado with 8-marker comprehensive B-cell panel results from the time of the panel's implementation in 2020. Inclusion criteria included: age ≥5 years and absolute CD19 B-cell measurement within 60 days of B-cell panel results. Subjects were assigned a diagnosis of CVID based on ICON criteria and by expert opinion when the workup was incomplete, such as in cases with borderline serum immunoglobulin levels or where polysaccharide antibody responses were not available. Patients that did not meet CVID criteria but were considered to have a humoral immunodeficiency based on immunoglobulin levels were separately categorized. Of the patients included (n = 64), 3 met all ICON criteria, 10 had a diagnosis by expert opinion, and 24 had a non-CVID immunological defect. Multinomial logistic regression accounting for age and sex demonstrated no significant association between absolute or percent CSB levels and whether the patient had a known or suspected CVID diagnosis; however, binary logistic regression indicated the odds of having any humoral immunodeficiency, including CVID, increased with decreasing CSB percentage (p = 0.026). Additionally, a linear regression between percent CSBs and in vivo serum IgG levels found a statistically significant relationship (p = 0.046), which has not been demonstrated previously. This observation is consistent with peripheral blood CD27+IgD- CSBs reflecting a person's general ability to class-switch to IgG production. Ultimately these findings suggest that CSBs may have utility as a general indicator of humoral immune disruption but are not an adequately specific metric in forming a CVID diagnosis.

Chronic mucocutaneous candidiasis and immune dysregulation due to STAT1 Gain of Function

BackgroundGermline gain-of-function (GOF) mutations in the Signal Transducer and Activator of Transcription 1 (STAT1) gene have been associated with autosomal dominant chronic mucocutaneous candidiasis (CMCC), autoimmune and inflammatory manifestations. Although most patients with STAT1 GOF have CMCC, the disease has a broad phenotypic spectrum.Case Description: A 13-year-old male born to non-consanguineous parents with a past medical history of chronic mucocutaneous candidiasis, autoimmune hypothyroidism, and recurrent viral respiratory tract infections presented for immune evaluation. His medical history was also significant for chronic fatigue refractory to thyroid replacement therapy, chronic paronychia, oral thrush, pneumonia requiring hospitalization, recurrent chalazia status post excision, and prolonged tonsillitis. Laboratory results showed high total serum IgG levels with elevated IgG1 and IgG3 subclasses, elevated B cell counts with atypical lymphocytes, and chronic EBV-viremia. He had no clinical or laboratory evidence of active lymphoproliferative disease. He had normal lymphocyte proliferation to mitogens with impaired response to antigens. He had an adequate humoral response to protein and polysaccharide antigens. Targeted genetic testing for inborn errors of immunity showed a heterozygous variant in the STAT1 gene (c.1169T>C, p.MET390Thr), which had been previously reported in patients with STAT1 GOF. The patient was treated with oral fluconazole with interval improvement in CMCC and subsequently maintained on prophylactic fluconazole and TMP/SMX. He had an unremarkable family history, which suggests a de novo mutation in STAT1. ConclusionThe presence of CMCC and autoimmunity should raise concern for STAT1 GOF. Genetic testing for inborn errors of immunity can be a valuable tool in the diagnosis of patients with CMCC and can help guide therapy. Unfortunately, hematopoietic stem cell transplant has been associated with a high mortality rate in patients with STAT1 GOF. JAK inhibition therapy was recommended for this patient. However, there is currently no consensus regarding JAK inhibitor selection, dosing, treatment duration or biomarkers in STAT1 GOF.

T-cell chronic active EBV diagnosed in a 65-year-old male presenting as idiopathic hypereosinophilic syndrome

A 65-year-old male from Nigeria, admitted with dehydration and painful oral ulcers, is seen by allergy/immunology for hypereosinophilia.The patient had idiopathic eosinophilia (mean 5,000 cells/uL) ongoing for nine years. There were no evident drug or infectious causes. The eosinophilia peaked at 28,000 cells/µL, accompanied by parotid swelling, pustular skin rash, and elevated serum-IgG4 level (400 mg/dL). Rheumatology evaluated for IgG4-related disease and hypereosinophilic syndrome. This work-up demonstrated elevated IgE (39,000 IU/mL) and tryptase (40 ng/mL) levels. Bone marrow biopsy showed a hypercellular marrow with erythroid hyperplasia and eosinophilia. Submandibular gland, skin, and excisional lymph node biopsies demonstrated IgGsecreting plasma cells, lymphocytic/eosinophilic infiltrates, and lymphoid hyperplasia, respectively. All biopsies stained negative for IgG4. Treatment for idiopathic hypereosinophilia was initiated with corticosteroids, rituximab, and mycophenolate mofetil (MMF). Symptomatic improvement was attained on MMF (1000 mg twice daily) with the addition of mepolizumab (300 mg every 4 weeks).He unfortunately progressed to high fevers with elevated ferritin (7,286 ug/L) and soluble IL-2Ra (31,276.7 pg/mL) levels. He did not meet full criteria for hemophagocytic lymphohistiocytosis and improved after corticosteroids. EBV PCR from blood was >220,000 IU/mL.Dedicated immune work-up showed a non-specific population of lymphocyte-like cells without clear lineage markers (CD2dim/- surface CD3-CD4-CD8-CD7-CD56-CD49d-CD294dim) on peripheral blood flow cytometry, with otherwise normal T, B, and NK cell enumeration. There was reduced cytotoxic killing function of CD8+ T cells and NK cells by chromium-51 release assay. Sorted peripheral blood mononuclear cells demonstrated positive EBV viral load in B cells (1,018,239 IU/mL), T cells (857,418 IU/mL),NK cells (237,459), and myeloid cells (532,641 IU/mL). EBV-encoded RNA was positive within lymph node T cells, most consistent with a diagnosis of T-cell CA-EBV. The Invitae 407 gene immunodeficiency panel was sent; however, a pathogenic variant was not identified. The patient was seen by hematology/oncology with plans for hematopoietic stem cell transplant. Unfortunately, he succumbed to complications from CA-EBV and multiorgan failure.We describe a male with lymphocytic-variant hypereosinophilic syndrome and a longstanding constellation of inflammatory and lymphoproliferative symptoms due to CA-EBV. His course initially eluded his care team and only after careful multidisciplinary discussion was a diagnosis reached.

A case of IgG4-related interstitial nephritis with ureteral obstruction: case report and literature review

BackgroundIgG4-related disease (IgG4-RD) is a newly discovered systemic disease that can affect any organ or tissue in the body. IgG4-related kidney disease (IgG4-RKD) is relatively rare but essential to IgG4-RD. However, there are few reports of IgG4-RD mimicking malignant ureteral tumors leading to hydronephrosis. We report here a rare case of IgG4-RD involving the ureter.Case presentationAn 87-year-old man presented to our nephrology department with anorexia, nausea, and acute kidney injury in November 2020. Urinary computed tomography (CT) examination revealed a right lower ureter mass with right renal and ureter hydronephrosis. The serum level of IgG4 was 1890 mg/dL, and the concurrently renal biopsy revealed extensive infiltration of IgG4-positive plasma cells in renal interstitium, which was diagnosed as IgG4-associated tubule-interstitial nephritis(IgG4-TIN). The renal function improved significantly after double-J tube implantation of the right ureter and moderate-dose hormone therapy. The serum IgG4 decreased to the normal range, and the right lower ureter mass almost disappeared after one year of low-dose hormone maintenance therapy.ConclusionIgG4-RD can present as a mass in the renal pelvis and (or) ureter, leading to hydronephrosis. Therefore, early recognition of this disease is significant. Most patients respond well to hormonal therapy to avoid surgical treatment due to misdiagnosis as malignant tumors, causing secondary harm to patients.

The quantity and quality of anti-SARS-CoV-2 antibodies show contrariwise association with COVID-19 severity: lessons learned from IgG avidity.

Gaining more appreciation on the protective/damaging aspects of anti-SARS-CoV-2 immunity associated with disease severity is of great importance. This study aimed to evaluate the avidity of serum IgG antibodies against SARS-CoV-2 spike (S) and nucleocapsid (N) in hospitalized symptomatic COVID-19 patients and asymptomatic RT-PCR-confirmed SARS-CoV-2 carriers as well as to compare antibody avidities with respect to vaccination status, vaccination dose and reinfection status. Serum levels of anti-S and anti-N IgG were determined using specific ELISA kits. Antibody avidity was determined by urea dissociation assay and expressed as avidity index (AI) value. Despite higher IgG levels in the symptomatic group, AI values of both anti-S and anti-N IgG were significantly lower in this group compared to asymptomatic individuals. In both groups, anti-S AI values were elevated in one-dose and two-dose vaccinees versus unvaccinated subjects, although significant differences were only detected in the symptomatic group. However, anti-N avidity showed no significant difference between the vaccinated and unvaccinated subgroups. Almost all vaccinated patients of different subgroups (based on vaccine type) had higher anti-S IgG avidity, while the statistical significance was detected only between those receiving Sinopharm compared to the unvaccinated subgroup. Also, statistically significant differences in antibody AIs were only found between primarily infected individuals of the two groups. Our findings indicate a key role for anti-SARS-CoV-2 IgG avidity in protection from symptomatic COVID-19 and calls for the incorporation of antibody avidity measurement into the current diagnostic tests to predict effective immunity toward SARS-CoV-2 infection or even for prognostic purposes.