Quantitative Serum Immunoglobulin Research Articles

SARS-CoV-2 serological cross-reactivity with autoantibodies.

In their report on the detection of IgM and IgG antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients with autoimmune diseases, Teng and colleagues1 found that the serological test that they assessed showed no cross-reactivity with autoantibodies present in patients with autoimmune disease. However, several potential confounding factors should be considered when assessing the study findings. Hypogammaglobulinaemia (reduced serum immunoglobulin concentrations) might result in false negative antibody test results; therefore, quantitative serum immunoglobulin measurements should be used to interpret SARS-CoV-2 serology results, along with knowledge of any patient history of immunodeficiencies.

Detection of IgM and IgG antibodies against SARS-CoV-2 in patients with autoimmune diseases.

Detection of IgM and IgG antibodies against SARS-CoV-2 in patients with autoimmune diseases.

NONPRODUCTIVE COUGH AS PREAMBLE OF RESPIRATORY FAILURE IN A PATIENT WITH HYPEREOSINOPHILIC SYNDROME

SESSION TITLE: Tuesday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/22/2019 01:00 PM - 02:00 PM INTRODUCTION: Hypereosinophilic syndrome (HES) is a rare disorder characterized by peripheral blood eosinophilia of 〖1.5 x 10〗ˆ3/μL or higher and evidence of end organ manifestations attributable to the eosinophilia and not otherwise explained in the clinical setting. HES has an unknown prevalence, most often affects people age 20 through 50. Few patients with prolonged eosinophilia develop organ dysfunction that characterizes HES. CASE PRESENTATION: This is the case of a healthy 52-year-old man without history of significant systemic illness who presents with non-productive cough, daily febrile episodes and left upper extremity pain for a period 2 months. On physical examination, lungs are clear upon chest auscultation and left sided axillary pain is elicited upon arm abduction. Initial blood work revealed WBC 〖40.62 x 10〗ˆ3/μL; eosinophil count 〖23.56 x 10〗ˆ3/μL, elevated sedimentation rate 112 mm/hr. Initial diagnosing testing for HES was performed. Complete blood count was remarkable for increasing trend in leukocytes and eosinophils. Routine chemistries, including liver function tests were within normal limits. Quantitative serum immunoglobulin levels, including IgE were normal. Serum troponin, echocardiogram, electrocardiogram, Pulmonary function tests revealed no abnormalities. Bone marrow biopsy including cytogenetics had no myeloproliferative abnormalities. Flexible bronchoscopy with bronchoalveolar lavage revealed eosinophils count less than 3%, no evidence of bacteria, viral or fungal infection. Serology examination for diagnosis of parasitic infection, HIV testing, antineutrophil antibodies ANCA, Serum tryptase and B12 levels, PET scan, lymph node biopsy, EBV viral load were completely negative. The patient’s eosinophilia continued to rise, peaking at 56.00 x 103/μL, despite high-dose prednisone therapy (200 mg by mouth daily), he went in to respiratory failure, cardiac arrest and developed multi organ dysfunction. Hydroxyurea (1 g daily) was added. He improved after the addition of hydroxyurea, and a decrease trending of his eosinophil count was seen. Hydroxyurea was discontinued, and prednisone was tapered. DISCUSSION: HES is a rare heterogeneous disease, any organ system is vulnerable to get affected. The symptoms are common in many other medical problems, making an initial diagnosis more difficult. Sometimes no underlying cause can be found for an observed eosinophilia, even after an extensive diagnostic evaluation. In the absence of an identifiable reactive cause for the eosinophilia, a diagnosis of idiopathic HES can be established if there is evidence of organ involvement and dysfunction. CONCLUSIONS: Our case illustrates the importance of considering diagnosis in patients with significant eosinophilia. Have a high index of suspicion in the background of persistent peripheral eosinophilia; after exclusion of secondary causes. Reference #1: https://doi.org/10.1182/asheducation-2018.1.326 ASH Education Book November 30, 2018 vol. 2018 no. 1 326-331 Reference #2: Klion AD. How I treat hypereosinophilic syndromes. Blood. 2015;126(9):1069-1077. Reference #3: Khoury P, Abiodun AO, Holland-Thomas N, Fay MP, Klion AD. Hypereosinophilic syndrome subtype predicts responsiveness to glucocorticoids. J Allergy Clin Immunol Pract. 2018;6(1):190-195. DISCLOSURES: No relevant relationships by Hector Cintron-Colon, source=Web Response No relevant relationships by Ricardo Fernandez, source=Web Response No relevant relationships by Vanessa Fonseca Ferrer, source=Web Response No relevant relationships by WIlliam Marrero, source=Web Response No relevant relationships by Luis Piñeiro, source=Web Response

P249 Common variable immunodeficiency presenting with recurrent ascending cholangitis

Common variable immunodeficiency (CVID) is a relatively frequent primary immunodeficiency affecting 1 in 50,000. It is a diagnosis made based on a history of recurrent upper and lower respiratory tract infections as well as a diminished to absent quantitative and qualitative serum immunoglobulin levels. We describe a case of a 61-year-old female who presented with recurrent ascending cholangitis every other week for 8 years as the primary manifestation of CVID.

Primary immunodeficiency and recalcitrant chronic sinusitis: a systematic review.

A subset of patients with chronic rhinosinusitis (CRS) has disease refractory to standard therapies. Primary immunodeficiency should be considered in this group. Past literature has demonstrated an association between immunodeficiency and chronic sinusitis. A systematic literature search was performed using OVID, MEDLINE, EMBASE, and Cochrane databases to identify English language papers containing original human data on subjects with primary immunodeficiency and chronic sinusitis. A total of 39 studies met inclusion criteria. Data was collected pertaining to immune dysfunction in patients with chronic sinusitis, the clinical workup for these patients, and the effectiveness of medical and surgical treatments. The studies were assessed to determine their level of evidence. The majority of studies were supported by Level 4 evidence. Up to 50% of patients with recalcitrant CRS were found to have immune dysfunction. The most frequent primary immunodeficiencies studied were common variable immunodeficiency (CVID) and X-linked agammaglobulinemia (XLA). Common collected data included measurement of serum immunoglobulins and functional antibody responses. Treatments reviewed include immunoglobulin replacement, long-term antibiotics and endoscopic sinus surgery. Patients with recalcitrant CRS should be evaluated for primary immunodeficiency. This should include as assessment of quantitative serum immunoglobulin levels as well as functional antibody responses. Medical therapy, particularly immunoglobulin replacement therapy, appears to be most effective when administered at high doses early in the disease course. The addition of surgery is less clearly supported, but may also provide benefit if performed early.

Use of vaccines in the evaluation of presumed immunodeficiency

The assessment of the humoral immune response is a critical component in the evaluation of patients suspected of having a primary immune deficiency disease (PIDD). [1] Bonilla F.A. Bernstein I.L. Khan D.A. Chinen J. Frank M. Kobrynski L. Practice parameter for the diagnosis and management of primary immunodeficiency. Ann Allergy Asthma Immunol. 2005; 94: S1-S63 Abstract Full Text PDF PubMed Scopus (437) Google Scholar In fact, more than 50% of the patients with immune deficiency have some impairment in the ability to make specific antibodies and/or have a quantitative deficiency of antibodies. Although there are a number of laboratory tools that are helpful in the evaluation of patients suspected of having an antibody deficiency disorder, such as quantitative serum immunoglobulin analysis, analysis of lymphocyte subpopulations by flow cytometry, or even genetic diagnoses of single-gene mutations, the evaluation of a patient's response to immunization with a vaccine and the production of specific antibodies are extremely important. The assessment of qualitative antibody responses is not only important in confirming a specific antibody immune deficiency but is also important in the decision-making process for using immunoglobulin replacement therapy. 2 Stiehm E. The four most common peditric immunodefiencies. J Immunotoxicol. 2008; 5: 227-234 Crossref PubMed Scopus (59) Google Scholar , 3 Stiehm E. Orange J. Ballow M. Lehman H. Therapeutic use of immunoglobulins. Adv Pediatr. 2010; 57: 185-218 Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar If on initial evaluation patients demonstrate a deficient quantitative antibody response, an antigen challenge or booster vaccine immunization with existing Food and Drug Administration (FDA)–approved vaccines can determine whether the patient has the ability to generate an adequate qualitative antibody response. In an effort to provide guidance in the evaluation of patients for a humoral PIDD, a working group of the Basic and Clinical Immunology Interest Section of the American Academy of Allergy, Asthma and Immunology (AAAAI) published a report in September 2012. [4] Orange J. Ballow M. Stiehm E. Ballas Z. Chinen J. De La Morena M. Use and interpretation of diagnostic vaccination in primary immunodeficiency: a working group report of the Basic and Clinical Immunology Interest Section of the American Academy of Allergy, Asthma and Immunology. J Allergy Clin Immunol. 2012; 130: S1-S24 Abstract Full Text Full Text PDF PubMed Scopus (289) Google Scholar This article discusses some of the topics related to the use and interpretation of vaccine responses in the evaluation of patients for a possible PIDD.

Incidence of Hypogammaglobulinemia in Patients Receiving Rituximab and the Use of Intravenous Immunoglobulin for Recurrent Infections

Rituximab targets normal B cells and tumor B cells. We used a unique data-mining tool to identify patients with lymphoma who were treated with rituximab and who had serial pre and post rituximab immunoglobulin concentrations evaluated. After treatment, 39% (69/179) of patients had low levels of immunoglobulin G. Recurrent sinopulmonary infections were seen in 6.6% (14/211). Intravenous immune globulin appeared to reduce the frequency of infection. Rituximab has altered the treatment approach to B-cell malignancies and other diseases. Reports consider that rituximab had limited impact on serum immunoglobulins. However, anecdotes suggest that rituximab can cause symptomatic hypogammaglobulinemia. This retrospective study examined the relationship among rituximab, hypogammaglobulinemia, and treatment of symptomatic hypogammaglobulinemia with intravenous immune globulin (IVIG). Patients with serial quantitative serum immunoglobulin (SIgG) concentrations before and subsequent to rituximab administration at Memorial Sloan-Kettering Cancer Center were identified. Information regarding rituximab administration, SIgG concentrations, frequency of infection, and administration of IVIG were recorded. Between December 1998 and April 2009, 211 patients with B-cell lymphoma treated with rituximab and with serial SIgG concentrations were identified. One hundred seventy-nine (85%) patients had normal SIgG before rituximab, 32 (15%) had low SIgG. After rituximab use, hypogammaglobulinemia was identified in 38.54% of patients with initially normal SIgG. The risk was greater in patients who received maintenance rituximab. Symptomatic hypogammaglobulinemia that prompted IVIG administration developed in 6.6% of patients. In this data set, rituximab administration was associated with a high frequency of hypogammaglobulinemia, particularly symptomatic hypogammaglobulinemia, among patients who received multiple courses of rituximab. Baseline and periodic monitoring of SIgGs is appropriate in patients who receive rituximab.

Two distinct subtypes of hepatitis B virus–related acute liver failure are separable by quantitative serum immunoglobulin M anti-hepatitis B core antibody and hepatitis B virus DNA levels

Hepatitis B virus (HBV)-related acute liver failure (HBV-ALF) may occur after acute HBV infection (AHBV-ALF) or during an exacerbation of chronic HBV infection (CHBV-ALF). Clinical differentiation of the two is often difficult if a previous history of HBV is not available. Quantitative measurements of immunoglobulin M (IgM) anti-hepatitis B core antibody (anti-HBc) titers and of HBV viral loads (VLs) might allow the separation of AHBV-ALF from CHBV-ALF. Of 1,602 patients with ALF, 60 met clinical criteria for AHBV-ALF and 27 for CHBV-ALF. Sera were available on 47 and 23 patients, respectively. A quantitative immunoassay was used to determine IgM anti-HBc levels, and real-time polymerase chain reaction (rtPCR) was used to determine HBV VLs. AHBV-ALFs had much higher IgM anti-HBc titers than CHBV-ALFs (signal-to-noise [S/N] ratio median: 88.5; range, 0-1,120 versus 1.3, 0-750; P < 0.001); a cut point for a S/N ratio of 5.0 correctly identified 44 of 46 (96%) AHBV-ALFs and 16 of 23 (70%) CHBV-ALFs; the area under the receiver operator characteristic curve was 0.86 (P < 0.001). AHBV-ALF median admission VL was 3.9 (0-8.1) log10 IU/mL versus 5.2 (2.0-8.7) log10 IU/mL for CHBV-ALF (P < 0.025). Twenty percent (12 of 60) of the AHBV-ALF group had no hepatitis B surface antigen (HBsAg) detectable on admission to study, wheras no CHBV-ALF patients experienced HBsAg clearance. Rates of transplant-free survival were 33% (20 of 60) for AHBV-ALF versus 11% (3 of 27) for CHBV-ALF (P = 0.030). AHBV-ALF and CHBV-ALF differ markedly in IgM anti-HBc titers, in HBV VLs, and in prognosis, suggesting that the two forms are, indeed, different entities that might each have a unique pathogenesis.

Hypogammaglobulinemia in pts receiving rituximab immunotherapy and the impact of rituximab maintenance.

8088 Background: Several randomized studies demonstrated that rituximab maintenance (RM) prolongs PFS but not OS following induction with rituximab immunotherapy (I) alone or chemoimmunotherapy (CI) in patients (pts) with indolent lymphoma. The long-term impact of rituximab (R) on immune reconstitution has not been well studied; however R has been associated with hypogammaglobulinemia (hypogam) with recurrent infections. This retrospective study sought to evaluate the relationship between R, hypogam, and treatment with intravenous immune globulin (IVIG). Methods: We identified 215 pts treated with R for lymphoma between 12/1998 and 4/2009 and also had quantitative serum immunoglobulin levels (sIg) evaluated prior to and after treatment with R. Data on the use of IVIG was collected. Frequencies were compared using Pearson χ2. Results: Histologies included: DLBCL, N=68; FL, N=42; CLL/SLL, N=38; MZL, N=26; MCL, N=22; other subtypes, N=19. Pts received a median of 6 doses of R (range:2–50). Prior to treatment with R, 85% (183/215) of pts had normal sIg levels and 15% (32/215) had low levels. Histologies among 32 pts with baseline hypogam were well distributed: DLBCL, N=10; CLL/SLL, N=5; FL, N=5; MZL, N=4; MCL, N=2; other, N=6. Of 183 pts with normal sIg levels prior to R, 26.7% (49) received RM while 73.2% (134) received R as I or CI alone. Hypogam was documented in 39% (71/183) of pts with baseline normal sIg levels following R. RM was associated with a higher risk of developing hypogam, 55% (27/49) compared to 33% (44/134) receiving I or CI alone, p=0.006. IVIG was administered to 13% (23/183) of pts with normal baseline sIg. Among patients who received RM, 20% (10/49) received IVIG compared to 10% (13/134) among patients treated with I or CI alone, p=0.05. IVIG for treatment of symptomatic hypogam was administered to 10% (18/183) of pts with normal sIg prior to R therapy. Conclusions: R was associated with developing hypogam in 39% of pts with normal baseline sIg. Pts receiving RM had a significantly higher risk of developing hypogam and requiring IVIG. The risk of symptomatic hypogam should be considered in the use of R maintenance. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech, GlaxoSmithKline, sanofi-aventis Physicians' Education Resource Amgen, Biogen Idec, Genentech, GlaxoSmithKline, Roche

Index of Suspicion

Index of Suspicion

Approach to acute renal failure in biopsy proven myeloma cast nephropathy: Is there still a role for plasmapheresis?

A 75-year-old Caucasian man with hypertension and severe, emphysema, presented to the Veterans Administration New York Harbor Health Care System Hospital outpatient clinic, for his bi-yearly physical in March 2003. The patient had a macrocytic anemia and a serum creatinine (Scr) level of 3.3mg per 100 ml (baseline Scr, 0.9 mg per 100 ml 1 month earlier). An outpatient nephrology consultation was initiated after a comprehensive negative gastrointestinal workup. Detailed history and physical examination were performed. He denied the following symptoms: headache, visual changes, hesitancy, frequency, oliguria, dysuria, nausea, vomiting, fever, chills, bone pain, and change in weight, appetite or bowel habits. He also denied the following: hematochezia, melena, fatigue, dyspnea, dizziness, or chest pain. His medications on presentation included lisinopril 20 mg day -1 and combination albuterol and atrovent inhaler. He denied occupational or chemical exposure, and use of herbal or over-the-counter medications. The patient quit smoking and drinking over 20 years ago. He had no history of diabetes mellitus, macroscopic hematuria, or tuberculosis. His family history was non-contributory. Physical examination revealed an alert, healthy-appearing older male with a blood pressure of 134/83 mm Hg (without orthostasis), pulse rate of 78 beats min -1 , weight of 89kg, and body mass index of 29 kg m -2 . There was no lymphadenopathy. Heart examination showed regular rate and rhythm, without murmurs, rubs, or gallops. Lungs were clear to percussion and auscultation. Abdomen had normal bowel sounds, was soft, non-tender, with no masses or hepatomegaly. There was dullness in Traube's space on deep inspiration. Extremities revealed no clubbing, cyanosis, rash, or edema. Neurological examination was essentially normal. Diagnostic studies were performed. Renal ultrasound showed 11.7 and 12.4 cm right and left kidney, respectively. Both kidneys demonstrated mildly increased, diffuse parenchymal echogenicity, consistent with mild medical renal disease, with no scarring or masses. There was no hydronephrosis. Renal veins were patent bilaterally. The bladder was not distended. Spleen was enlarged, measuring 12.6 cm. Results of the laboratory studies are detailed in Table 1. Urinary dipstick showed trace protein but sulfosalicyclic acid testing was not performed. Twenty-four-hour urine protein level was 3.1 g day -1 . Urine protein electrophoresis was unremarkable, but urine and serum immunofixation electrophoresis and serum protein electrophoresis showed a monoclonal band (IgAκ). His quantitative serum immunoglobulin A (IgA) level was 2330 mg per 100ml. Bone marrow biopsy revealed 90% plasma cells (Figure 1). Skeletal survey was negative. A diagnosis of multiple myeloma (MM) Durie-Salmon stage III was made.

The use of commercially available genetic tests in immunodeficiency disorders

As the gene defects that cause many of the currently recognized immunodeficiency disorders are elucidated, genetic testing is becoming clinically available for most of these disorders. The practicing allergist often has to coordinate the initial immunologic workup for patients with suspected primary immunodeficiencies. The purpose of this review is to inform the practicing allergist of the current availability of testing for genetic defects associated with primary immunologic disorders. In many cases, the allergist may want to refer complex immunologic analyses to an academic referral center. Table 1 is an easy reference for most common primary immunodeficiencies. Although commercial genetic testing is available for an expanding number of genes, this testing is rarely indicated in the initial workup for immunodeficiency. The physician must first consider the phenotypic presentation of the patient and focus the laboratory evaluation based on this presentation. General guidelines for initial immunologic evaluations are reviewed by Ballow1 and in Middleton’s Allergy: Principles and Practice.2 Specifically, if evaluating a patient for a suspected phagocytic defect, the physician should obtain repeated evaluation of the absolute neutrophil count and consider further testing for neutrophil chemotaxis, dihydrorhodamine assay, and/or flow cytometry for CD11/18. Possible humoral defects should be evaluated with quantitative serum immunoglobulin levels, specific polysaccharide and protein antibody responses, and the presence or absence of B cells. If a cellular immune defect is suspected, the workup should start with flow cytometric analysis of T-, B-, and NK-cell subsets and in vitro or in vivo evaluation of T-cell function. Identification of a patient with severe combined immunodeficiency warrants immediate referral to a bone marrow transplantation service since acquiring an infection (viral or opportunistic) may compromise the transplantation outcome. Detailed discussions of these initial evaluations may be found in other articles from this miniseries.3–7 In certain cases, such as leukocyte adhesion deficiency type 1, genetic testing is rarely clinically indicated because these diseases can be effectively diagnosed by phenotypic and functional assays and can be managed without the specific gene defect ever having been identified. Genetic testing is not typically required in common variable immunodeficiency (CVID), in this case because known genetic defects cause only a small number of all cases of CVID and would not alter treatment. One exception to this approach, however, is when the B-cell count is low or absent. In this instance, genetic testing for X-linked agammaglobulinemia is warranted since approximately 10% of male patients with CVID have BTK mutations despite the presence of some serum immunoglobulins. Some general points should be considered when ordering gene testing. Genetic testing should only be performed with informed consent from the patient and/or legal guardian. Most genetic laboratories have their own consent forms, often available online. Signed consent forms should always be sent with the laboratory specimen. Gene testing can be run on whole blood samples, and most can also be run on buccal swab samples. Buccal samples are preferred in patients who have undergone bone marrow transplantation, in which whole blood contains donor cells, or in severely leukopenic patients, in which an adequate amount of DNA may be difficult to obtain from blood samples. Pricing has not been included in Table 1. In general, genetic testing for diagnosis of a new mutation through a clinical laboratory is expensive, ranging from several hundred to several thousand dollars per gene. The cost of genetic testing in a relative of a proband with a known mutation costs considerably less, and prenatal testing for a known mutation often costs much more, but these are situations less frequently encountered by the practicing allergist.

IKBKG (nuclear factor-κB essential modulator) mutation can be associated with opportunistic infection without impairing Toll-like receptor function

Patients with hypomorphic nuclear factor-kappaB essential modulator (NEMO) mutations have extensive phenotypic variability that can include atypical infectious susceptibility. This study may provide important insight into immunologic mechanisms of host defense. Immunologic evaluation, including studies of Toll-like receptor (TLR) function, was performed in a 6-month-old boy with normal ectodermal development who was diagnosed with Pneumocystis pneumonia and cytomegalovirus sepsis. Genomic and cDNA sequencing demonstrated a novel NEMO missense mutation, 337G->A, predicted to cause a D113N (aspartic acid to asparagine) substitution in the first coiled-coil region of the NEMO protein. Quantitative serum immunoglobulins, lymphocyte subset numbers, and mitogen-induced lymphocyte proliferation were essentially normal. The PBMC responses to TLR ligands were also surprisingly normal, whereas natural killer cell cytolytic activity, T-cell proliferative responses to specific antigens, and T-cell receptor-induced NF-kappaB activation were diminished. Unlike the unique NEMO mutation described here, the most commonly reported mutations are clustered at the 3' end in the tenth exon, which encodes a zinc finger domain. Because specific hypomorphic variants of NEMO are associated with distinctive phenotypes, this particular NEMO mutation highlights a dispensability of the region including amino acid 113 for TLR signaling and ectodysplasin A receptor function. This region is required for certain immunoreceptor functions as demonstrated by his susceptibility to infections as well as natural killer cell and T-cell defects.

Dysproteinemia-related nephropathy associated with crystal-storing histiocytosis

CASE PRESENTATION A 41-year-old white man presented with a 6-month history of worsening neck pain accompanied by 20Ib weight loss. He was initially referred to an orthopedic surgeon and work-up including magnetic resonance imaging revealed shoulder bursitis for which he received a steroid injection. However, neck pain continued and laboratory tests revealed anemia and renal insufficiency, leading to his referral to an internist. The patient had no significant past medical history or family history of renal disease and he was not taking any medications. Physical examination revealed temporal wasting but was otherwise unremarkable. Laboratory investigations revealed the following: blood urea nitrogen 32 mg/dl (normal 7-25 mg/dl), serum creatinine 4.2 mg/dl (normal 0.5-1.4 mg/dl), serum calcium 9.8 mg/dl (normal 8.5-10.4 mg/dl), phosphorous 4.3 mg/dl (normal 2.5-4.5 mg/dl), sodium 143mmol/l (normal 135-146 mmol/l), potassium 3.6mmol/l (normal 3.5-5.3 mmol/l), chloride 109 mmol/l (normal 98-110 mmol/l), bicarbonate 17 mmol/l (normal 21-33 mmol/l), glucose 95 (normal 65-139 mg/dl), lactate dehydrogenase 505 (normal 105-333 IU/I), white blood cell count 9800/μl, hemoglobin 9.7 g/dl, hematocrit 28.3%, and platelet count 316000/μl. Erythrocyte sedimentation rate was markedly elevated (>100mm/h). Total serum protein was 8.8 g/dl (normal 6.0-8.3 g/dl), serum albumin was 4.2 g/dl (normal 3.5-4.9 g/dl), and β2-microglobulin was elevated (10.7 mg/l, normal < 1.85 mg/l). Quantitative serum immunoglobulins (Ig) revealed elevated IgD (842 mg/dl, normal 0-14 mg/dl) and decreased levels of IgG (450 mg/dl, normal 694-1618 mg/dl), IgA (32 mg/dl, normal 81-463 mg/dl), and IgM (9.9 mg/dl, normal 48-271 mg/ dl). Serum protein electrophoresis revealed a monoclonal spike (0.82 g/dl) with IgD kappa (κ) specificity, elevated free K light chains (81 200 mg/l, normal range 3.3-19.4 mg/l), and normal level of lambda (λ) light chains (10.6 mg/l, normal range 5.7-26.3 mg/l). Urinalysis revealed 100mg/dl glucose; these findings, together with the normal serum glucose, normal serum phosphate, and low serum bicarbonate levels, suggested partial Fanconi's syndrome. Urinalysis also revealed 1 + protein; however, 24-h urine collection contained 20.2 g protein of which 13.975 g (69.2%) consisted of free K light chains. Bone marrow examination revealed diffuse infiltration by IgD K-positive plasma cells, accounting for 50% of overall cellularity, consistent with multiple myeloma. Based on the finding of significant urinary light chain excretion, the patient's multiple myeloma was stage III-B. A skeletal survey revealed no bony lesions, and magnetic resonance imaging of the axial skeleton revealed marrow abnormalities consistent with myeloma but no osseous lesions. Given the new onset of renal insufficiency and partial Fanconi's syndrome with massive urinary light chain excretion, a renal biopsy was performed to determine the pattern of dysproteinemia-related renal disease.

Analysis of phase I study of chronic rhinosinusitis

RATIONALE: Allergy clinic patients with clinical manifestations of chronic rhinosinusitis (CRS) were enrolled in a two-year outcomes study to assess the demographics, diagnostic analysis, and progression of their disease.METHODS: Forty-four patients with a clinical history of CRS were enrolled in the study over a six-month period. These patients were evaluated by comparing their serum IgE levels, total eosinophil count, presence of atopy, quantitative serum immunoglobulins (QIG), and sinus computed tomography (CT) scans.RESULTS: The mean age of our patients was 56, with a range of 35 to 83 years old. No significant deficiencies in serum immunoglobulins were noted in any of our patients. High serum IgE levels were associated with significant findings on CT scans. Of those patients with normal serum IgE levels, 68% had normal CT scan findings. Though all patients had a clinical diagnosis of (CRS), only 41% were confirmed by sinus CT scans. In addition, the presence of CRS was associated with an increased absolute eosinophil count, and nearly all patients with severe finding of CRS on CT scan were atopic. Of those patients who were not atopic, only 1 (11%) had severe CRS findings on CT scan. Despite the high degree of atopy, only 3 patients (7%) were receiving immunotherapy.CONCLUSIONS: Characterizing patients with CRS continues to be a challenging process. The variability of the spectrum of this disorder contributes to the difficulty in managing the disease. RATIONALE: Allergy clinic patients with clinical manifestations of chronic rhinosinusitis (CRS) were enrolled in a two-year outcomes study to assess the demographics, diagnostic analysis, and progression of their disease. METHODS: Forty-four patients with a clinical history of CRS were enrolled in the study over a six-month period. These patients were evaluated by comparing their serum IgE levels, total eosinophil count, presence of atopy, quantitative serum immunoglobulins (QIG), and sinus computed tomography (CT) scans. RESULTS: The mean age of our patients was 56, with a range of 35 to 83 years old. No significant deficiencies in serum immunoglobulins were noted in any of our patients. High serum IgE levels were associated with significant findings on CT scans. Of those patients with normal serum IgE levels, 68% had normal CT scan findings. Though all patients had a clinical diagnosis of (CRS), only 41% were confirmed by sinus CT scans. In addition, the presence of CRS was associated with an increased absolute eosinophil count, and nearly all patients with severe finding of CRS on CT scan were atopic. Of those patients who were not atopic, only 1 (11%) had severe CRS findings on CT scan. Despite the high degree of atopy, only 3 patients (7%) were receiving immunotherapy. CONCLUSIONS: Characterizing patients with CRS continues to be a challenging process. The variability of the spectrum of this disorder contributes to the difficulty in managing the disease.

Coexistent yellow nail syndrome and selective antibody deficiency

Yellow nail syndrome (YNS) is a rare, often underdiagnosed condition of unknown origin. The clinical features of the syndrome include yellow nails, chronic sinusitis, bronchiectasis, pleural effusion, and lymphoedema. Despite the frequent occurrence of upper and lower respiratory tract infections in patients with YNS, comprehensive analysis of their humoral immunity has not been previously reported. To present the case of a patient with YNS whose recurrent upper and lower respiratory tract infections may have been caused by an underlying selective antibody deficiency that manifests as impaired IgG antibody response to polysaccharide antigens. The patient underwent cultures of purulent sputum for Streptococcus pneumoniae and Haemophilus influenzae, bronchial washings for H. influenzae, and nail scrapings for fungi. Her serum levels of IgG, IgA, IgM, IgG subclasses, and serum titers of IgG antitetanus toxoid, anti-H. influenzae, and anti-S. pneumoniae antibodies were measured. Cultures of purulent sputum were positive on multiple occasions for S. pneumoniae and H. influenzae and bronchial washings were positive for H. influenzae. Nail scrapings were consistently negative for fungi. She had no reductions in serum levels of IgG, IgA, IgM, or IgG subclasses and had normal serum titers of IgG antitetanus toxoid antibodies. However, she demonstrated impaired IgG antibody responses following immunization with Pneumovax and an H. influenza B vaccine. This case report describes the first comprehensive analysis of humoral immune function in a patient with YNS. The finding of a selective antibody deficiency in our patient provides a potential explanation for the occurrence of respiratory infections in YNS. Accordingly, we recommend that functional antibody determinations and quantitative serum immunoglobulins be evaluated in patients diagnosed as having this unusual, enigmatic syndrome.

Life-threatening tinnitus

A 68-year-old woman presented in October, 1998, with an 8-week history of tinnitus and dizziness. She had no history of cardiovascular, or neurological disease. Computed tomography (CT) scan of the head was not diagnostic. She returned 3 weeks later with new symptoms of altered taste sensation, dysphagia, left-sided numbness, unsteady gait, and diplopia. She had no vertigo, nausea, vomiting, fevers, headaches, or anorexia. There was no history of changes in personality, mood, or cognitive decline, or of seizures. She had lost 7 kg in weight over the past 6 months. Heart rate, blood pressure, temperature, mental state examination and speech were normal. The pupils were reactive and symmetrical. Fundoscopic examination was normal. She had a slow gaze to the left with a 1 syndrome (one eye was fixed in the midline, the other eye could only make abducting movements with horizontal nystagmus in the direction of the abduction). She had decreased left facial sensation and a diminished left corneal reflex. The cranial nerves were otherwise normal. Muscle tone and power were normal. Heel to skin testing was adequate but finger to nose was dysmetric on the left side. She had decreased light touch sensation on the left side of the body. Deep tendon reflexes were normal and symmetrical and the plantar response was flexor bilaterally. The patient’s gait was wide based with severe truncal ataxia. Full blood count, peripheral blood smear, coagulation tests, a biochemistry profile, serum vitamin B12 and folate, thyroid function tests, erythrocyte sedimentation rate, Creactive protein, antinuclear antibodies, antineutrophil cytoplasmic antibody, rheumatoid factor, complement levels for C3 and C4, serum protein electrophoresis, cryoglobulins, and quantitative serum immunoglobulins were normal. Cerebrospinal fluid (CSF) analysis showed protein 0·65 g/L and glucose 4·2 mmol/L, 139 red cells and nine white cells per L (mostly lymphocytes with a few atypical cells). There was no immunological evidence of syphilis (VDRL). CSF cultures and polymerase chain reactions for herpes and cytomegalovirus were negative. Oligoclonal bands were absent. Doppler study of carotid and vertebro-basilar arteries was normal. Gadoliniumenhanced magnetic resonance imaging (MRI) of the head showed bilateral contrast enhancement in the medial aspects of the temporal lobes in the amygdala and hippocampi, as well as in the posterior aspect of the medulla, pons, and midbrain (figure). The imaging was diagnostic for limbic and bulbar encephalitis. CASE REPORT

Sexually transmitted esophagitis: primary herpes simplex virus type 2 infection in a healthy man

A previously healthy 32-year-old man presented with fever, malaise, and odynophagia. Five days before presentation, he awoke with a sore throat and fatigue. During the next several days he developed fever, chills, anorexia, and bloating. He had several episodes of retching but no emesis. Retrosternal pain with swallowing began 2 days after onset of his intial symptoms. The pain quickly became severe, occurred with dry swallows, and limited his oral intake to milk shakes and cottage cheese. He lost 7 pounds. H2 antagonists and liquid antacids did not provide relief of his symptoms. He noted no mouth sores or rash. One week before the onset of his initial symptoms, the patient had begun a sexual relationship with a new female partner that involved orogenital contact. He took no medication, did not smoke, drank only small amounts of alcohol and denied use of illicit drugs. Examination showed him to be moderately uncomfortable, even when swallowing saliva. He was afebrile. There were no oral, genital, or skin lesions. His neck was supple, without adenopathy. The remainder of the examination was normal. Laboratory studies, including a complete blood count and differential, renal and liver function tests were normal. Endoscopy showed many 2 to 3 mm diameter discrete shallow ulcerations with erythematous halos in the midesophagus. The ulcerations became confluent in the distal esophagus. The stomach and duodenum were normal. Histopathologic evaluation of endoscopic biopsies revealed severe acute and chronic inflammation and superficial ulceration (Fig. 1A), as well as intranuclear Cowdry type A inclusion bodies and multinucleated giant cells (Fig. 1B). Culture grew HSV-2. At a later date, serologic studies by Western blot technique showed antibodies to HSV-2 and none to HSV-1. Tests of general immune function included quantitative serum immunoglobulins and standard skin testing, both normal. Human immunodeficiency virus (HIV) 1 and 2 were negative at presentation and again 6 months and 12 months later. Human T cell lymphotrophic virus 1 and 2 were both negative. One year after presentation, his total white blood cell count was 4500 cells/mm3 (normal 4000-11,000) with 25% lymphocytes. CD4 count was 440 cells/mm3 (normal 500-1600) (39%), with a CD4/CD8 ratio of 1.3. The patient was treated with acyclovir, omeprazole, sucralfate, and analgesics and had complete resolution of symptoms within 2 weeks. Two years after the primary infection, there has been no evidence of reactivation.

Effect of Calcitriol and Pamidronate in Multiple Myeloma

Addition of bisphosphonates to standard treatment of multiple myeloma (MM) decreases bone pain and skeletal events without influencing bone healing. Calcitriol, besides its established effects on bone remodeling and calcium metabolism, has both immunoregulatory and cell differentiating effects in vitro and in vivo. Moreover, low serum calcitriol has been reported in MM. We tested the effects of supportive treatment with calcitriol and pamidronate on bone disease in two stage-lll-B MM patients with diffuse bone involvement, normal serum calcium, and low serum calcitriol. Complete blood counts, serum calcium, creatinine, quantitative serum and urine immunoglobulins, and biochemical indices of bone turnover, serum calcidiol, calcitriol, parathyroid hormone, skeletal radiographs, and bone mineral density by dual x-ray absorbtiometry were measured every 1–6 months for 16 months in the first patient and 7 months in the second patient. Both patients showed a dramatic improvement of MM activity and in bone disease documented by serial radiographs in the first patient and by increased bone mineral density (approximately 15%) in the second. The reduced serum calcitriol in both patients and the elevated parathyroid hormone observed in the first patient before treatment returned to normal. Supportive treatment with pamidronate does not induce bone healing in MM. Therefore, the results observed with the addition of calcitriol suggest that this hormone may have contributed to the apparent arrest of the progression of MM and caused stimulation of bone healing.

The spectrum of Evans’ syndrome

Eleven patients (10 boys, one girl) with Evans’ syndrome with a median follow up time of 8.0 years were evaluated retrospectively. Six patients had either persistent hepatosplenomegaly or generalised lymphadenopathy,...