Allergy & Asthma Disease Management Center: Ask the Expert: Immune Deficiency

- Immune Deficiency -

12/15/2005 RE: CD11b levels on LAD-1

I inquire about a 4 year old male child presenting with clinical picture of LAD 1, recurrent skin infections with absent pus formation eventually leading to scar formation & recurrent periodontitis. There is no history of delayed separation of the umbilical stump.Lab investigations revealed persistent leukocytosis. CD11b was done and it was 46%.1- Are these data enough to make a final diagnosis of LAD1 knowing that CD18 assessment is not available for sometime?2- What are the cut-off levels of both CD11b and CD18 for confirming LAD?

In leukocyte adhesion deficiency (LAD)-1 the levels of the beta 2 integrin CD11b/CD18 heterodimer are usually 0-30% of normal ( J.Clin Invest 1997;100:1728-33). Most of such patients have major infections within the first 2 years of life. There have been occasional reports of a variant of LAD-1 in which the CD11b/CD18 levels are not that low but there is a mutation so that this integrin does not become activated by a conformational change. As a result this altered integrin does not bind avidly to its ligand in the vascular endothelium. The disease may be milder in such individuals. Therefore, in face of the non-typical history (no separation of umbilical cord), it would be worth assessing CD18 levels as well.

12/2/05 re: Selective deficiency of anti-pneum response

I am a nurse who is an asthmatic, recurrent sinusitis, respiratory infections, and I have had pneumonia twice. My last IgM was 8, IgE was 1100, IgA and IgG were normal. My CD3, CD4, lymphocytes and CD19 were normal, I have built up titers to HIB and Td but no titers to the pneumococcal immunization. I was given the pneumococcal immunization twice and tested twice. Do you have any thoughts on this?

Occasionally, healthy adults will not make good antibody responses to the pneumococcal polysaccharide vaccine (Pneumovax-23). However, the clinical picture you describe raises the possibility that you have a selective defect associated with IgG2 subclass deficiency. Individuals with this problem usually have normal total IgG levels (since the IgG2 component is usually less than 25% of total IgG). There is frequently an associated IgA deficiency (apparently not present in your case). They make normal antibody responses to protein or protein-conjugated antigens such as DT or the conjugated Hib vaccines but make weak or no antibody responses when immunized with pure polysaccharide antigens as in Pneumovax 23. The significance of the low serum IgM levels in your case is uncertain to me since the anti-pneumococcal antibody responses are mainly IgG. There are reported cases of possible decreased local host defenses in the upper respiratory tract associated with a low IgM antibody response but these are not well-defined.

One thing that should be considered in your case is trying immunization with Prevnar. Although this vaccine contains only 7 of the 23 pneumococcal serotypes present in Pneumovax 23, the polysaccharides of these 7 types are conjugated to a protein in Prevnar. Therefore, you may well make an antibody response to them. . The lab should be able to determine whether you have made such antibody responses. Since these 7 types are responsible for many of the more serious pneumococcal infections, you may well be benefited by this approach.

The question of whether individuals with selective deficiencies such as I discussed above are helped by monthly IV immunoglobulin (IV Ig) infusions is still unsettled. Such treatment is very expensive and not completely free of side-effects.

I have enclosed below (FYI) several abstracts of articles related to my comments.

N Engl J Med. 1985 Nov 14;313(20):1247-51. Related Articles, Links
Recurrent sinopulmonary infection and impaired antibody response to bacterial capsular polysaccharide antigen in children with selective IgG-subclass deficiency.
Umetsu DT, Ambrosino DM, Quinti I, Siber GR, Geha RS.

We studied 20 children with recurrent sinopulmonary infections and serum IgG levels within the normal range, who had selective IgG-subclass deficiency. Twelve of the children were IgG2 deficient, five were IgG3 deficient, and three were deficient in both IgG2 and IgG3. IgA deficiency was present in 3 of the 20 patients. In the children with IgG2 deficiency, serum antibody concentrations to the capsular polysaccharide of Hemophilus influenzae type B (Hib) were significantly lower than those in age-matched controls, both before and after immunization with the Hib capsular polysaccharide antigen, which elicits antibody predominantly of the IgG2 subclass. In contrast, their serum antibody titers to the tetanus and diphtheria toxoid protein antigens, which elicitantibody predominantly of the IgG1 subclass, were normal in comparison with those of age-matched controls. These results suggest that impairment of the antibody response to specific microbial antigens predisposes patients with selective IgG-subclass deficiencies to recurrent infections. Thus, as an aid in determining therapy, children with recurrent infections and normal total serum IgG should be evaluated for this condition.

Ann Allergy Asthma Immunol. 2003 Nov;91(5):496-500. Related Articles, Links
Coexistent yellow nail syndrome and selective antibody deficiency.
Bokszczanin A, Levinson AI.
Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania 19104-6160, USA.

BACKGROUND: Yellow nail syndrome (YNS) is a rare, often under diagnosed 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.
OBJECTIVE: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.

JAMA. 2005 Oct 26;294(16):2043-51. Related Articles, Links
Changing epidemiology of invasive pneumococcal disease among older adults in the era of pediatric pneumococcal conjugate vaccine.
Lexau CA, Lynfield R, Danila R, Pilishvili T, Facklam R, Farley MM, Harrison LH, Schaffner W, Reingold A, Bennett NM, Hadler J, Cieslak PR, Whitney CG;
Active Bacterial Core Surveillance Team. Minnesota Department of Health, Minneapolis 55155-2538, USA.

CONTEXT: A conjugate vaccine targeting 7 pneumococcal serotypes was licensed for young children in 2000. In contrast to the 23-valent polysaccharide vaccine used in adults, the 7-valent conjugate vaccine affects pneumococcal carriage and transmission. Early after its introduction, incidence of invasive pneumococcal disease declined among older adults, a group at high risk for pneumococcal disease.
OBJECTIVE: To determine among adults aged 50 years or older whether incidence of invasive pneumococcal disease, disease characteristics, or the spectrum of patients acquiring these illnesses have changed over the 4 years since pneumococcal conjugate vaccine licensure.
DESIGN, SETTING, AND POPULATION: Population-based surveillance of invasive pneumococcal disease in 8 US geographic areas (total population, 18,813,000), 1998-2003.
MAIN OUTCOME MEASURES: Incidence of invasive pneumococcal disease by pneumococcal serotype and other characteristics; frequency among case patients of comorbid conditions and other factors influencing mortality.
RESULTS: Incidence of invasive pneumococcal disease among adults aged 50 years or older declined 28% (95% confidence interval [CI], -31% to -24%), from 40.8 cases/100,000 in 1998-1999 to 29.4 in 2002-2003. Among those aged 65 years or older, the 2002-2003 rate (41.7 cases/100,000) was lower than the Healthy People 2010 goal (42 cases/100,000). Among adults aged 50 years or older, incidence of disease caused by the 7 conjugate vaccine serotypes declined 55% (95% CI, -58% to -51%) from 22.4 to 10.2 cases/100,000. In contrast, disease caused by any of the 16 serotypes only in polysaccharide vaccine did not change, and disease caused by serotypes not in either vaccine increased somewhat, from 6.0 to 6.8 cases/100,000 (13%; 95% CI, 1% to 27%). Between 1998-1999 and 2002-2003, the proportion of case-patients with human immunodeficiency virus infection increased from 1.7% (47/2737) to 5.6% (124/2231) (P<.001), and those with any comorbid condition that is an indication for pneumococcal polysaccharide vaccination increased from 62.3% (1842/2955) to 72.0% (1721/2390) (P<.001).
CONCLUSIONS: Our findings indicate that use of conjugate vaccine in children has substantially benefited older adults. However, persons with certain comorbid conditions may benefit less than healthier persons from the indirect effects of the new vaccine.

9/3/05 re: Anti-Pneumovax antibody response

I have a 48 year-old male patient with an IgG of 453, IgM of 12, and normal IgA with recurrent sinusitis. He received Pneumovax 1 year ago and I checked his titers to 12 serotypes and has >12.5 level on serotypes 4, 8, 14, 19, 51 and all others are above 3. His serum albumin and protein are normal. How much of a response on Pneumovax does he need in order to label him as a non-responder? If he is a non-responder, what is his diagnosis? When should I repeat Pneumococcal titers?

Although the exact cut-offs for normal anti-Pneumovax responses do vary among labs, the antibody levels you described would all be considered normal (protective) by the lab we use. Therefore, your patient would not be considered a non-responder. However, you did not mention whether antibody responses to immunization with a protein antigen (e.g., diphtheria or tetanus toxoid) were assessed. If not, this should be done. If the patient has only recurrent sinusitis but no other evidence or recurrent infection, one should also have a careful evaluation for an underlying anatomic obstructive abnormality in the osteo-meatal area of the nasal cavities.

7/26/05 re: Natural killer cell deficiency

I would appreciate your thought on a 14 you female with a history of sinusitis and osteomylelitis and asthma. Lab tests revealed the following: WBC 5.8 ( (nl) Normal CD3+,CD4+,CD8+ lymphocytes. CD19+ cells (wnl) IgG( 774 mg/dl) A( 114 mg/dl), M ( 82 mg/dl) levels are WNL Natural Killer cells Surface Ag - Ab NK ( CD56) 66/ ul (low) normal range ( 70-1200) NK cells- 2.2 ( low) nl range( 6.0-27.00). Is there any current treatment for natural killer cell deficiency?

To help respond to your questions, I obtained input from Dr. Jordan Orange of the Children's Hospital of Philadelphia (CHOP), an expert in NK cell disorders (see his review of NK cell deficiency in Microbes Infect. 2002 ;4:1545-58). His response is enclosed below.

As you can see, Dr. Orange and I both feel that a diagnosis of NK cell deficiency is not established and likely not present here based on the information you provided. Typically, the types of infection most commonly associated with NK cell deficiency are by members of the herpesvirus group of viruses. If you still wish to explore a possible diagnosis of NK cell deficiency, you can request that an NK functional test be performed in one of the institutions listed by Dr. Orange. However, this requires shipment of a blood specimen in a way that NK cell function is not altered.

Dr. Orange's comments

I agree with your concern over the diagnosis of NK cell deficiency here.

Firstly, as you point out, this is not a typical clinical presentation for an NK cell defect.

Secondly, I would not consider the absolute count of 66 something to be concerned about.

If the physician is still concerned about this NK cell number, she can check the quality of the NK cells by requesting a functional NK cytotoxicity assay (test can be performed here at CHOP, at the University of Iowa, or at Cincinatti Children's).

To answer your question about enhancement of NK cell function, the best intervention would be IL-2 subcutaneous treatment. I do not, however, feel that that is in any way indicated in the case described here.

7/25/05 re: Evaluation for immune deficiency

I would appreciate your thoughts on a 4 year old male with a history of recurrent pneumonia, (four times within a 4 month period). This year and a previous admission last year for pneumonia. He also has asthma and is maintained on Advair. He was referred for evaluation of the immune system. His labs returned with a normal total IgG, M and A levels. Pneumococcal IgG, Diptheria and Tetanus IgG levels were also within normal limits. Tcell profile results were as follows: Absolute CD3+ 3864 (H) nl range (220-3000)% CD4+ 26(L) (28-52) Absolute CD4+ 1472 (nl) (670-1938)% CD8 37(H) ( 16-34) Absolut CD8+ 2096(H) (350-1150) Helper/Suppressor Ratio 0.07 (L) ( 1.00-3.00) Absolute Lymphocytes 5713 (nl) (2000-8000) Given the marginally decreased CD4 and marginally increased CD8 counts would you recommend any other further evaluation other than HIV testing?

The lab abnormalities described in your message do not sound impressive to me. If you wish to confirm that the minimal CD4+ cell abnormalities described are not indicative of a clinically relevant defect in cell-mediated immunity, I suggest that you carry out delayed hypersensitivity (DH0) skin testing using a panel of validated antigens (candida, tetanus, mumps, tuberculin). As noted in the abstract below, a recent study has shown an overall frequency of at least one positive DH response in 65-70% of all children tested.

Most of those with negative reactions to all antigens in such an "anergy panel" skin testing were very young children (< 2 years old). Therefore, one would expect at least one positive DH response in the majority of 4 year olds. Previous studies have shown that a lack of DH skin test reactivity. (anergy) correlates better with defective cell-mediated host defenses against infection that the very modest decrease in CD4+ cell levels described by you.

As an aside, I think that it is very important to determine whether the recurrent pneumonia episodes all involved the same area of lung in chest x-rays obtained at the time. If so, one should investigate whether there is some local anatomic condition pre-disposing to pneumonia, including aspirated foreign body. If the lung infiltrates involve grossly different regions of the lungs, check for blood eosinophilia (consideration of the pulmonary infiltrate with eosinophilia syndrome. One should also rule out cystic fibrosis or primary mucus dysmotility disorder. If the PPD (tuberculin) skin test is positive in a child who has not received the BCG vaccine, make sure that this is not an atypical presentation of childhood Tbc.

Ann Pharmacother. 2004 Jun;38(6):973-7. Epub 2004 Apr 14.
Pediatric case series evaluating a standardized Candida albicans skin test product.
Ohri LK, Manley JM, Chatterjee A, Cornish NE.
Department of Pharmacy Practice, School of Pharmacy and Allied Health Professions, Creighton University, 2500 California Plaza, Omaha, NE 68178-0117, USA. lohri@creighton.edu

BACKGROUND: A ready-to-use, standardized Candida albicans skin test product (Candin) first became available in 1995. As of April 6, 2004, no published reports have been found describing efficacy or safety with pediatric use of this reagent. OBJECTIVE: To present a case series describing experience with use of Candin to assess 78 pediatric cases for delayed-type hypersensitivity. METHODS: The standardized C. albicans reagent was one of up to 4 antigens used to evaluate patients' cellular immunity. Candin was used with purified protein derivative tuberculosis testing for 76 patients (4 mo-16 y of age) and for anergy testing alone in 2 cases. Candin was used with at least one other skin test reagent for 24 subjects. RESULTS: Fifty-three of 78 subjects (68%) responded to at least one skin test antigen. Candin had an overall response rate of 64% (50/78). There was a response to Candin in 54% (13/24) of subjects with multiple reagents applied, the highest rate of any antigen used. There was a 27% (3/11) positive Candin response for subjects <1 year of age; this compared with 21% and 23% in 2 published reports on use of nonstandardized tests for this age group. No adverse events were associated with use of Candin. CONCLUSIONS: Candin testing gives similar or better response rates compared with published data on older, nonstandardized C. albicans reagents and other anergy test antigens used in this case series. It should be used in combination with multiple other control antigens to most effectively assess for anergy, particularly in infants, as well as in patients recognized to be immune deficient.

6/9/05 re: IgM deficiency

I recently saw a 50 year old lady, who had required a spenectomy for unknown reason during childhood, with chronic sinusitis and in whom I discovered an absent IgM. Is there any relationship? Thanks.

I assume from your not mentioning it is that the serum IgG and IgA levels in this patient are normal.

Most, but not all, reports describe decreased serum IgM and usually normal IgG and IgA levels in splenectomized individuals, even when the previous splenectomy was for trauma to the spleen in presumably normal individuals (see enclosed abstracts). In some of these individuals there is a predilection to recurrent infections, particularly with S. pneumonia and H influenza.

There is a rare disorder called selective IgM deficiency characterized by an increased incidence of recurrent respiratory infections with polysaccharide-expressing bacteria (S. Pneum., H. Influenza) occasionally diarrhea and dermatitis and possibly autoimmunity.

Occasionally, IgM deficiency can occur in association with some lymphoid malignancies.

A question in this patient is whether there is some decreased protective immunity that may be responsible for the chronic/recurrent sinusitis. One can obtain helpful information by determination of antibody levels directed against a panel of pneumococcal antigens in sera obtained before and 3 weeks after a Pneumovax injection.

If there is decreased humoral immune function in the patient, unfortunately there is no definitive treatment of the underlying deficiency . I have not seen reports of any trials of Ig therapy (consisting of practically all IgG) in such IgM-deficient patients. I would imagine that one would want to use Ig obtained from normals with good serum levels of anti-pneumococcal antibodies. Prompt treatment of recurrent infections with an increased awareness of the potential for spreading infection (including septicemia) would be important.

Zentralbl Chir. 1997;122(10):909-13. Related Articles, Links
New arguments to explain the high infection rate in posttraumatic spleenless patients.
el Akkad H, Sass W, Colberg A, Knippert A, Seifert J.
Dept. of Surgery and Thoracic Surgery, University of Kiel.

To get more information about the high infection rate in splenectomized adult patients 211 spleenless patients were investigated with regard to clinical and laboratory data and compared to healthy blood donors. The results show that the infection rate is markedly increased to 30%. Splenectomized patients have decreased IgG levels which is due to diminished IgG1 and IgG4. Whereas IgA, complement factors C3, C4, and transferrin are not changed in patients without spleen, fibronectin and IgM are significantly reduced and the phagocytosis as well as the migration of neutrophilic granulocytes is impaired to 50%. With these changes in laboratory data it is possible to identify patients which bear an increased risk with regard to infection.

Ann Med. 1989 Aug;21(4):265-7. Related Articles, Links
Immunoglobulins and complement in splenectomised and autotransplanted subjects.
Ge Y, Gao H, Kong XT.
Department of Surgery, Chang Zheng Hospital, Second Military Medical College, Shanghai, China.

Serum immunoglobulins and complement factors were investigated retrospectively in 35 splenectomised (n = 28) and autoreplanted (n = 7) patients following trauma. The main deficiency of the immune system following splenectomy was a reduction in the concentrations of serum IgM, C3, and Factor B with normal IgG, IgA and C4 values. These changes were not correlated with the time elapsed after splenectomy. However, patients who had splenic tissue autoreplantation had normal values of immunoglobulins and complement factors compared with healthy controls. Splenic replantation may be able to stop a fall in immunoglobulin and complement factor values after splenectomy.

Fortschr Med. 1984 Mar 15;102(10):263-8. Related Articles, Links
[Behavior of immunoglobulins following traumatologically indicated splenectomy]
[Article in German]
Schneck HJ, von Hundelshausen B, Tempel G, Oberdorfer A, Rastetter J.

Blood levels of the immunoglobulins A, G and M were determined in a group of thirty patients, who had been splenectomized subsequent to splenal trauma, as part of a series of follow-up studies on polytrauma patients. These levels were compared with the corresponding values of an otherwise similar group of patients who had not been splenectomized. With few exceptions the majority of globulin levels in both groups were with the norm. The levels of IgG and IgA were significantly higher in the group of splenectomized patients, the IgM level was significantly lower than that of the comparison group of non-splenectomized patients. The medical history of the splenectomized patients showed no increase in susceptibility to infections and the average globulin levels were also well within the norm. Therefore, the clinical significance of these findings seems doubtful.

5/13/05 re: Diagnosis of common variable immunodeficiency

Patient is a 39 year old female with bronchiectasis. I saw her in consultation and ordered immunoglobulins. Her IgG is 419, IgA is 734, and IgM is 212. I repeated the results and they were similar. Would label her as common variable immunodeficiency?

The findings you describe are compatible with a diagnosis of common variable immunodeficiency disease (CVID). However, most experts in immunodeficiency disorders would require demonstration of significantly reduced antibody responses to immunization with protein and/or polysaccharide microbial antigens before making a diagnosis of CVID. If you have not done this in your practice, I suggest that you read the appropriate section of the Practice Parameters in Immunodeficiency dealing with diagnosis (this can be accessed online at the Joint Council website- www.jcaai.org then click on Practice Parameters).

In our clinic, the usual approach is to obtain a baseline serum specimen which is stored frozen in our clinic. The patient is then immunized with the diphtheria/tetanus booster vaccine and the Pneumovax. Three weeks later a second serum specimen is obtained. The two paired serum specimens (each labeled with patient name and date it was obtained) are then sent to a lab which can perform anti-diphtheria and anti-pneumococcus antibody assays. Your local clinical lab director should be able to arrange having these assays done for you.

3/9/05 re: Cause of high serum IgE and recurrent infections

Age : Patient is 5 years old male
Problem: High IGE level by heriditary
Symtoms: Excess Mucous, severe Cough, frequent colds and chest infections
History: Exezema at birth but disappreared after few months
History of parents: Father had similar problems, Mother has slight skin allerergic
Present Treatment: Singulair+Theophyline+ cortisone inhallation and antibiotics if needed.

Please give your expert opinion on the above case

You did not mention the exact serum IgE levels in your patient. If the serum IgE is moderately elevated (up to about 500 I.U) this is compatible with active atopic dermatitis (AD), also called infantile eczema. A high percentage of children with AD in infancy later manifest respiratory allergies and asthma. Thus the patient could have asthma, manifested mainly by a chronic/recurrent cough triggered by the usual viral infections (usually with the rhinovirus). One can investigate whether asthma is present by special pulmonary function tests used in 5 year old children. Referral to a pediatric pulmonary specialist and allergist for evaluation may be needed.

However, if the serum IgE is higher than 500, the possibility of the hyper-IgE (Job-Buckley) syndrome should be considered. This disorder is characterized by skin eruptions and immunodeficiency with recurrent infections and skeletal/dental abnormalities (J Pediatr 2004;144:93-9).

If the child is resident in an area endemic for certain types of parasitic infections, that must also be considered as a cause of a very high serum IgE.

2/16/05 re: Clinical significance of low levels of CD19+ cells

I have a 1 year old patient with h/o recurrent ear infections, diaper rash and 2 episodes of pneumonia. IgA, IgG, IgM are normal. She made a very good response to diphtheria, tetanus, Prevnar, and H. influenza. Hemisoagglutinis titers were good. Response to Candida skin test was good, read at pediatrician's office. She had low CD 19 cells on the Tand B cell enumeration panel. The absolute CD 19+ cells was 153 with normal being 600-2700 and CD19+ % was 3% with normal being 15-39. These were drawn only once. Is this of concern although she is making good functional antibody titers? What else needs to be looked at if patient continues to be sick?

After obtaining the additional information from you, I obtained input about the material you sent from Dr. Kathleen Sullivan of the Childrens' Hospital of Philadelphia, a Pediatric Immunologist with an extensive experience in immunodeficiency disorders. Her response is enclosed below. I would add that a repeat determination of the lymphocyte profile by flow cytometry in about 6-12 months may be worthwhile to see whether the low CD19+ cell level you described was not just a �one time� finding.

Dr. Sullivan's comments:

I would just follow her. It is true that the B cell numbers and percent are low for her age but because her antibody titers are normal I would just imagine her to be a normal variant. There is certainly no specific immunodeficiency states associated with low B cell numbers and normal antibody. There are rare reports of boys with XLA having pretty normal looking antibody levels but aberrant titers- in one case just to polysaccharide antigens. Since there are four autosomal recessive antibody disorders that can look like XLA, I would follow her to make sure she doesn't lose her antibody titers or levels over time and when able- immunize her to pneumovax (2 years of age). Overall, I would be very optimistic about the absence of a defined immunodeficiency.

1/5/05 re: Seborrheic keratosis

65 year old woman with 4 month history of multiple �disfiguring� seborrheic keratosis. Other than the appearance she claims they itch and burn slightly.

She has been fairly healthy except for Breast CA in 2002 now on Tamoxifen.

She has no history of infections and family history is remarkable for cancer.

The Dermatologist ask to R/o allergy and immunologic problems. The patient was desperate for help so immune work up was as follows.

C3 and C4 normal
IgG 628 (nl 694-1618) IgA and M normal, repeated 617
Sed rate �4
IgE <2

She had received a Pnuemococal vaccine. Past titers were pretty pitiful�only responding to Type 1 (3.7) and 19 3.8.

Lymphocyte panel showed a decrease in CD8 with absolute number of 137 and CD 19 with absolute number of 109. Functional studies have not been done. She has not had HIV testing.

Again she has NO HISTORY OF INFECTION

As you may know, seborrheic keratoses (SK) are usually benign skin epithelial tumors occurring predominantly in older patients. Occasionally, a lesion that looks superficially like SK may be"hiding" a more malignant process (see enclosed abstract). When SKerupt in crops, one should consider whether they are related to an infection with papillomavirus or HIV (see enclosed abstract). Another consideration in prominent "eruptive" SK is that they represent a sign of Leser-Trelat (L-T). The L-T sign is an unusual phenomenon thought by some investigators to be a marker for on-going malignancy, although this is debated (see enclosed abstracts). In most reported cases, the malignancy was in the G-I tract. However, malignancies in other organs have been reported occasionally. Therefore, the question arises whether the patient you described might be experiencing spread of her breast cancer. Stools should be checked for occult blood and colonoscopy considered. If there are upper G-I symptoms, investigation is warranted.

Your questions were about the significance of the slightly low serum IgG, and diminished antibody responses to the pneumococcal immunization in a woman without evidence of increased infections. The first thought that comes to my mind is whether there is a protein loss leading to lower serum levels of several proteins including IgG.

This can be investigated readily by checking the serum albumin since albumin is lost more readily than other serum proteins into the G-Tract or urine.

You asked whether the findings you described could be due to the patient's age. The most common effect of aging on the immune response is an inhibition of cell- mediated immunity (CMI). The status of the patient's CMI can be investigated with an "anergy" skin test panel. I have enclosed a section dealing with that subject from a chapter I wrote for the textbook " Middleton's Allergy". As noted, occasionally age-related defects in T cell function may lead to impaired responses to immunization. This may explain why pneumococcal immunization does not induce a protective antibody response in 100% of older individuals. However, such impairment is generally seen in individuals in the 70's or older. In any event, I think that the antibody findings are not likely related to her SK. I do not think that immunoglobulin therapy is indicated at this time

If the patient has had a prominent eruption of SK over a few months, I would concentrate initial investigative efforts on looking for an associated malignancy and checking for evidence of papillomavirus or HIV infection.

Dermatol Surg. 2004 Apr;30(4 Pt 1):559-61.
Melanoma within the seborrheic keratosis.
Thomas I, Kihiczak NI, Rothenberg J, Ahmed S, Schwartz RA. Dermatology, New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103-2714, USA.

Seborrheic keratoses (SKs) are common benign non melanocytic epidermal tumors with characteristic clinical features, which are thought to allow a straightforward diagnosis in most situations. As a result, it is an accepted practice to destroy them without histopathologic confirmation. However, systematic reviews of histologic specimens reveal an erroneous clinical diagnosis or associated malignant tumors in a number of cases, including malignant melanomas. We describe a patient with a clinically typical-appearing SK, which was biopsied and histologically proven to be a malignant melanoma arising in the SK. Our report is a reminder that the reliability of clinical diagnosis of SKs needs to be questioned. In addition, a biopsy of SKs is not only warranted but necessary in order to identify a malignant melanoma that would otherwise be misdiagnosed or even completely missed

J Am Acad Dermatol. 1996 Jul;35(1):88-95.Related Articles, Links
Sign of Leser-Trelat.
Schwartz RA.
New Jersey Medical School, Newark 07103-2714, USA.

The sign of Leser-Trelat is rare. It is defined as the suddeneruption of multiple seborrheic keratoses caused by a malignancy. Because both seborrheic keratoses and cancer are common in the elderly, it is not always easy to tell from the literature or in any given patient if this sign is present. In fact, its validity has been questioned. Its association with malignant acanthosis nigricans is one of several of its features that support its legitimacy as a trueparaneoplastic disorder.

J Am Acad Dermatol. 2000 Aug;43(2 Pt 2):386-90. Related Articles, Links
The sign of Leser-Trelat in a case of adenocarcinoma of the lung.
Heaphy MR Jr, Millns JL, Schroeter AL.
Department of Dermatology, Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA.

This is what we believe to be the first report of the sign of Leser-Trelat in association with occult adenocarcinoma of the lung. The sign of Leser-Trelat is proposed as a sign of possible occult malignancy, despite various suggestions to the contrary. Also, it is suggested that a tumor-produced humoral factor (eg, transforming growth factor-alpha [TGF-alpha]) could be responsible for both theacute eruption of the monomorphous seborrheic keratoses and the nearly concomitant development of acanthosis nigricans, which occurred in our case. The possible distinction between a hyperplastic and a neoplastic origin of various types of seborrheic keratosis is discussed in relation to this hypothetical humoral factor. In addition, we suggest a refinement of the definition of the sign of Leser-Trelat and discuss the use of "sign of Leser-Trelat" and "syndrome of Leser-Trelat" in relation to physical findings. All patients with the sign of Leser-Trelat should undergo a thorough evaluation for occult malignancy.

Excerpt from chapter in textbook "Middleton's Allergy"

Most studies report decreased CMI during the aging process with some discrepant findings, likely reflecting heterogeneous patient populations, nutritional factors and assessment methods (142,143). Also, populations surviving to 80 years or older may be selected for individuals with more long-lasting immune responsiveness. With these caveats in mind, aging is associated with: a) normal or decreased DTH recall skin test reactivity in different studies (143); b) decreased immature (CD2+ / CD3-) and naive T cells with a relatively increased frequency of memory T cells, likely associated with progressive thymic involution (142,143); These findings may explain impaired CMI responses to newly encountered antigens (e.g. DNCB) while recall DTH responsiveness is retained; c) decreased in vitro T cell responses to antigens and mitogens. Most studies show alterations in the ratio of functional T cell subsets and decreased IL- 2 production (142); d) immunoregulatory disturbances suggested by increased incidence of non-organ specific auto antibodies and decreased T cell responses to immunization with some antigens (144). In some studies, depressed CMI in elderly individuals is due mainly to dietary nutritional deficiencies, particularly protein-energy and micronutrient deficiencies (143). The relation of these findings to the increased incidence of infections, cancer, and autoimmunity in the elderly is still not well defined.

J Dermatol Sci. 2003 Apr;31(2):143-9. Related Articles, Links
Detection and sequences of human papillomavirus DNA in non genital seborrhoeic keratosis of immunopotent individuals.
Gushi A, Kanekura T, Kanzaki T, Eizuru Y.
Faculty of Medicine, Department of Dermatology, Kagoshima University, 8-35-1, Sakuragaoka, 890-8520, Kagoshima, Japan. akiyo@m2.kufm.kagoshima-u.ac.jp

BACKGROUND: The etiology of seborrhoeic keratosis (SK) is unknown. Its clinical and histopathological similarities to verrucae vulgaris and condyloma acuminatum prompted us to examine whether human papillomavirus (HPV) is present in SK lesions. In the present study, HPVs were frequently detected from genital lesions or hair follicle in immunocompromised host. OBJECTIVE: We analyzed 104 nongenital SK specimens diagnosed by clinical and histopathological examinations for HPV DNA in immunopotent individuals.
METHOD: We analyzed SK specimens for HPV DNA using in situ hybridization (ISH), polymerase chain reaction (PCR), Southern blot hybridization, and sequencing ofviral DNA of PCR-amplified fragments. And we also examined virion, which is the capsid protein of HPV in ISH-positive specimens by immunochemical examination. We identified eight mucosal and two cutaneous type HPVs. RESULT: ISH revealed that 30 of 104 (28.8%) SK samples contained HPV DNA. All ISH-positive specimens were demonstrated virion in the nuclei of the epidermal keratinocytes. PCR analysis showed that 87 (83.7%) samples contained HPV-18, 81 (77.9%) HPV-6, and 73 (70.2%) contained both HPV-18 and -6. The incidence of HPV-1 (7.7%) and HPV-2 (14.4%) was relatively low. All 20 normal controls were negative for HPV DNA by ISH but seven were positive by PCR sequencing.
CONCLUSION: Our results suggest that HPV, possibly coinfection with HPV-6 and -18 and unknown type(s) of HPV, plays an important role in the pathogenesis of SK

1/4/05 re: Diagnosis & immunotherapy in Hyper-IgE syndrome

a) Is Immunotherapy contraindicated in Job syndrome? b) How to diagnose a Job syndrome in adults? Especially in a country where only plasma level of IgE can be detected not antigen-specific IgE.

The hyper IgE syndrome (HIES) is characterized by not only very high serum total IgE levels (generally much higher than seen in typical respiratory allergies) but also an eczematous rash, evidence of pronounced and recurrent Staph infections of the skin with abscesses and some times staph infections in other organs as well. Pneumatoceles are also found commonly as are certain skeletal abnormalities. Some groups have described very high levels of IgE anti-Staph antibodies in the HIES patients. However, there is no one test that makes the diagnosis of HIES. One must also consider other disorders that have at least some of the same manifestations. This is particularly true of pronounced atopic dermatitis with secondary Staph infection of involved skin areas and associated very high serum IgE levels. However, the multiple skin abscesses, secondary skin scarring and pneumatoceles found commonly in the HIES would be very uncommon in the usual case of atopic dermatitis (see enclosed abstract).

I know of no reports of the usual of traditional allergy immunotherapy (AIT) in patients with the HIES. Of note, there does not appear to be a marked increase in the frequency of the usual allergic respiratory disorders in HIES patients, despite the very high serum IgE levels. However, such allergies could certainly occur independently. I would be reluctant to use traditional AIT in someone with the HIES for these reasons:1) the stimulus for IgE production in the HIES is not well- defined; 2) AIT in the usual atopic (without the HIES) by the usual injection methods is frequently followed by a transient increase in the level of specific IgE antibodies. This increase appears to be counter-balanced by a greater increase in the levels of specific IgG (possibly protective) antibodies. However, we do not know whether this balance would occur in someone with the HIES. Therefore, there is a potential for stimulation of a marked increase in IgE production One might consider treatment with a monoclonal ant-IgE antibody such as omalizumab. However, such therapy would be very expensive and likely not very effectual in a HIES patient with very high serum IgE levels.

1: Arch Dermatol. 2004 Sep;140(9):1119-25.
Dermatitis and the newborn rash of hyper-IgE syndrome.
Eberting CL, Davis J, Puck JM, Holland SM, Turner ML.
Dermatology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-1908, USA. ebertinc@mail.nih.gov

OBJECTIVE: To characterize the dermatitis, the newborn rash, and cutaneous findings in hyper-IgE syndrome, also known as Job's syndrome. DESIGN: Prospective and retrospective evaluation and treatment of cutaneous manifestations in patients with a clinical diagnosis of hyper-IgE syndrome (HIES). Analysis of the newborn rash encountered in this population. SETTING: Dermatology clinic at the National Institutes of Health, Bethesda , Md. PATIENTS: Forty-three patients seen in our clinic between January 1998 and August 2003 who had a clinical diagnosis of HIES.
INTERVENTIONS: The UK Working Party's Diagnostic Criteria for Atopic Dermatitis were used to assess for atopic dermatitis in this population. To assess the newborn rash, we performed a retrospective chart review and an in-person or telephone interview of the parent or caregiver of each patient. RESULTS: Twenty-eight (65%) of 43 patients fulfilled the criteria for atopic dermatitis. Thirty-five (81%) of 43 patients reported a newborn rash. Eight (19%) of 43 were born with the rash; 23 (53%) of 43 had acquired the rash within 7 days; 32 (74%) of 43 within 14 days; 34 (79%) of 43 within 30 days; and 35 (81%) of 43 had the rash within 35 days of birth. CONCLUSIONS: The dermatitis in HIES resembles classic atopic dermatitis but may have distinctive features. A newborn rash is almost always a presenting sign of HIES. After the newborn period, skin findings include retroauricular fissures, external otitis, infected dermatitis of the axillae and groin, folliculitis of the upper back and shoulders, cutaneous abscesses, mucocutaneous candidiasis, and in some patients pitted scarring of the face.

12/13/04 re: Inactivated vaccine in immunodeficient patients

I would like to know if there are any specific guidelines with regard to immune deficient pts (XLA, CVID pts) receiving their regular childhood immunizations. We routinely advise our pts not to receive any live viral vaccines MMR, Varicella, Flumist) but there are differing opinions with regards to the other vaccines. All these pts receive IVIG.

Tp help respond to your question, I obtained input from Dr. Kathleen Sullivan of the Children's Hospital of Philadelphia. Dr. Sullivan is an outstanding Pediatric Immunologist with an extensive experience treating immunodeficient patients. Her response is enclosed below.

Dr. Sullivan's response

Patients on IVIG typically can't make antibody responses to immunizations and usually don't need them because they are fully protected by the "herd" antibodies in the pooled IVIG preparation they receive regularly. The one exception to this general policy of not giving inactivated vaccines to these patients is influenza immunization for which there is no consensus. Some experts believe that the T cell response to the influenza vaccine can be helpful in inducing protective immunity while others feel there are no findings to support that stance; therefore, why waste the influenza vaccine?

11/19/04 re: Recurrent vaginitis in IgA deficient child

I saw a 4 yrs old girl with Serum IGA def (mom also has IGA def) ,with the history of recurrent colds, sinusitis and this year 2 episodes of Vaginitis-first one caused by pseudomonas and cleared with antibiotics, second one culture grew H.Flu and responding to Augmentin. What are your thoughts? What kind of work- up does she need? She otherwise is healthy. Selected prick-skin tests were negative.

I have obtained input to help respond to your question from Dr. Kathleen Sullivan, an expert Clinical Immunologist in the Children's Hospital of Philadelphia. Her comments are enclosed below. If looking for more extensive immunodeficiency than selective IgA defic, further evaluation for functional IgG antibody responses to immunization, including H flu, should be obtained as well as assessment of cell-mediated immunity capacity.

Dr. Sullivan's comments

For a four year old with IgA def, there should really not be vaginitis with weird organisms. If she is recently toilet trained, I would wonder about poor toileting hygeine. If that isn't a factor, I would wonder if there is more to her immunodefficiency.

11/19/04 re: Neutropenia with monocytosis

I have a 1 yr old boy absolutely healthy, no family history of auto-immunity is found to have moderate neutropenia, monocytosis.What do I do as an allergist?

I have obtained input to help respond to your question from Dr. Kathleen Sullivan, an expert Clinical Immunologist in the Children's Hospital of Philadelphia. Her comments are enclosed below. Cyclic neutropenia, one of the disorders she mentioned, generally presents with varying neutrophil counts (episodic neutropenia) and with episodes of pharyngitis with associated complications. Unless there is evidence of a drug allergic reaction that might cause neutropenia, I cannot think of any approach by an allergist that will likely turn up clinically important information. As Dr. Sullivan intimated, better to first have an evaluation by a pediatric hematologist

Dr. Sullivan's comments

Generally if you see neutropenia with monocytosis, there is a problem. This is the case for some malignancies, for congenital neutropenia and for cyclic neutropenia. I would vote for a trip to hematology.

10/27/04 re: Possible immunodeficiency in an infant

I follow a 2 year old black male patient with Allergic rhinitis, Asthma, a history of Otitis media and food allergies who is adopted. His parents requested an immune evaluation. He had not had pneumonia sepsis or meningitis etc.

On 3/03 his serum IgA level returned 9 mg/dl with an IgG of 572 which is within normal limits. On 4/04 the IgA level returned at 30 mg/dl with an IgG of 789 mg/dl. His T/B cell profile revealed some interesting results

His CD19 was low at 2% (range 6-23%) and the Absolute CD19 was low at 25u/L (62-540). His CD8+ CD3 ABS was normal (900u/L- range 171-914u/L as was his Absolute CD3 count (1051 (782-2204. His CD8+CD3 % was High at 73% (13-40) His CD16CD56 % and Absolute CD16CD56 counts were within normal limits.

His CD4+CD3 count was low 14% (31-58) as was his Absolute CD4+CD3 count (170 (443-1345)u/L. His CD4CD45 RO % and absolute counts were normal. However CD4CD45 RA count was low 2% (9-37%) as well the absolute CD4 CD45 RA count was low 32u/L with the normal range being 117 to 816u/L. His CD4CD8 ratio was low at 0.19 (0.80 to3.50). Given these laboratory findings what suggestions would you make for further evaluation. What diagnostic considerations should be made in view of these findings?

To help respond to your question, I consulted Dr. Kathleen Sullivan of the Children's Hospital of Philadelphia, an expert in childhood immunodeficiency disorders. Her response is enclosed below. In addition, I would also add these suggestions:

1) Check for the child's HIV status, particularly if little is known about the medical status of the biologic mother of this adopted child.

2) Check the serum albumin to make sure no leakage of plasma components and CD4+ cells into the G-I tract (in some forms of protein-losing enteropathy

3) Check by flow cytometry for expression of Dr epitopes of the MHC-II histocompatibility complex if not already done. As noted by Dr. Sullivan below, absence of Dr expression strongly suggests a bare lymphocyte syndrome

4) Check anti-diphtheria and/or anti-tetanus antibody levels 3 weeks after the child receives a D/T booster immunization

5) Check for expression of cell-mediated immunity by performing anergy panel delayed hypersens skin tests, inclidon a standardized candida reagent (see enclosed abstracts)

Dr. Sullivan's comments:

Although his B cell percents are low, he makes antibody making XLA less likely but not impossible. To rule out a significant B cell problem I would check diphtheria and tetanus titers and if normal, I would turn my attention to the T cells which are more clearly abnormal. The combination of low T cells with a particular decrement in CD4 T cells could be due to any of a number of things. With everything else looking so good, I would give a thought to bare lymphocyte syndrome II in which MHC class II is not expressed and selection for CD4 cells in impaired the immunodeficiency is variable. Often mitogen responses are normal but proliferative responses to specific antigens are low. Measuring DR expression by flow cytometry is diagnostic. Idiopathic CD4 penia is a consideration. Mitogen and antigen proliferative responses may be helpful in that setting as well. Also, if these were done while acutely ill, consider repeating the T cell studies.

J Pediatr. 1996 Aug;129(2):245-50.
Delayed-type hypersensitivity skin testing in human immunodeficiency virus-infected pediatric patients.
Raszka WV, Moriarty RA, Ottolini MG, Waecker NJ, Ascher DP, Cieslak TJ, Fischer GW, Robb ML.
Department of Pediatrics, Uniformed Services University of Health Sciences, Bethesda, Maryland, USA.

Objective: To evaluate whether pediatric patients infected with human immunodeficiency virus (HIV) can mount appropriate delayed-type hypersensitivity (DTH) skin responses to recall antigens and whether these responses can be correlated with clinical or immunologic parameters.

Design: Prospective evaluation of DTH responses in HIV-infected children. Uninfected children born to HIV-infected mothers served as control subjects. Antigens used for yearly DTH testing included Candida albicans (1:100, 1:10); mumps virus; Trichophyton; purified protein derivative of tuberculin; and tetanus toxoid (1:100, 1:10)

Ann Pharmacother. 2004 Jun;38(6):973-7.
Pediatric case series evaluating a standardized Candida albicans skin test product.
Ohri LK, Manley JM, Chatterjee A, Cornish NE.
Department of Pharmacy Practice, School of Pharmacy and Allied Health Professions, Creighton University, 2500 California Plaza, Omaha, NE 68178-0117, USA.

Background: A ready-to-use, standardized Candida albicans skin test product (Candin) first became available in 1995. As of April 6, 2004, no published reports have been found describing efficacy or safety with pediatric use of this reagent.

Objective: To present a case series describing experience with use of Candin to assess 78 pediatric cases for delayed-type hypersensitivity.

Methods: The standardized C. albicans reagent was one of up to 4 antigens used to evaluate patients' cellular immunity. Candin was used with purified protein derivative tuberculosis testing for 76 patients (4 mo-16 y of age) and for anergy testing alone in 2 cases. Candin was used with at least one other skin test reagent for 24 subjects.

Results: Fifty-three of 78 subjects (68%) responded to at least one skin test antigen. Candin had an overall response rate of 64% (50/78). There was a response to Candin in 54% (13/24) of subjects with multiple reagents applied, the highest rate of any antigen used. There was a 27% (3/11) positive Candin response for subjects <1 year of age; this compared with 21% and 23% in 2 published reports on use of nonstandardized tests for this age group. No adverse events were associated with use of Candin.

Conclusions: Candin testing gives similar or better response rates compared with published data on older, nonstandardized C. albicans reagents and other anergy test antigens used in this case series. It should be used in combination with multiple other control antigens to most effectively assess for anergy, particularly in infants, as well as in patients recognized to be immune deficiency

2/10/04 re: Treatment of CVID during pregnancy

We look after patients with antibody deficiency and have recently been referred a pregnant lady with CVID. We do not have that much clinical experience with pregnant patients, as usually our patients present having already had their children. Do any of the immunologists have a protocol on how to manage pregnant ladies with CVID and ongoing monitoring of their immunoglobulin levels?

To help respond to your questions, I consulted my colleague, Dr. Arnold Levinson, director of a large Adult Immunodeficiency Clinic and someone with extensive experience with CVID. His response is enclosed below. I have also enclosed below for your interest abstracts of two of the limited reports about CVID in pregnancy which I found in a Medline search.
______________________________________________

Dr. Levinson's response:

We increase their IVIG dose in concern with their weight. My limited experience is that in addition to increased volume of distribution, I think there is increased catabolism and shortened half-life. So, don't be surprised if higher mg/kg (adjusted for weight) do not provide the desired trough levels. Particularly important considerations during last trimester when sufficient passive immunity needed to protect mom and fetus.
______________________________________________

J Clin Immunol. 2001 Mar;21(2):150-4.
Rapid subcutaneous IgG replacement therapy at home for pregnant immunodeficient women.
Gardulf A, Andersson E, Lindqvist M, Hansen S, Gustafson R.
Department of Immunology, Microbiology and Pathology, Karolinska Institutet at Huddinge University Hospital, Stockholm, Sweden.

The use of slow or rapid, subcutaneous, IgG (SCIG) infusions in pregnant women with primary antibody deficiencies has been described earlier, though only in single-case reports. In this study, we have evaluated the effect of rapid, SCIG infusions during 11 pregnancies in nine women [six women with common variable immunodeficiency (CVID), two with IgG-subclass deficiencies, and one with combined IgA and IgG2 deficiency]. The weekly infusions were given by the women themselves at a dose of 100 mg/kg/week throughout the pregnancy. No adverse systemic reactions or pronounced, local tissue reactions were recorded during or after the more than 400 infusions. The 11 babies were healthy and were born after 38-42 weeks of uneventful gestation. The concentrations of maternal S-IgG at the time of delivery in the four women with CVID ranged from 6.0 to 8.3 g/L, with cord/maternal S-IgG ratios of 1.0-1.5. The IgG subclasses were transferred to the infants. The SCIG home-therapy regime was greatly appreciated by the women.
____________________________________________

J Perinatol. 1994 Mar-Apr;14(2):114-7.
Intravenous gamma globulin administration to common variable immunodeficient women during pregnancy: case report and review of the literature.
Schaffer FM, Newton JA. Department of Pediatrics, State University of New York at Buffalo 14222.

Women with common variable immunodeficiency have decreased serum concentrations of all immunoglobulin isotypes. Their offspring are at a high risk for the development of neonatal infection caused by the minimal quantity of maternal immunoglobulin G (IgG) transplacentally transported during pregnancy. These patients are usually given frequent doses of exogenous IgG during the third trimester to increase the amount of IgG transported to the fetus. In this article, we describe the results of initiating a therapeutic regimen of high doses (400 mg/kg) of intravenous gamma globulin every 3 weeks starting in the first trimester of pregnancy for a woman with common variable immunodeficiency. In contrast to most reports, this regimen enables the patient to attain high.

1/22/04 re: Diagnosis/ adult with PCP

A 44 yo man who had PCP. HIV - neg. No history of pneumonia, skin infections, UTI's, sinusitis, otitis in the past. Labs: HIV PCR - neg, WBC = 4.4 ( 54% segs, 13% lymphs, 13% monos, 20% eos). IgG = 1420, IgA = 255, IgM = 77.7, IgE = 109. CD3 absol = 321, 46%, CD3&4 absol = 219 31%, CD3&8 absol = 118 17%, CD19 absol = 102 14%. NK cells = 142 20%. Lymphocyte responses to PHA, ConA, and PWM were normal. Lymphocytes responses to Candida were normal. Lymphocyte responses to Tetanus were absent. How would he be classified? Is other testing needed?

The picture you described sounds somewhat atypical. However, the degree of CD4 lymphopenia listed, if persistent, suggests the possible diagnosis of Idiopathic CD4 Lymphopenia if no extrinsic causes of such lymphopenia are found (see enclosed abstract). PCP infection has been reported as a complication of this disorder (see enclosed abstract). To help respond to your questions, I consulted Dr. William Shearer of the Texas Children�s Hospital/Baylor Med Center. As you may know, Dr. Shearer is an internationally-recognized expert in immunodeficiency disorders. He chaired a Task Force that drew up practice parameters in immunodeficiency disorders. Dr Shearer�s response is enclosed just below.

In response to your question, the first study I would do is an anergy skin test panel. A number of studies have shown that anergy detected by such skin testing correlates better than findings in in vitro studies with a state of depressed cell-mediated immunity that could be responsible for unexplained PCP infection. You may wish to find out more information in this area contained in my chapter "Cell-Mediated Immunity" in the latest (recently released) edition of the "Middleton's Allergy" textbook

Dr. Shearer�s comments

Presuming that there is no obvious source for this patient's lymphocytopenia (immunosuppressive drugs, alcohol abuse, viral illness, etc), the patient could qualify for that diagnosis. At the moment the low CD4 cells counts (219) are a reflection of the low abolute lymphocyte count (572 vs 1400-3300 control range). The percent CD4 lymphocytes is normal (31% vs 31-52% control range). The abolute WBC is normal (4400 vs 4400-3100).

Clin Infect Dis. 2000 Oct; 31(4): E20-2.
Progressive multifocal leukoencephalopathy and idiopathic CD4+lymphocytopenia: a case report and review of reported cases.
Haider S, Nafziger D, Gutierrez JA, Brar I, Mateo N, Fogle J.
Division of Infectious Diseases, Henry Ford Hospital, Detroit, MI 48202,
USA.

Progressive multifocal leukoencephalopathy (PML) is a well recognized demyelinating neurological disorder caused by JC virus. Idiopathic CD4(+) lymphocytopenia (ICL) is a syndrome first described by the Centers for Disease Control and Prevention as a CD4(+) count <300 cells/mm(3) or a CD4(+) count that is <20% of the total T cell count on 2 occasions, with no evidence of human immunodeficiency virus (HIV) infection on testing, and absence of any defined immunodeficiency or therapy that depresses the levels of CD4(+) T cells. To the best of our knowledge, this is the third reported case of PML and ICL, and also the first reported case of the use of cidofovir to treat PML in a patient not infected with human immunodeficiency virus.

1: Intern Med. 1998 Oct; 37(10): 891-5.
Two cases of idiopathic CD4+ T-lymphocytopenia in elderly patients.
Matsuyama W, Tsurukawa T, Iwami F, Wakimoto J, Mizoguchi A, Kawabata M, Osame M.
Department of Respiratory Medicine, National Minami-kyushu Hospital, Kagoshima.

We present 2 cases of idiopathic CD4+ T-lymphocytopenia (ICL) in elderly patients. Case 1, a 73-year-old man, with pneumonia had received several antibiotics with unsuccessful results at another hospital. On admission, his CD4+ T-lymphocyte count was 109/microl and Pneumocystis carinii was detected by bronchoalveolar lavage fluid staining. No evidence of human immunodeficiency virus (HIV) infection was found. Despite therapy, the patient died of respiratory failure. Case 2, a 72-year-old man, contracted severe pneumonia, and Hemophillus influenzae was believed to be the pathogen. On admission, his CD4+ T-lymphocyte count was 238/microl. No evidence of HIV infection was found. He received antibiotics and improved successfully. We suggest that ICL may currently be incubating in a number of elderly pneumonia patients.

5/13/03 re: Measurement of anti-pneumococcal antibody responses

Is there a standard for interpretation of pneumococcal pre and post titers? In a 21 year old woman with frequent infections (bronchitis, OM, sinusitis, pharyngitis) and titers of:

type 1 pre - 2.1 post > 12.5

type 3 2.8 4.6

type 4 2.6 > 12.5

type 6 2.0 6.8

type 8 2.2 >12.5

type 9N 1.4 2.3

type 12 1.9 2.3

type 14 5.0 6.2

type 19F 2.7 8.8

type 23F 2.5 > 12.5

type 51 (7F) 4.3 > 12.5

type 56 4.4 > 12.5

Is the response normal?
Tetanus and diphtheria titers were normal.

Your question deals with an area of some uncertainty. Although almost all experts in immunodeficiency disorders recommend evaluating the serum antibody response to the polysaccharide antigens in the pneumococcal vaccine as part of an evaluation for possible humoral immunodeficiency, there are significant differences in the exact way that such responses are measured and interpreted in different labs.

For example:

1) The standard pneumococcal vaccine used in the USA (Pneumovax) currently contains polysaccharides of 23 strains of S. pneumoniae. However, some labs analyze antibody responses to as few as 4 strains of S. pneumoniae. It appears that the lab whose findings you sent us analyzes responses to 12 strains. As pointed out in the Practice Parameters on Immunodeficiency (See these parameters in the JCAAI website- (www.jcaai.org)

" Not all pneumococcal antigens are equally immunogenic and normal patients may not respond to all pneumococcal vaccine antigens. Considerable care is therefore necessary in selecting patients for intravenous immunoglobulin replacement therapy based on lack of antibody responses to pneumococcal antigens."

2) The method of measuring and expressing antibody responses varies among labs. Most labs use an ELISA, as I assume that was done in your patient. Most labs now express the antibody level in mcg/mL of antibody IgG, an absolute number rather than the traditional titer which is generally expressed as a ratio (see enclosed abstracts). Most labs interpret an antibody IgG level of at least 1.0-1.3 mcg/mL 3 weeks after immunization as evidence of production of protective anti-Pneumo Ab levels. In labs that express findings using the older antibody titer ratio, at least a 4 fold increase in titer is considered normal (e.g- 1/2 before, 1/8 titer after immunization).- see enclosed abstract). Occasionally, groups report levels using arbitrary unitages (see enclosed abstract)

However, other investigators claim that an opsonophagocytic assay more accurately reflects the level of protective antibodies against S. pneumoniae infection (see enclosed abstract)

3) The age of the patient may affect antibody responses even when there is no evidence of immunodeficiency. The pneumococcal vaccine is not recommended for children under 2 years of age because normal children do not respond to the pneumococcal antigen at this age. Individuals 80+ years in age may well have decreased antibody responses even without clinical evidence of decreased host defenses against infection.

My "bottom line" impression is that the antibodies levels described in your message are compatible with a normal immune response.
________________________________________________________
J Infect Dis 1996 Feb;173(2):387-93
Antibody response to pneumococcal capsular polysaccharide vaccine in the elderly.
Sankilampi U, Honkanen PO, Bloigu A, Herva E, Leinonen M.
National Public Health Institute, Department in Oulu, Finland.

Antibody response to 23-valent pneumococcal vaccine was assessed in 350 subjects (131 men, 219 women) aged 65-91 years. IgG antibodies to pneumococcal serotypes 4, 6B, 9V, 14, 19F, and 23F were measured by EIA after blocking of antibodies to cell wall polysaccharide. Antibody concentrations in both pre- and postvaccination sera (mean interval, 35 days) were higher in elderly men than women; in the women, the concentrations decreased significantly with increasing age, but not in the men. Antibody fold increases were good in the elderly, including those > or = 85 years old. The overall percentage of the elderly with antibody concentrations > 1 microgram/mL to the 6 antigens increased by vaccination from 61% to 87%, but in the women > or = 85 years old, only to 75%. Antibody response to 23-valent pneumococcal vaccine was satisfactory in the elderly.

Clin Diagn Lab Immunol 1997 Mar;4(2):168-72
Characterization of specific immunoglobulin G (IgG) and its subclasses (IgG1 and IgG2) against the 23-valent pneumococcal vaccine in a healthy adult population: proposal for response criteria.
Rodrigo MJ, Miravitlles M, Cruz MJ, de Gracia J, Vendrell M, Pascual C, Morell F.
Department of Biochemistry (Immunology Unit), Hospital General Vall d'Hebron, Barcelona, Spain.

The aim of the study was to standardize an enzyme-linked immunosorbent assay (ELISA) method for the quantification of immunoglobulin G (IgG) and its subclasses (IgG1 and IgG2) against the 23-valent pneumococcal vaccine and to establish the criteria for a normal response to the vaccine. Forty healthy individuals (20 women and 20 men; mean age, 29 years) were studied. All were vaccinated with the 23-valent pneumococcal vaccine; blood samples were drawn just prior to and 3 weeks after immunization. Quantification of specific IgG and its subclasses was performed by an ELISA with the vaccine as the antigen. The linearity of the ELISA method was demonstrated by the similar slopes of the linear regression lines generated from the titration of sera with different antibody concentrations. The specificity of the antibodies against the vaccine was demonstrated by (i) an absorption test with pneumococcal vaccine, (ii) a cross-reactivity experiment with Haemophilus influenzae type b polysaccharide, and (iii) affinity chromatography with protein A-Sepharose. Response to the vaccine was defined by using the lower level of the 90% probability interval (one-tailed) for postimmunization-specific IgG, IgG1, and IgG2. By using this cutoff, responders were considered to be those with an absolute increase in antibody titers higher than 395 arbitrary units/ml for IgG, 0.350 A450 units for IgG1, and 0.314 A450 units for IgG2. Overall, 20 (50%) subjects had IgG, IgG1, and IgG2 responses, 9 (22.5%) had IgG and IgG2 responses, 4 (10%) had IgG1 responses, 3 (7.5%) had IgG and IgG1 responses, and 4 (10%) were nonresponders. Ninety percent of our population responded to the 23-valent pneumococcal vaccine. Up to 10% of healthy individuals may respond to an IgG subclass without significant increases in total IgG titers. The ELISA method that is described may be useful for evaluating the specific antibody response against polysaccharides
________________________________________________

J Allergy Clin Immunol 1998 Aug;102(2):215-21
Influence of age on the response to Streptococcus pneumoniae vaccine in patients with recurrent infections and normal immunoglobulin concentrations.
Sorensen RU, Leiva LE, Javier FC 3rd, Sacerdote DM, Bradford N, Butler B, Giangrosso PA, Moore C.
Department of Pediatrics, Louisiana State University Medical Center, New Orleans 70112-2822, USA.

BACKGROUND: A deficient antibody response to polysaccharide antigens is determined by measuring the response to the 23-valent pneumococcal polysaccharide vaccine. However, the diagnosis of this specific antibody deficiency is hampered by the lack of sufficient data and standardized testing of the response to pneumococcal polysaccharides. METHODS: All patients evaluated in our allergy/immunology clinic for recurrent respiratory infections between 1995 and 1997 without immunoglobulin, IgG subclass, or other known primary or secondary immunodeficiency were included in this analysis. IgG antipneumococcal serotypes 1, 3, 4, 6B, 9V, 14, 18C, 19F, and 23F were determined by a modified ELISA protocol. An adequate IgG antibody response to an individual serotype was arbitrarily defined as a postimmunization antibody titer of 1.3 microg/ml or greater or at least four times the baseline value. RESULTS: A total of 113 patients fulfilling the criteria for inclusion in this analysis were divided into five age groups. The geometric means for preimmunization and postimmunization pneumococcal antibody titers for all serotypes increased with age. For post-immunization antibody concentrations, there was a sharp increase in the specific antibody concentrations in adults in comparison with all pediatric age groups ranging in age from 7 months to 16 years. Similarly, the number of serotypes to which there was an adequate response also increased with age. CONCLUSION: We conclude that the definition of what constitutes an adequate response to pneumococcal immunization needs further definition. It is clear, however, that age has an important influence on the intensity of the response to most pneumococcal polysaccharides. Correlation studies between antibody concentrations in different IgG subclasses, functional studies, and protection studies against mucosal and invasive pneumococcal infections are in progress, and these should contribute to a refined definition of a normal response. The availability of a standardized method for the measurement of IgG antibodies against relevant pneumococcal serotypes is an important step toward this goal.

11/20/02 re: Iv Ig therapy indicated?

This is a 13 year old boy with a history of upper recurrent respiratory tract infection. He has never been hospitalized, no history of pneumonia or bronchitis, no ear infection, but has 4 episodes of sinus infection in the last four years. At this moment, he is in immunotherapy for grass, weeds and trees. Bronchospasm is present with U.R.T. infection and has seasonal allergy exacerbations. He never has any problems with the skin. But he has been treated three times for parasites.
IgE 1540
IgG 1080
IgG1 671 NL
IgG 237 NL IgG3 10 BELOW NL IgG4 11 NL
IGM 34 ( NL 80-280 )
IgA 183

We don�t have titers for specific antigens polysacaride respond. Will you consider this patient for IVIG?

I assume that you are questioning whether the somewhat low serum level of IgG3 in your patient is evidence of a humoral immunodeficiency that warrants IV Ig replacement therapy. Most experts in immunodeficiency disorders such as Dr. Rebecca Buckley feel that the measurement of IgG subclasses levels is not a reliable assessment of immunodeficiency and that assessment of antibody responses to a protein antigen (e.g., diphtheria or tetanus toxoid) and polysaccharide antigen (e.g., pneumococcal vaccine) are required to determine whether a humoral immunodeficiency is present (see enclosed abstract). There is little evidence that modestly decreased serum IgM levels as an isolated finding are associated with a particular clinical immunodeficiency state. In any event, as you likely know, there is little if any IgM present in the commercial Ig preparations used clinically. Therefore, I would not recommend IV Ig therapy unless there is evidence of deficient antibody production in response to an immunization. Such responses are usually assessed by obtaining serum specimens just before and 3 weeks following the immunization. My practice involves keeping the pre-immunization serum specimen frozen in our clinic freezer until the post-immunization serum specimen is obtained. Then both serum specimens are sent for analysis at the same time in a reliable laboratory.

Also, you described a serum IgE of 1540, considerably higher than usually seen in children with respiratory allergies without atopic dermatitis. You also mentioned that the patient was treated for parasitic infection, but did not mention the type. Serum IgE levels in the 1500 range can be seen with certain parasitic infections, but it is usually those with an extra-intestinal migration phase, not just G-I tract residence. Particularly if there has been no such evidence of that type of parasitic infection, one should consider other conditions leading to considerably increased serum IgE levels. One such condition is allergic fungal sinusitis, which can present as persistent/recurrent sinusitis. The presence of fungal hyphae and/or prominent eosinophil accumulation in an adequate specimen of pus draining from the sinuses would raise the possibility of this disorder. However, it is not unusual to find some fungi in cultures of such fluid in individuals receiving prolonged/repeated antibiotic treatment. So the presence of such fungi in cultures by itself is insufficient evidence of allergic fungal sinusitis.

Current Allergy Asthma Rep 2002 Sep;2(5):356-60
Immunoglobulin G subclass deficiency: fact or fancy?
Buckley RH.
Pediatrics/Allergy/Immunology, Duke University School of Medicine, Box 2898, Durham, NC 27710, USA.

Over the past four decades, many patients have been reported to have deficiencies of one or more subclasses of immunoglobulin G (IgG), despite normal total IgG serum concentrations. However, except for those with extremely low or absent IgG2 concentrations and an inability to produce antibodies to polysaccharide antigens, it is difficult to know the true biologic significance of the many reported IgG subclass deficiencies. Completely asymptomatic individuals who totally lack IgG1, IgG2, IgG4, or IgA1 because of heavy-chain gene deletions have been described as producing antibodies normally. In addition, numerous healthy children who have low levels of IgG2 but normal responses to polysaccharide antigens when immunized have been similarly described. From these observations, it can be concluded that IgG subclass measurement is not very helpful in the general assessment of immune function. Such assays provide no information about the patient's capacity to produce specific antibodies to protein, polysaccharide, or viral antigens.

11/13/02 re: Immunodeficiency responsible for tinea infection

A local dermatologist in my community is sending me a patient for evaluation of a possible immune deficiency. He is a 52 year old male with a 35 year history of continuous tinea corporis despite multiple courses of multiple antifungal medications. He has been biopsied and sent to the local medical school for evaluation and discussion by the dermatology department. The dermatologists feel that he must have some subtle immune problem that does not allow him to fight tinea. He has no other history of recurrent infections. I am seeking advice regarding the work up of this patient. I don't think anyone is expecting me to "cure" the tinea but rather offer some explanation of the reason for the persistence.

To help me respond to your question, I consulted Dr. William Shearer of the Texas Children's Med Center in Houston, an expert in immunodeficiency disorders. His response is enclosed below. I have also enclosed an abstract of a recent report relevant to your question.

Dr. Shearer's comments:
Tinea infections are seen in several primary and secondary states of immunodeficiency, but usually the serious nature of other infections clues the physician into the underlying course rather than the recurrent tinea infection. Personal hygiene is important in prevention of recurrence (I assume that is not an issue here). HIV infection can predispose to tinea infection and patients with substance abuse and poor social behavior also can have this problem. A delayed hypersensitivity skin test would be the best screening test for immunocompetence.

Cutis 2001 Jul;68(1 Suppl):6-14
Role of oral antifungal agents for the treatment of superficial fungal infections in immunocompromised patients.
Millikan LE.
Department of Dermatology, Tulane University, New Orleans, Louisiana, USA.

Superficial fungal infections or tinea infections (also known as the dermatophytoses) are commonly encountered conditions in clinical practice, affecting the skin, hair, and nails. The most commonly prescribed modality to treat these infections is topical antifungal therapy. However, this method of treating tinea infections may be less convenient and efficacious in the immunocompromised patient. In such patients, skin infections are more difficult to treat because the disease is often more extensive and severe. Tinea infections of the hair and nails usually require oral therapy. Further, topical treatment is not as efficacious as oral antifungal therapy and, with the exception of the topical antifungal agent ciclopirox, is not indicated for the treatment of tinea unguium (onychomycosis). The 2 most frequently prescribed oral antifungal agents to treat onychomycosis are itraconazole and terbinafine. In the general population, both agents are effective in treating fungal nail infections; however, differences in the agents' mechanism of action and metabolic pathways result in differences in efficacy and drug-drug interaction potential. However, limited data exist on the use of these agents in immunocompromised patients for the treatment of onychomycosis and superficial tinea infections. The available efficacy data we have are limited to case reports or small pilot studies; thus, data supporting the efficacy of these agents for the treatment of tinea infections in the immunocompromised patient must be extrapolated from the general population. For safety issues, however, some postmarketing data exist supporting the safety of these agents in the diabetic and human immunodeficiency virus (HIV) patients populations; indeed, both agents appear to be safe. However, one contrasting point between these 2 agents is drug interactions. Oral terbinafine, unlike itraconazole (a potent cytochrome P-450 [CYP] 3A4 inhibitor), has a relatively low potential for drug-drug interactions, making terbinafine a useful agent for the treatment of tinea infections in immunocompromised patients (e.g., those who are HIV positive and those with diabetes), who are likely to be receiving concomitant medications. Further, recently conducted studies of terbinafine for the treatment of tinea pedis, tinea cruris, and tinea corporis infections in these high-risk patient groups also support efficacy claims and reemphasize its relatively safe profile and low potential for drug interactions. Additional studies in other immunocompromised patient populations may be useful to confirm recent studies and expand the potential use for this agent.

9/3/02 re: Approach to chronic sinusitis in XLA

I would appreciate your thoughts on a 34 y/o patient with XLA, on IVIg, with chronic (>8 months) sinusitis. He transiently improves with long hefty abx courses then relapses immediately. He has already had sinus surgery without significant improvement. The ENT consultants seem hesitant about prophylactic abx. Are there any "new" therapies out there? When are prophylactic antibiotics indicated?

I consulted my colleague, Dr. Arnold Levinson, Chief of the Adult Immunodeficiency program in our institution. In a patient such as you described ( X-linked agammaglobulinemia (XLA) with persistent sinus infection), he made these suggestions:

1) Has there been thorough microbiologic study of the tissue removed at previous sinus surgeries including special culture techniques for unusual organisms or those not readily cultured with "standard" culture technique? If you cannot be assured that such studies were done relatively recently, it may be worth having your ENT consultant aseptically irrigate the relevant sinus cavities to obtain purulent drainage which is then sent to the microbiology lab with advance instructions to carry out extensive investigation including antibiotic sensitivity testing. Of course, such studies should be done when the antibiotics have been discontinued for at least 3 days (perhaps longer if Zithromax is being used). If a different antibiotic appears warranted by such studies, a thorough trial with such an agent is warranted.

2) Have serum IgG levels at the trough point (just prior to the next IV Ig infusion) been checked recently.? Our group generally aims for trough levels of at least 500 ng/dL, perhaps even 600 mg/dL in someone like your patient.

3) Dr. Levinson tries to avoid empiric continuous "prophylactic" antibiotic therapy in such patients unless there has been recurrent lower respiratory tract infection and/or strong evidence of bronchiectasis. However, if the above measures are not helpful in reducing the recurrence of sinusitis, Dr. Levinson would try a regimen of a cycle of 3 different antibiotic (macrolide such as Biaxin, Cipro, and doxycycline) for 5 days each on weekdays, leaving the weekends as "antibiotic-free" periods. He has found little evidence of antibiotic resistance developing in individuals treated for months in this manner.

4) I would add a comment concerning the sinus surgery. I assume that you have confidence in your local ENT consultants. However, if matters cannot be improved with the approaches suggested above, you may wish to consider referring the patient for out-patient evaluation by an ENT specialist with extensive experience in endoscopic sinus surgery such as Dr. David Kennedy who is usually credited with bringing endoscopic sinus surgery to the USA. A well-done CT exam of the sinuses with good coronal views of the osteo-meatal complex should be done shortly before the consultation with the films hand-carried by the patient to the examination.

7/26/02 re: Eczema flare after IV Ig therapy

Is there any association between IVIG administration and dyshydrotic eczema or genital herpes? A patient of mine who has CVID has noticed that both of these problems have flared over the last year since she has been on IVIG. Could this flare be a result of T-cell dysfunction form the underlying immune dysfunction? Her IgG levels have varied from 400-750 while on IVIG.

I consulted 2 experts in the field of immunodeficiency diseases and IV Ig therapy ( Drs. Mark Ballow and Arnold Levinson). Neither had heard anything about or seen the association with IV Ig therapy that you describe. I also could not find any reference to this picture as a complication of IV Ig therapy in a Medline search. If the genital herpes is a major problem here, you may wish to consider treatment with Valtrex (see enclosed abstract).

Expert Opin Pharmacother 2002 Jan;3(1):51-8
Valacyclovir in the treatment of genital herpes and herpes zoster.
Baker DA.
Division of Infectious Diseases, Department of Obstetrics/Gynaecology, State University of New York at Stony Brook, Stony Brook, New York 11794-8091, USA.

Genital herpes is prevalent and sometimes debilitating. Likewise, herpes zoster ('shingles') can be painful and often disabling. The treatment of these conditions has been advanced over the past two decades by the introduction of guanosine nucleoside antivirals such as valacyclovir (Valtrex), Glaxo Wellcome), the highly bioavailable prodrug of acyclovir (Zovirax), Glaxo Wellcome). This review describes the pharmacology, pharmacokinetics, clinical efficacy and tolerability of valacyclovir and considers its clinical attributes in the context of those of the antivirals, acyclovir and famciclovir (Famvir), SmithKline Beecham). The data demonstrate that valacyclovir is more effective than placebo and as effective as other antivirals in the episodic and suppressive treatment of recurrent genital herpes. Valacyclovir is the only antiviral shown to be effective with a short (3-day) course in the episodic treatment of recurrent genital herpes, as well as with once-daily dosing for daily suppressive therapy. In herpes zoster, valacyclovir is as effective as famciclovir and more effective than either placebo or acyclovir at facilitating cutaneous healing and healing of zoster-associated pain and post-herpetic neuralgia. Valacyclovir is well tolerated, with convenient dosing frequencies for the treatment of genital herpes or herpes zoster, it also has the option for use as a short course therapy in the episodic treatment of recurrent genital herpes, all of which are important benefits in the management of these conditions.

6/6/02 re: Normal immunoglobulin ranges

Can you assist in finding information about the changes in the reference ranges for immunoglobulins, especially IgM (total), IgG (total), IgG sub1.?

Years ago, a doctor would put a patient on prophylactic antibiotics and recommend aggressive antibiotic therapy with usual illnesses for someone whose levels were, for example IgM 60, IgG 700, IgG sub1 360, and was having generally poor health, (recovering from the complications of one infection in time for the next.)

Why do the current reference ranges now call these levels "normal"? What is the current thought on treating people who are inside or just outside the lower levels of the current reference ranges?

I should first mention that the normal ranges for serum levels of the immunoglobulin (Ig) isotypes will vary with the technique used and the age of the patient (values for some do not reach "adult" normal agent until after age 7 years. Therefore, optimally each lab should establish its own normal ranges for children of increasing age up to age 7 years as well as adults.

With that background, my impression is that most investigators of humoral immunodeficiency have found that IgG levels of at least 600 mg/dl are usually sufficient to provide protection against encapsulated bacterial infection. Levels of 500 mg/dl are often sufficient. Individuals with common variable immunodeficiency (CVA) usually have levels in the 100-300 mg/dl level and those with X-linked agamma (Bruton's type) usually have levels less than 100 mg/dl. In secondary hypogammaglobulinemia, the levels may be higher, but still less than 600 in those with predisposition to infection

(see enclosed description in those with lung transplantation)

However, many experts in this field feel that measuring the antibody response to immunization with protein (e.g.-diphtheria toxoid) or polysaccharide (pneumococcal) vaccines is a more relevant way to investigate humoral immunodeficiency than measurement of serum Ig levels. This is true for at least 2 reasons: 1) there are occasional cases of individuals with frequently recurrent systemic infections where there are deficient antibody responses in the face of normal total serum Ig levels; 2) there is considerable controversy about the pathogenic significance of decreased serum levels of one IgG subclass in the face of normal total IgG levels. Also recall that IgA deficiency is relatively common (1 in about 600 individuals in the USA); however, most of such individuals are healthy without recurrent infections. Selective IgA deficiency is usually defined as less than 7 mg/dl.

For the above reasons, it has been the practice in the Adult Immunodeficiency Clinic in our institution to treat hypogammaglobulinemic individuals with histories of recurrent individuals with I.V. Ig in dosage schedules to maintain the serum "trough" IgG level of at least 500 mg/dl (trough levels are obtained 3-4 weeks after the last I.V. Ig treatment).

I have enclosed below excerpts from the Immunodeficiency Practice Parameters (check www.jcaai.org website, click on practice parameters section to get more details). Also enclosed FYI are abstracts from some reviews of immunodeficiency.

From - Immune Deficiency Practice Parameters
Multiple methods are available for the quantitation of immunoglobulin levels. These methods can be classified into two major groups. The first group involves measurement of physical properties (light scattering, precipitation in gels) from immune complexes generated by serum immunoglobulins and specific antibodies. The second group involves measurement of serum immunoglobulins using specifically labelled antibodies.(27) Three commonly used procedures include rate nephelometry, radial immunodiffusion in the first group(28), and solid-phase enzyme-linked immunosorbent assay (ELISA) in the second group.(29) TheWorld Health Organization has prepared reference standards for serum immunoglobulin quantitation which are expressed in international units. Normal ranges of human serum immunoglobulins can vary with age, especially in children, environmental factors, and race.(30) It is extremely important to remember, however, that concentrations of IgG and IgA are both normally lower than adult levels until 6 to 7 years of age. Any values obtained other than those that are far below published normal ranges, should be investigated further in a laboratory which has its own age-appropriate normal values for infants and young children.

J Allergy Clin Immunol 2002 Apr;109(4):581-91
Primary immunodeficiency disorders: antibody deficiency.
Ballow M.
Division of Allergy/Clinical Immunology and Pediatric Rheumatology, Department of Pediatrics, Children's Hospital of Buffalo, SUNY Buffalo School of Medicine and Biomedical Sciences, Buffalo 14222, USA.

As a group, antibody deficiencies represent the most common types of primary immune deficiencies in human subjects. Often symptoms do not appear until the latter part of the first year of life, as passively acquired IgG from the mother decreases to below protective levels. As with the T-cell immune deficiencies, the spectrum of antibody deficiencies is broad, ranging from the most severe type of antibody deficiency with totally absent B cells and serum Igs to patients who have a selective antibody deficiency with normal serum Ig. In addition to the increased susceptibility to infections, a number of other disease processes (eg, autoimmunity and malignancies) can be involved in the clinical presentation. Fortunately, the availability of intravenous immune serum globulin has made the management of these patients more complete. Recently, molecular immunology has led to identification of the gene or genes involved in many of these antibody deficiencies. As discussed in this review, this has led to a better elucidation of the B-cell development and differentiation pathways and a more complete understanding of the pathogenesis of many of these antibody deficiencies.

2/5/02 re: Does patient have IgA deficiency?

A 30 yr. old white male had acute renal failure in Oct 2001. This followed a several week history of a "viral infection" with URI and flu type symptoms. He had been taking Motrin, sudafed, and reported poor sleeping ability. He had many URIs as a child and later on several episodes of sinusitis. He otherwise had excellent health. Evaluations for an underlying autoimmune and/or vasculitis process were negative. A renal biopsy was consistent with acute tubular necrosis. It was felt his renal failure was due to a multiple-injury hypothesis. Viral syndrome, volume depletion, Motrin, Sudafed and ginseng all converging to induce an ATN that required dialysis for several weeks. At present his renal function has returned to normal and he is well. The following labs now raise other questions of an underlying immune deficiency.
OCT. IgA < 0.06 g/l

IgG 7.49

CRP 6.15

C3 0.72,C4 13

Jan 02

IgA < 0.06

IgG 10.5

IgM 0.28

C3 1.06, C4 0.16

Questions:

Does this patient have IgA deficiency?

Is there a treatment that would be beneficial?

Is there any association between IgA deficiency and renal failure?

Based on the laboratory data you provided, it appears that your patient likely has isolated IgA deficiency (serum IgA < 6 mgm/dl on more than one occasion with normal serum IgG and IgM levels). As you likely know, isolated IgA deficiency occurs relatively commonly in the USA with about 1 out of 600 people affected. Most IgA deficient individuals are generally healthy, with frequent bacterial infections in the respiratory tract seen in a minority. Viral infections of the respiratory tract do not appear to occur with greatly increased frequency/severity in IgA-deficient individuals. Because only a minority of IgA-deficient people have recurrent infections, investigators have looked for associated defects in host defenses in those with repeated infections. Some groups have found low serum levels of the IgG2 subclass while other reports describe decreased antibody responses to immunizations in some cases even when the total serum IgG levels are normal (see abstracts below). There is an increased incidence of autoimmune reactions in IgA-deficient individuals, including systemic lupus (see enclosed abstract). Lupus can cause renal failure of course. However, I assume from your comments that lupus was looked for with negative findings. Also, your description of the kidney pathology does not suggest lupus nephritis. I am unaware of any reports of idiopathic renal failure as a consequence of IgA deficiency. As you may know, there is a form of nephritis characterized by prominent IgA deposits in the kidney. However, these individuals are not IgA-deficient. One would likely not want to try to replace the serum IgA by infusion of IgA-containing plasma products in your patient. Some IgA-deficient patients have anti-IgA antibodies of an IgG type. Anaphylactic reactions have occurred in some of these patients when IgA-containing preparations are infused I.V. Therefore, the approach to IgA-deficient individuals with normal IgG levels is to use preventive immunizations wherever feasible and treat bacterial respiratory infections promptly.

J Clin Immunol 2001 Sep;21(5):303-9
Physiology of IgA and IgA deficiency.
Cunningham-Rundles C.
Department of Medicine and Pediatrics, Mount Sinai Medical Center, New York, New York 10029, USA.

"Although secretory immunoglobulin A (IgA) is important in mucosal immunity. Selective IgA deficiency is the most common primary immunodeficiency of humans. In most cases this defect is not associated with any illness. The reasons for this are unknown, but other immunological compensations might provide sufficient or complete restitution. Alternatively, it is possible that IgA deficiency alone may not predispose to disease, but additional immunological abnormalities might be present in symptomatic individuals. Some IgA-deficient individuals have a reduced antibody response to immunizations (even with normal IgG and IgM levels) and others have deficient responses to bacterial polysaccharides when IgG subclass levels are normal. The physiological role of IgA, the frequency and causes of IgA deficiency, the diseases associated with its absence, and current limited understanding of the pathogenesis of selective IgA deficiency will be reviewed."

Adv Perit Dial 2000;16:237-42
High prevalence of selective immunoglobulin A deficiency in peritoneal dialysis patients.
Kuo MC, Chang JM, Hwang SJ, Tsai JC, Lai YH.
Department of Medicine, Kaohsiung Medical University, Taiwan.

"We encountered two hemodialysis (HD) patients with recurrent infections and complete immunoglobulin A deficiency (IgAD). To survey the possibility of a similar occurrence in other populations, we conducted the present study. We used nephelometry to examine the levels of immunoglobulins G (IgG), A (IgA), and M (IgM) in 42 continuous ambulatory peritoneal dialysis (CAPD) patients, 246 HD patients, 56 chronic renal failure (CRF) patients, and 250 normal adults. Four CAPD patients (9.5%) and five HD patients (2.0%) were found to be completely IgA deficient (IgA < 6.67 mg/dL). Peritoneal dialysis patients therefore had a significantly higher prevalence of IgAD compared with HD and CRF patients. The underlying diseases leading to dialysis therapy in the IgAD patients varied. Their dialysis durations also varied. The occurrence rate of peritonitis in CAPD patients with IgAD was no higher than in patients without IgAD. The clinical significance of IgAD was focused on mucosal immunity, but the exact prevalence of infection was difficult to define. However, these patients' medical records did suggest more frequent respiratory tract infections and cellulitis events than did the records of patients without IgAD. Two PD patients with IgAD died of pneumonia. Immunodiffusion and indirect ELISA methods were used to detect the presence of auto-antibodies, successfully identifying them in three patients. Further research is needed to study other mechanisms of IgAD."

Lupus 1997;6(4):390-4
IgA deficiency and SLE: prevalence in a clinic population and a review of the literature.
Rankin EC, Isenberg DA.
Department of Medicine, University College London.

"An association between systemic lupus erythematosus (SLE) and immunoglobulin A (IgA) deficiency has been reported previously and may have therapeutic consequences for patients who require treatment with intravenous immunoglobulin. We report the prevalence of IgA deficiency in a clinic population of 96 patients with SLE. Five patients were found to be consistently IgA deficient. These patients were more likely to be West Indian, to have anti-Sm and anti-La antibodies and to have a speckled pattern of antinuclear antibody. There were no significant differences in clinical features between IgA deficient and other SLE patients, or in SLE-related HLA alleles. We thus confirm the increased prevalence of IgA deficiency in patients with SLE. A review of the literature is presented and we speculate on the nature of the link between IgA deficiency and SLE."

1/21/02 re: Immunologic evaluation in lichen sclerosis

I am seeing an 8-y/o female with Dx lichens sclerosis atrophicus. She has no hx of pneumonia, sinusitis or otitis! her dermatologist asked for an immunological workup. I see no reason to do one. Also no history of T cell infections. Please give me your opinion and if I do need to do one what do you recommend I request?

I assume that the referring dermatologist is referring to one of the variants of lichen planus. Dermatologists frequently use different Latin terms for the same group of disorders. I am not familiar with the term "lichens sclerosis atrophicus" and found no reference to it in a Medline search. If the dermatologist is referring to something completely different, please send another query with clarification. If the condition described is a variant of lichen planus, my understanding is that this is a relatively rare condition in children. I am not familiar with any significant association with immunodeficiency. There has been a long-known association with chronic liver disease, particularly Hepatitis C infection and chronic active hepatitis (see enclosed abstracts of selected articles below). The lichen planus also seems to flare during treatment of the Hepatitis C infection with Interferon-alpha. There has also been a reported association of lichen planus with vitiligo, alopecia areata and possible underlying autoimmunity (see enclosed abstract below)

Gastroenterol Clin Biol 1995 Oct;19(10):833-6
[Lichen planus and hepatitis C virus. Apropos of 5 new cases]
[Article in French]
Hyrailles V, Peyron N, Blanc P, Mark Y, Meunier L, Meynadier J, Larrey D, Michel H.
Service d'Hepato-Gastroenterologie, Hopital Saint-Eloi, Montpellier.

"Lichen planus is an immunologically mediated skin or mucous disease, which has recently been described in some patients with hepatitis C virus-related liver disease. We report 5 new cases of the association of hepatitis C with lichen planus, to be added to the 15 cases published in the literature. The sex ratio (female/male) was of 1.2. Lichen planus occurred more frequently in chronic active hepatitis (2/3 of cases) than in cirrhosis (1/3 of cases). Lichen planus manifestations were only mucous (30%), only cutaneous (40%) or both (30%). Mucous lesions were mainly observed in patients with cirrhosis (3/4 of cases). The onset of skin and hepatic manifestations was variable, with liver disease as the most frequent revealing symptom (60%). The influence of interferon remains unclear. However, it seemed to trigger more than to relieve lichen planus."

Arch Dermatol 1994 Jan;130(1):73-6
Lichen planus and hepatitis C virus--related chronic active hepatitis.
Jubert C, Pawlotsky JM, Pouget F, Andre C, DeForges L, Bretagne S, Mavier JP, Duval J, Revuz J, Dhumeaux D, et al.
Department of Dermatology, University of Paris XII, Creteil, France.

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