Serum sickness due to amoxicillin

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology

A 17-year-old male with a history of chronic sinusitis is here for evaluation of suspected antibiotic allergy. Last year, he developed a reaction to Augmentin (amoxicillin clavulanate) with fever, joint swelling and hives. He had been on Augmentin previously without clinical symptoms. This year, he needed another course of antibiotics. He was placed on Omnicef (cefdinir) and he developed a rash. He had been on Omnicef prior to that without issues.

Past medical history

Chronic sinusitis.

He was not on any medications. Physical examination was unremarkable.

What is the most likely diagnosis?

This is a patient with a suspected penicillin and cephalosporin allergy and history of chronic sinusitis. Penicillin and cephalosporins share a beta lactam ring and there is reported historic evidence of cross reactivity of 5% to 15% between these two antibiotic groups.

Is the reaction due to IgE-mediated allergy or serum sickness?

The described reaction to amoxicillin with fever, joint pain and rash can be diagnostic of a relatively mild episode of serum sickness. Serum sickness is an example of the type III, or immune complex–mediated, hypersensitivity condition that is self-limited and caused by exposure to foreign proteins or hapten. The most common cause is antibiotics, penicillins in particular.

What diagnostic test would you suggest?

Work-up for penicillin and cephalosporin allergy can be started with testing for specific immunoglobulin E for penicillin. However, the conclusive testing will require skin testing for penicillin with major and minor penicillin metabolites. At this point, it is advisable to avoide penicillin and cephalosporin antibiotics. If he needs an antibiotic for treatment of infections in the future, he can be prescribed azithromycin. Currently, there is no validated test to rule out cephalosporin allergy, however a negative skin test to penicillin greatly diminishes the risk of a fatal anaphylactic reaction to cephalosporin. However, these tests are not helpful for predicting which patients are at risk for developing serum sickness. Premedication with steroids is not protective either. Further use of the offending agent, in this case, amoxicillin, should be withheld.

Final diagnosis

Serum sickness due to amoxicillin.

Summary

Serum sickness typically occurs 7 to 10 days after exposure and causes fever, arthralgias, and rash. Mechanism involves drug-antibody complexes and complement activation (type III reaction). Some patients have frank arthritis, edema, or GI symptoms. Symptoms are self-limited, lasting 1 to 2 wk. Beta-Lactam and sulfonamide antibiotics, iron-dextran, and carbamazepine are most commonly implicated.

In one study which included chidlren with serum sickness, all but one of the antibiotic-related cases occurred in children who had relatively heavy lifetime antibiotic exposure. The risk of serum sickness was significantly elevated after cefaclor compared with amoxicillin. Most cases prompted several physician visits, but none required hospitalization.

Desensitization does not work and must never be attempted for certain types of reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis, erythroderma, and erythema multiforme). Desensitization also does not work for other types of immunologic reactions to antibiotics, such as serum sickness, drug fever, or hemolytic anemia.

Mnemonics for penicillin allergy skin testing

Major penicillin determinant test detects

Majority of patients with penicillin allergy

Minor determinant test

Minorizes the risk

References

Serum sickness in children after antibiotic exposure: estimates of occurrence and morbidity in a health maintenance organization population. Am J Epidemiol. 1990 Aug;132(2):336-42.

Drug Hypersensitivity. Merck Manual.

Severe serum sickness-like reaction to oral penicillin drugs: three case reports. Tatum AJ, Ditto AM, Patterson R. Ann Allergy Asthma Immunol. 2001 Mar;86(3):330-4.

Serum Sickness. eMedicine Specialties > Rheumatology > Vasculitis.

Patient information: Allergy to penicillin and related antibiotics. UpToDate.

Published: 06/28/2009
Updated: 09/27/2010

Difficult to control asthma in a child - what to do?

Author: V. Dimov, M.D., Fellow, Creighton University Division of Allergy & Immunology
Reviewer: S. Randhawa, M.D., Fellow, LSU (Shreveport) Department of Allergy & Immunology

A 9-year-old African American girl with asthma diagnosed at age 15 months, and with a history of allergic rhinitis and atopic dermatitis is referred for evaluation. The atopic dermatitis has improved with age. She now has symptoms mostly during the winter. Her rhinitis is better controlled with the use of intranasal steroid, however her asthma has proved challenging to control. She has been diagnosed with asthma at age 15 months and she has been treated with inhaled steroids for the last several years, including Advair 115/21 for the last year. She still needs to use albuterol 3-4 times per day, including before exercise. Her symptoms are manifested by chest tightness and cough, not much wheezing, but definitely the chest tightness is one of her predominant symptoms. The triggers of her symptoms include infections, exercise and changes in weather. She has symptoms once to twice per week, including during the night once to twice a week and the last course of oral steroids was 5 months ago. She was never hospitalized with asthma and has no emergency room visits. She had spirometry done 5 months ago which showed FEV1 of 74%, which actually decreased by 10% with bronchodilator use. She had ImmunoCAP specific IgE testing for allergens and it was all negative apart from a positive to one of the trees, oak. She also complains of congestion and itchy eyes which are worse during the spring and fall, and snoring at night. She was evaluated with a sleep study which showed mild sleep apnea. They do not report a history of recurrent skin infections. She was treated with for a respiratory infection earlier this year with antibiotics and chest x-ray done years ago was negative.

Past medical history is positive for asthma, rhinitis and atopic dermatitis. Past surgical history is negative. She has no known drug allergies.

Family history is positive for mother with allergic rhinitis, sister with asthma and allergic rhinitis.

On social history, she is exposed to second-hand smoke from a neighbor in the apartment complex and also her father is a smoker. They have no pets at home. There is no carpet and no visible mold in the house.

On birth history, she was born via C-section. She was born at term and she was breast fed for a short period of time.

Her current outpatient prescriptions include Advair 115/21 one inhalation b.i.d. with Aero-Chamber, albuterol p.r.n., Pataday eye drops, Zyrtec and Nasacort one spray in each nostril daily.

Physical examination

HEENT examination showed some dry discharge in both nostrils and boggy turbinates which are mildly erythematous. Chest was clear to auscultation bilaterally. Cardiovascular system showed clear S1, S2. Abdomen was soft, nontender and nondistended. Extremities showed no clubbing, cyanosis or edema and skin showed mild lesions of atopic dermatitis on upper extremities.

Procedures: Skin prick test and spirometry. The skin prick test was negative to cat, dog, cockroach, dust mite, trees, grasses, weeds, ragweed and mold and had a good reaction to histamine. The size of the wheel was 6 x 6 mm. She had spirometry which initially showed FVC of 79% and FEV1 of 66%. FEV1 improved significantly with the administration of nebulized albuterol. There was an improvement of 19% in FEV1 from 1.47 L to 1.77 L, so the bronchodilation test was positive.

What is the most likely diagnosis?

This is a child with severe asthma, including night symptoms with inadequate response to Advair at the dose of 115/21. She does not provide a certain history of reflux disease, although she has some night cough, but no heartburn or metallic taste in her mouth. She has not been on Singulair in the past and we discussed the possibility of vitamin D deficiency or insufficiency in patients with severe asthma, and other comorbidities. She is not a likely candidate for the diagnosis of vocal cord dysfunction (VCD) as she does not have symptoms of VCD (voice change, etc.) during her asthma attacks. Her rhinitis is most likely nonallergic with negative skin prick test today and negative specific IgE 7 years ago, apart from the mild sensitization to oak. There is no history of food allergy. She has mild eczema which is easy to control with moisturizers.

What treatment approach would you suggest?

Considering that even with the moderate dose of Advair she did not have full control of her symptoms in the past and she needed to use albuterol 3-4 times a day, I would suggest a trial of a different combination of inhaled steroids and long-term beta agonist, namely Symbicort at a dose of 160/4.5 two puffs twice a day with an AeroChamber. The formoterol in Symbicort has some short-acting and long-acting bronchodilator effects and she may have better control of symptoms with that. Also, I would recommend adding Singulair 5 mg chewable tablet to her regimen and taking a multivitamin for the vitamin D component, 1 tablet p.o. daily. Considering that her skin prick was negative, I would probably discontinue cetirizine at this point. She, however, can continue to use the Nasacort at a dose of 1 spray each nostril twice a day to control her nasal inflammation, which is most likely due to nonallergic rhinitis at this point. I suggested followup in approximately 1-2 months for repeat spirometry to verify that these changes in her treatment have the desirable effect. If there is a suspicion for GERD, we can consider a PPI addition to the therapy at that point.



Severe asthma - differential diagnosis and management (click to enlarge the image).

Related reading

Worldwide, 40% of children, 33% of male non-smokers, 35% of female non-smokers are exposed to second-hand smoke http://goo.gl/xFGef

Published: 07/12/2010
Updated: 01/12/2011

Allergy to pasta sauce

Author: V. Dimov, M.D., Fellow, Creighton University Division of Allergy & Immunology
Reviewer: S. Randhawa, M.D., Fellow, LSU (Shreveport) Department of Allergy & Immunology

A 17-year-old male is in the clinic for evaluation of suspected food allergy. He has had 4-5 episodes of facial angioedema when consuming pasta sauce with pasta. The symptoms start typically while he is eating the food, within a few minutes, and they are manifested by lip swelling, oral itching and the feeling of "throat closing". This happened when consuming whole grain pasta with JTM frozen pasta sauce from Gordon's food products. He reports having those reactions starting from approximately 1.5 years ago with different foods, but mostly pasta sauce. He also had a mild reaction when consuming bean tortilla. He had no respiratory symptoms, no wheezing and shortness of breath. He had no hives with those events, but he reported some abdominal discomfort. We evaluated each of the major food groups associated with allergic reactions. He has no reactions when consuming tree nuts, peanuts, eggs, milk, fish, shellfish, wheat or soy products. During the evaluation for oral allergy syndrome he reported nasal congestion throughout the year, worse in the fall. He was never formally tested or diagnosed with allergic rhinitis. He reports oral itching when consuming watermelon and some other foods in raw form. He has never been to the emergency room for those symptoms. He took Benadryl for the symptoms of food allergy described above and that helped his symptoms. They do not have an Epi-Pen and that has not been administered in the past.

Past medical history is positive the described symptoms of facial angioedema affecting mostly the lips after consuming pasta sauce based foods.

Past surgical history is negative.

On social history he lives at home with his family, a cat and a dog. There are no smokers in the home. There is carpet, but no visible mold.

There are no known medication allergies.

Current medications include a multi-vitamin, and the above-mentioned Benadryl during food allergic reactions and he has not taken it since them.

On physical examination, his nose has pale boggy turbinates on both sides with some mild mucoid discharge.

Procedures: He had spirometry and skin prick testing. The spirometry was normal. The skin prick test was strongly positive to mold mix, trees, grass, birch, ragweed, weeds, Aspergillus and Homodendrum.

What is the most likely diagnosis?

This is a patient with facial angioedema after consuming pasta-based meals with a specific food sauce. He has no reported reaction to wheat or any of the major food allergens, including tree nuts, peanuts, eggs, milk, shellfish, fish, soy and wheat.

He does report some symptoms of oral allergy syndrome, especially with watermelon which is known to have a cross-reactivity with ragweed. He does have evidence of allergic rhinitis with sensitization to ragweed and weed mix, which includes mugwort, and birch. Oral allergy syndrome is certainly a consideration for him. The symptoms are oral allergy, however, typically appear when consuming raw foods, not processed foods, such as pasta sauce.

Hereditary angioedema can be of consideration, however he does not have symptoms of abdominal pain and there is no family history, and this can be ruled out by blood work.

We do not have any information about the pasta sauce that he consumed. This pasta sauce is produced by JTM and Gordon food suppliers (food service companies) and they do not publish the ingredients of their products because they are not available in the stores. I asked them to bring the container/label with the ingredients so we can do a testing with the sauce and the specific ingredients as well.

What diagnostic test would you suggest?

We provided Epi-Pen and training to be used in case of a severe food allergic reactions. For his allergic rhinitis, I provided a sample of nasal steroid to be used and also he can use an oral antihistamine daily.

Regarding the further workup of his food allergic reactions, it is advisable to obtain the ingredients and a sample of the sauce from JTM and Gordon's food services. We can perform a skin prick-puncture test with the sauce, and also specific IgE testing for the ingredients of the sauce, as well as beans and paprika (in the chili).

If this is negative, then a food challenge can be considered.

Published: 07/12/2010
Updated: 10/12/2010

Textile Dermatitis and Contact Dermatitis

Author: V. Dimov, M.D.,
Reviewer: S. Randhawa, M.D.

A 53-year-old female is in the clinic for evaluation of her complaints of feeling of skin "burning", discomfort and mild erythema with different clothes. These symptoms mostly affect the lower part of the body but also occasionally the upper extremities. They started approximately 6 years ago after she used a hair dye with quaternary ammonium. An allergist at the time performed contact allergy testing with T.R.U.E. Test and, as per patient, this test was positive for cobalt, nickel and quaternary ammonium. It has been a struggle for her to avoid the use of products with quaternary ammonium, also known as benzalkonium chloride, which is widely used as a disinfectant. She is able to tolerate pure cotton clothes, but she has difficulty finding those in the stores.

Past medical history

Her past medical history is remarkable for the above-referenced symptoms of contact dermatitis/textile dermatitis, as well as anxiety and panic attacks.

Drug allergies include Bactrim with rash and also possiblle allergic reactions with Augmentin, Levaquin and amoxicillin, and pruritus but no rash with Motrin and Cipro.

Her current medications include Ativan b.i.d.

Her family history and social history are unremarkable.

The physical examination is normal.

Procedures: CBC, differential and CMP were ordered.

What is the most likely diagnosis?

This is a patient with a history of contact dermatitis with positive T.R.U.E. Test to cobalt, nickel and quaternary ammonium, which is also know as benzalkonium chloride, with a suspected diagnosis of textile dermatitis. Interestingly, she does not actually have a skin rash. It is mostly manifested by burning sensation and pruritus with some mild erythema. However, the presence of rash is important for the conclusive diagnosis of dermatitis. In any case, textile dermatitis can be caused by irritant reactions to textile fibers or contact allergy to textile dyes and finishing chemicals. It is important to be aware that dispersed dyes can also cause a reaction in sensitive patients.

What would you suggest in terms of diagnostic tests?

We recommended that she has CBC with differential count and CMP for basic screening for other causes of the sensation of skin "burning" and pruritus. Also, we advised her to take loratadine 10 mg p.o. daily, and to use "All Clear" detergent without any perfumes to wash her clothing. She will request the T.R.U.E. Test results from her previous allergist. There is currently no evidence of environmental sensitization to trees, gasses, mold and no evidence of symptoms for allergic rhinitis, conjunctivitis, asthma or food allergy and we decided to postpone skin prick testing to environmental allergens and food allergens at this time because it is not likely that IgE mediated allergy plays a role in this clinical setting. After we review the T.R.U.E. Test results, it may be reasonable to refer her to a dermatologist who can perform an expanded T.R.U.E. test for more contact allergens (50 or 74 rather than the initial 25 allergens included in T.R.U.E.) to see if any other allergens play a role. It is recommended to avoid the triggering substances or textiles that cause irritation in this patient.

Related reading

Thin-Layer Rapid-Use Epicutaneous Test (patch test) misses allergens in 12.5% of patients with contact dermatitis http://goo.gl/nqUsn

Published: 07/12/2010
Updated: 10/12/2011

B cell activation and signal transduction

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology

Phosphorylation events in B cell activation:

Src kinases Lyn, Fyn, Blk
Syk

PLC
SLP/Btk
Grb2

SOS
RAS, MAPK

NAN (NFAT, AP-1, NFkB)

Complement receptor CD21 (CR2) activates BCR if the antigen is opsonized by C3b component of the complement.

CR2-CD19-CD81 complex is expressed on the surface of B lymphocytes.

Complement receptor 2 (CR2/CD21) is part of the B-cell coreceptor and expressed by mature B cells and follicular dendritic cells. CD21 is a receptor for C3d-opsonized immune complexes and enhances antigen-specific B-cell responses. Viruses, such as HIV and EBV, use the complement receptors (CR2) to the enter the cell. Genetic CD21 deficiency is associated with hypogammaglobulinemia (JACI, 2011).

When CD21 (CR2) interacts with C3d, the complex is brought into the BCR. CD19 has an ITAM that is phosphorylated, thus recruiting Lyn to enhance phosphorylation.

Bruton’s tyrosine kinase (Btk) is unique to B lymphocytes. Btk and Syk activate PLC

to break PIP2 down to IP3, and make DAG - this is analogous to the TCR pathway.

Btk is also involved in B lymphocyte maturation and loss of Btk causes Brutons’s

agammaglobulinemia, also called X-linked agammaglobulinemia.

B cell survival depends on survival and promoting signals such as BLYSS, BAFF, and APRIL. The receptors for these molecules include BR3, TACI and BCMA.

Activation of B cells depends on the following:

- CD 19 and CD21 (CR2)
- TAPA 1
- CD81
- ITAM (universal activation motif)

Inhibition of B cells depends on the following:

- CD22
- CD45
- FcγRIIb (CD32)
- CTLA-4 (Cytotoxic T-lymphocyte antigen-4)
- ITIM (universal inhibition motif)

CD22 is a B-lymphocyte cell adhesion molecule (BL-CAM)that binds sialic acid with an immunoglobulin (Ig) domain. CD22 is a member of Ig superfamily and SIGLEC family. CD22 is an inhibitory receptor for B cell receptor (BCR) signalling.

Fc gamma receptors for IgG (CD 16, 32, 64) are labeled in "reverse" order:

CD 16 - FcR III - low-affinity

CD 32 - FcR II - intermediate-affinity

CD 64 - FcR I - high-affinity

T and B Cells - Naive and Memory Cell Markers (click to enlarge the image).

Abatacept (Orencia) is CTLA4-human IgG1 fusion protein against B7-1 (CD80) and B7-2 (CD86). It is used for treatment of rheumatoid arthritis and juvenile rheumatoid arthritis.

T cell activation involves all of the following steps EXCEPT:

A. RAS-MAPK pathway

B. activation of Syk

C. activation of NFAT

D. activation of Protein Kinase C

Answer: B. Syk is part of the B cell activation. ZAP-70 is its equivalent in T cells.

References

Src (gene). Wikipedia.
LYN. Wikipedia.
Lck. Wikipedia.
SYK. Wikipedia.
LAT, Linker of activated T cells. Wikipedia.

Published: 08/29/2009
Updated: 10/29/2011

Complement receptors (CR)

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist

There are 4 types of complement receptors (CR):

- CR1 (CD35) promote phagocytosis of antigens coated by complement fragments
- CR2 (CD21) connect the innate and adaptive immune systems through humoral response
- CR3 (Mac-1, CD11b/CD18) (integrin receptors) promote both phagocytosis and leukocyte adhesion

- CR4 (gp 150/95, CD11c/CD18) is a market for dendritic cells

To remember: CR3 (CD11b/CD18) and CR4 (CD11c/CD18) are affected in LAD type I.

CD55 (DAF) and CD59 are affected in PNH. Eculizumab (Soliris) is a humanized mAb against complement protein C5. It is used for treatment of paroxysmal nocturnal hemoglobinuria (PNH).

Complement receptor 2 (CR2/CD21) is part of the B-cell coreceptor and expressed by mature B cells and follicular dendritic cells. CD21 is a receptor for C3d-opsonized immune complexes and enhances antigen-specific B-cell responses. Viruses, such as HIV and EBV, use the complement receptors (CR2) to the enter the cell. Genetic CD21 deficiency is associated with hypogammaglobulinemia (JACI, 2011).


Complement receptors (click to enlarge the image).

All of the following are correct pairings of complement receptors and function except:

A. CR1 (CD35) with phagocytosis, immune complex clearance

B. CR4 with phagocytosis

C. CR3 with EBV receptor, leukocyte adhesion, phagocytosis

D. CR2 (CD21) with B cell activation, trapping of antigens in germinal centers

Answer: C. EBV use CR2 (CD21) to enter the cell.

Place in increasing order the CD designation of complement receptors CR1, CR2, CR3, CR4:

A. CD21, CD35, CD11b/CD18, CD11c/CD18

B. CD35, CD21, CD11b/CD18, CD11c/CD18

C. CD35, CD21, CD11c/CD18, CD11b/CD18

D. CD11b/CD18, CD11c/CD18, CD21, CD35

Answer: B.

Deficiency of which component of the complement is among the causes of paroxysmal nocturnal hemoglobinuria (PNH)?

A. CR2 (CD21)

B. Factor I

C. DAF

D. MCP

Answer: C.

References

Allergy and Immunology MKSAP, 3rd edition.
Chapter 2. Innate immunity. Abbas et al: Cellular & Molecular Immunology, 6th Ed.

Published: 09/05/2010
Updated: 10/02/2011

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