Types of hypersensitivity reactions:

1. Type I (anaphylactic): due to preformed IgE antibodies, which cause release of vasoactive amines (e.g., histamine, leukotrienes) from mast cells and basophils. Examples are anaphylaxis (bee stings, food allergy [especially peanuts and shellfish], medications [especially penicillin and sulfa drugs], rubber glove allergy), atopy, hay fever, urticaria, allergic rhinitis, and some forms of asthma.

■ With chronic type I hypersensitivity (atopy, some asthma, allergic rhinitis), look for eosinophilia, elevated IgE levels, family history, and seasonal exacerbations. Patients also may have allergic "shiners" (bilateral infraorbital edema) and a transverse nasal crease (from frequent nose rubbing), Pale, bluish, edematous nasal turbinates with many eosinophils in clear, watery nasal secretions also are classic.

■ If patients have nasal polyps, do not give aspirin; you may precipitate a severe asthmatic attack.

a Treat anaphylaxis immediately by securing the airway. laryngeal edema may prevent intubation, in which case do a cricothyrotomy, if needed. Give subcutaneous epinephrine, then an antihistamine. Steroids are sometimes given for severe reactions, but only if other options are not present.

b Watch for C I esterase inhibitor (complement) deficiency as a cause of hereditary an-gioedema. Patients have diffuse swelling of lips, eyelids, and possibly the airway, unrelated to any allergen exposure. The deficiency is autosomal dominant; look for a positive family history. C4 complement is low. Treat acutely as anaphylaxis; androgens are used for long-term treatment to increase liver production of Ct esterase inhibitor.

a Skin testing may identify an allergen if it is not obvious.

2. Type II (cytotoxic): due to preformed IgG and IgM, which react: with antigen and cause secondary inflammation. Examples are autoimmune hemolytic anemia (classic causes are methyldopa or penicillin/.sulfa drugs) and other cytopenias caused by antibodies, such as idiopathic thrombocytopenic purpura, transfusion reactions, erythroblastosis fetalis (Rb incompatibility), Goodpasture's syndrome (watch for linear immunofluorescence on kidney biopsy), myasthenia gravis, Graves' disease, pernicious anemia, pemphigus, and hyperacute transplant rejection (as soon as the anastomosis is made at: transplant surgery, the transplanted organ deteriorates in front of your eyes).

Not«: With anemia, watch for a positive Coombs' test; in pregnancy, watch lor a positive indirect Coombs' test.

3. Type III (immune complex-mediated): due to deposits of antigen-antibody complexes (usually in vessels) that cause an inflammatory response. Examples are serum sickness, lupus, rheumatoid arthritis, polyarteritis nodosa, cryoglobulinemia, and glomerulonephritis (e.g., chronic hepatitis).

4. Type IV (cell-mediated [delayed]): due to sensitizedT lymphocytes, which release inflammatory mediators. Examples include tuberculosis skin test, contact dermatitis (especially poison ivy, nickel earrings, cosmetics, medications), chronic transplant rejection, granulomas.

Human immunodeficiency virus (HIV) /AIDS: initial seroconversion may present as a mononucleosis-type syndrome (fever, malaise, pharyngitis, rash, lymphadenopathy). Keep seroconversion in the back of your mind as a differential diagnosis for any sore throat or Epstein -Barr virus-type presentation. Diagnosis is made with the enzyme-linked immunosorbent assay (ELISA), which, if positive, should be confirmed with a second assay. If the second assay is positive, confirm with a Western blot test. Do all tests before yoti tell the patient anything! It takes at least I month for antibodies to develop; therefore, if a patient comes to you for testing because of recent risk-taking behavior, you should retest the patient: in 6 months if the initial test is negative.

Important points:

1. Once the diagnosis of HIV infection is made, the patient should get a CD4 count every 6 months.

2. Antiretroviral therapy should be started when the CD4 count falls below 500 (or sooner).

3. Once the CD4 count is less than 200, start prophylaxis for Pneumocystis carinii pneumonia (PCP). Use trimethoprim-sulfamethoxazole (TMP-SMX) or pentamidine (if the patient is allergic to or intolerant of TMP-SMX).

4. Once the CD4 count is less than 100, start prophylaxis for Mycobacterium avium intracdlulare with rifabutine; consider cryptococcal and candidal prophylaxis with fluconazole.

5. Once CD4 < 200, the patient automatically is considered to have AIDS (even without opportunistic infections).

6. Give measles, mumps, and rubella (MMR) vaccine to HIV-positive patients (the only live vaccine given to HIV patients!).

7. Give pneumococcal, hepatitis B, inactivated polio vaccine, and annual influenza vaccines to all HIV-positive patients.

8. Do annual purified protein derivative test for tuberculosis in HIV-patients; get an annual chest x-ray if the patient is anergic.

9. Do not give oral polio vaccine to HIV-positive patients or their contacts.

10. Watch for Kaposi's sarcoma or non-Hodgkin's lymphoma (especially primary B-cell lymphomas of the central nervous system).

11. A positive India ink preparation of the cerebrospinal fluid means Cryptococcus neoformam meningitis.

12. Ring-enhancing lesions in the brain usually mean toxoplasmosis or cysticercosis (Taenia solium).

13. Other commonly seen HIV sequelae include wasting syndrome (progressive weight loss), dementia, peripheral neuropathies, thrombocytopenia, and loss of delayed hypersensitivity (type IV) on skin testing (anergy).

14. Give pregnant HIV-positive patients zidovudine (AZT), and give the infant AZT for 6 weeks after birth. This protocol reduces mother-to-child transmission from roughly 25% to 8%. The infant may have a positive HIV vest for 6-12 months because of maternal antibodies. Retest after 6-12 months. Recent studies indicate that cesarean section also may reduce transmission.

15. HIV-positive mothers should not breast-feed, because they can transmit the disease to their infants through breast milk,

16. Use ganciclovir for cytomegalovirus retinitis; foscarnet is the second choice.

17. In any patient with HIV and pneumonia, think of PCP first. Look for severe hypoxia with normal x-ray or diffuse, bilateral interstitial infiltrates. Usually the patient has a dry, nonproductive cough. PCP may be detectable with silver stains (Wright-Giemsa, Giernsa, nrethenamine silver) of induced sputum; if not, use bronchoscopy with bronchoalveolar lavage and brush biopsy to make the diagnosis.

18. Any adult patient with thrush should make you think of HIV or leukemia.

19. Any young adult who presents with herpes zoster should make you think of HIV

28. Cryptosporidium and Isospora spp. are diarrheal infections uniquely seen in HIV-positive patients

Primary immunodeficiencies: because they are rare, your job is simply to recognize the classic case presentation:

1. IgA deficiency: most common primary immunodeficiency. Look for recurrent respiratory and GI infections. IgA is low, and IgG subclass 2 may be low. Do not give im munoglobulins; you may cause anaphylaxis due to development of ami IgA antibodies. Alternatively, in any patient who develops anaphylaxis after immunoglobulin exposure, yon should think of IgA deficiency.

2. X-linked agammaglobulinemia (Bruton's agammaglobulinemia): X-!inked recessive disorder that affects males. B-cells are low or absent; infections begin after 6 months when maternal antibodies disappear. Look for recurrent lung and sinus infections with Streptococcus and Haemophilus spp.

3. DiGeorge syndrome; caused by hypoplasia of the third and fourth pharyngeal pouches. Look for hypocalcemia and tetany (from absent parathyroids) in the first 24-48 hours of life. Also look for absent or hypoplastic thymus and congenital heart defects.

4. Severe combined immunodeficiency (SCID): may be autosomal recessive or X-linked. Many cases are due to adenosine deaminase deficiency (autosomal recessive). Patients have B- andT-cell defects and severe infections in the first few months of life, and cutaneous anergy usually is present. Other signs include an absent or dysplastic thymus and. lymph nodes.

5. Wiskott-Aldrich syndrome: X-linked recessive disorder that affects males. Look for classic triad: eczema, thrombocytopenia (look for bleeding), and recurrent infections (usually respiratory).

6. Chronic granulomatous disease: usually X-linked recessive disorder that affects males. Patients have a defect in reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and thus get recurrent infections with catalase-positive organisms (e.g., Staphylococcus aureus, Pseudomoiws sp.).The diagnosis is clinched if the question mentions deficient nitroblue tetrazolium dye reduction by granulocytes. This test measures respiratory burst, which patients lack.

7. Chediak-Higashi syndrome: usually autosomal recessive, Look for giant granules in neutrophils and associated oculocutaneous albinism. The cause is a defect in microtubule polymerization.

8. Complement deficiencies: C5-C9 deficiencies cause recurrent Neisseria infections; specific complement component is low.

9. Chronic mucocutaneous candidiasis: a cellular immunodeficiency specific for Candida sp. Patients have candidal thrush, scalp, skin, and nail infections and anergy to Candida sp. with skin testing. Hypothyroidism is often an associated finding. The rest of immune function is intact.

10. Hyper IgE syndrome (Job-Buckley syndrome): patients get recurrent staphylococcal infections (especially of the skin) and have extremely high IgA levels. They also commonly have fair skin, red hair, and eczema.

Questions often ask you to give genetic counseling to a parent or to predict the likelihood of having a second affected child after the first is born with a given disease. Because it is assumed that you know the inheritance pattern of the disease, the following lists should come in handy:

Autosomal dominant: look for affected mother or father who passes the disease to 50% of offspring:

■ von Willebrand disease

■ Neurofibromatosis: cafe-au-lait spots, profuse peripheral nerve tumors, acoustic neuroma

■ Multiple endocrine neoplasia (MEN) type I and II syndromes » Achondroplasia: diagnosis by picture of a patient a Marian syndrome: tall patient with arachnodactyly, mitral vaive prolapse, aortic dissection, lens dislocation s Huntington's disease s Familial hypercholesterolemia: look for xanthomas, early coronary artery disease, markedly elevated cholesterol

■ Familial polyposis coli «Adult polycystic kidney disease

■ Hereditary spherocytosis

«Tuberous sclerosis: hypopigmented skin macules, seizures, mental retardation, central nervous system hamartomas, rhabdomyomas, renal tumors

■ Myotonic dystrophy: muscle weakness with inability to release grip, balding, cataracts, mental retardation, cardiac: arrhy thmias

Autosomal recessive: look for family history and unaffected parents who pass the disease to 25% of children:

■ Sphingolipidoses (e.g., Tay-Sachs disease, Gaucher's disease; exception is Fabry's disease, which is X linked)

■ Mucopolysaccharidoses (e.g., Hurler's disease; exception is Hunter's disease, which is-X-linked)

■ Glycogen storage diseases (e.g., Pompe's and McArdle's disease.) « Cystic fibrosis h Galactosemia: look for congenital cataracts, neonatal sepsis; avoid galactose- and lactose-

containing foods a Amino acid disorders (e.g., phenylketonuria, alkaptonuria)

■ Sickle cell disease

H Children s polycystic kidney disease »Wilson's disease b Hemochromatosis (usually)

■ Adrenogenital syndrome (e.g., 21-hydroxylase deficiency)

X-linked recessive: look for affected fathers to pass the gene only to their daughters, who become carriers but do not get disease. Carrier mothers (family history in male relatives) who pass the gene to their sons, who get the disease:

a Hemophilia

■ G-6-P-D deficiency a Fabry's disease

■ Hunter's disease

■ Lesch-Nyhan syndrome: liypoxanthine-guanine phosphoribosyltransferase enzyme deficiency. Look for mental retardation and self-mutilation (patients may bite off their own fingers)

h Duchenne muscular dystrophy

■ Wiscott-Aldrich syndrome

■ Bruton's agammaglobulinemia

■ Fragile X syndrome: second most common cause of mental retardation in males (after Down syndrome). Patients have large testes.

Polygenic disorders: relatives are more likely to have disease, but there is no obvious heritable pattern:

s Pyloric stenosis

■ Cleft lip and/or palate a Type II diabetes

Obesity a Neural tube defects s Schizophrenia

Bipolar disorder

■ Ischemic heart disease a Alcoholism

Chromosomal disorders

« Down syndrome (trisomy 7.1): most common known cause of mental retardation. The major risk factor is age of the mother (1/1500 offspring of 16-year- old mothers, 1/25 for 45-year-old mothers). At birth look for hypotonia, transverse palmar crease, and characteristic facies. Congenital cardiac defects (especially ventral septal defect) are common, and patients are at increased risk for leukemia, duodenal atresia, and early Alzheimer's disease.

Edwards syndrome (trisomy 18): more common in females than males. Patients are small for their age and have mental retardation, small head, hypoplastic mandible, low-set ears, and clenched fist with index finger overlapping third and fourth fingers (almost pathognomonic).

Patau's syndrome (trisomy 13): mental retardation, apnea, deafness, holoprosencephaly (fusion of cerebral hemispheres), myelomeningocele, cardiovascular abnormalities, rocker-bottom feet.

Turner's syndrome (XO instead of XX): lymphedema of neck at birth, short stature, webbed neck, widely spaced nipples, amenorrhea, and lack of breast development (due to primary ovarian failure). Coarctation of the aorta is common, and patients may have horse -shoe kidneys or cystic hygroma.

Klinefelter's syndrome (XXY): tall patient with microtc.stes (< 2 cm in length), gynecomastia, sterility (the classic presentation is for infertility), arrd decreased IQ.

Cri-dn-ebat: due to a deletion on the short arm of chromosome 5; look for high-pitched cry like a cat along with severe mental retardation.


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