An 8-year-old boy presents to your clinic with a 3-day history of a “white coating” in his mouth. He denies having a sore throat, upper respiratory infection symptoms, gastrointestinal distress, change in appetite, or fever. His immunizations are current, he has no significant past medical history, and he has been developing normally per his mother. His weight, however, has fallen from the 25th percentile to the 5th percentile, and he has been hospitalized on three occasions in the last year with pneumonia or dehydration. His family history is remarkable only for maternal hepatitis C infection related to past intravenous (IV) drug use. The patient is afebrile today, but his examination is notable for severe gingivitis, bilateral cervical and axillary lymphadenopathy, exudates on his buccal mucosa, and hepatomegaly.
What is the most likely diagnosis?
What is the next step in evaluation?
ANSWERS TO CASE 4: Immunodeficiency
Summary: A child with lymphadenopathy, organomegaly, weight loss, recurring infection, and oral lesions consistent with candidiasis.
• Most likely diagnosis: Immunodeficiency.
• Next step in evaluation: Gather additional history, including birth history, details of hospitalizations, dietary history, and patient and family histories of recurring or atypical infection. Consider testing for human immunodeficiency virus type 1 (HIV) and obtaining a complete blood count and comprehensive metabolic panel to assess cell counts, organ function, and nutritional status.
1. Differentiate between primary and secondary immunodeficiency.
2. Understand selected etiologies of pediatric immunodeficiency.
3. Identify and manage pediatric HIV disease.
Recurring infections in this patient presenting with oral lesions, weight loss, and lymphadenopathy are concerning for immune system dysfunction. He may have a primary immunodeficiency due to an inheritable defect or an acquired (secondary) immunodeficiency related to HIV infection, malignancy, malnutrition, or other disorder. The maternal history of IV drug use makes pediatric HIV infection a strong likelihood, probably due to vertical transmission. Additional patient and family histories and selected initial laboratory tests will aid in diagnosis and help guide management.
The Child with Immunodeficiency
HIV DNA POLYMERASE CHAIN REACTION (PCR): Primary assay to diagnose HIV infection in children under 18 months of age; detects HIV DNA in white blood cells; sensitivity and specificity greater than 95%; definitive exclusion of HIV with two negative assays after 1 month of age, assuming other immunologic studies are negative.
HIV ANTIBODY ELISA: Enzyme-linked immunosorbent assay (ELISA) screening for HIV immunoglobulin G (IgG); initially detectable 2 weeks to 6 months after exposure; sensitivity and specificity greater than 99%; false-positive rate less than 5 in 100,000 assays; false-negative results may occur after immunization or in hepatic disease, autoimmune disease, or advanced acquired immunodeficiency syndrome (AIDS).
WESTERN BLOT: Direct visualization of antibodies to virion proteins; can be used to confirm screening antibody assay; results can be indeterminate and require repeat testing.
CD4 (T HELPER) CELL: Essential for humoral (B-cell) and cellular (T-cell) immunity; binds to antigens presented by B cells, prompting antibody production, and to antigens presented by phagocytes, prompting lymphokine release; rendered dysfunctional in HIV infection.
Evaluation of patients with recurring or atypical infection starts with a comprehensive history and systems review. Clinicians should inquire about perinatal history, growth and development, and past illnesses. Immunosuppressionis suggested by failure to thrive (FTT) or atypical or difficult-to-eradicate infections (recurring otitis refractory to multiple antimicrobials). Family history includes parental health concerns (unexplained weight loss, growth failure, or developmental delay in siblings) and recurring or atypical infection in immediate family members. A focused physical examination should then be performed to identify signs consistent with immunosuppression (wasting, generalized lymphadenopathy, and organomegaly).
Primary (syndromic) immunodeficiency is due to a genetic defect, either inherited or related to gene mutation; most are humoral in origin or characterized by both humoral and cellular dysfunction (severe combined immunodeficiency). Other primary immunodeficiencies include phagocytic cell deficiency (chronic granulomatous disease due to defective macrophages) and complement deficiency (autoimmune disease or serious bacterial infection due to C2 deficiency). Patients with secondary immunodeficiency have normal immune function at birth, but subsequently develop an illness or metabolic abnormality that disrupts immune cell production or function. Conditions adversely affecting a patient’s immune status include HIV infection, diabetes mellitus, malnutrition, hepatic disease, autoimmune disease (scleroderma), aging, and stress.
HIV is a global epidemic, with over 30 million people presumably infected worldwide. Unprotected sexual intercourse and needle sharing with IV drug use are known means of transmission. Prior to the mid-1980s, blood transfusion was also a risk factor. In the pediatric population, HIV is typically acquired through vertical transmission. Approximately 80% of pediatric cases involve intrapartum transfer, but HIV can also be acquired from infected secretions at delivery and from breast milk. It is important to know the HIV status of the pregnant female, so that antiretroviral therapy can be administered during pregnancy to decrease viral replication and diminish the potential for transfer to the neonate. An infected mother has a 25% chance of transmitting the virus to her newborn if antiretroviral therapy is not received during pregnancy. Zidovudine, when started by the mother during the second trimester and given to the baby through the age of 6 weeks, reduces the risk of HIV transmission to less than 10%.
HIV infection gives rise to dysfunctional CD4 cells resulting in overall immune system compromise and eventual opportunistic infection. Approximately 75% of pediatric patients who acquire HIV vertically follow a course similar to adults, with an extended period of disease inactivity; a patient will often remain asymptomatic for a decade or more until the CD4 count falls to a critical level. The remainder of patients progress rapidly during the first several months of life. Therefore, early determination of maternal HIV status and measures to decrease transmission are critical (avoiding breast-feeding, aggressive and appropriate neonatal HIV testing, early antiretroviral therapy).
Verification of HIV infection is made in the patient older than 18 months by performing an HIV antibody ELISA and subsequent Western blot for confirmation. Because of placental transfer of maternal antibodies, diagnosis in younger patients is made by HIV DNA PCR testing. Two assays are performed on separate occasions to confirm the diagnosis. Subsequently, HIV RNA activity, CD4 cell count, and clinical findings are used to determine disease status. Centers for Disease Control and Prevention (CDC) classification of HIV status is based on the presence and severity of signs or symptoms and degree of immunosuppression. For example, a patient with Pneumocystis jiroveci (carinii) pneumonia (PCP), an AIDS-defining opportunistic infection, is classified “severe” disease (category C). Degree of immunosuppression is based on an age-adjusted CD4 count. For the patient in this case, a normal CD4 count would be more than or equal to 500 or 25%. Severe suppression is denoted by a CD4 count less than 200 or 15%.
Neonates born to HIV-positive women are tested at birth and at selected intervals through approximately 6 months of age. Traditionally, the exposed neonate receives 6 weeks of antiretroviral therapy in the form of zidovudine starting in the first few hours of life. PCP prophylaxis in the form of trimethoprim (TMP)-sulfamethoxazole (SMX) commences at approximately 6 weeks of age for HIV-positive infants. CD4 levels are followed in quarterly intervals in the patient who becomes HIV-positive. HIV RNA activity is followed and typically correlates with disease progression; RNA activity of more than 100,000 copies/mL has been associated with advanced progression and early death.
Treatment for HIV-positive patients is started early to diminish viral replication before mutation and antiretroviral resistance occur. The three major classes of anti-retrovirals are nucleoside reverse transcriptase inhibitors(didanosine, stavudine, zidovudine),nonnucleoside reverse transcriptase inhibitors (efavirenz, nevirapine), and protease inhibitors (indinavir, nelfinavir). Combination retroviral therapy in children has led to a marked decline in child mortality. Common adverse effects for all include headache, emesis, abdominal pain, and diarrhea. Osteopenia and drug rash can also be seen. Possible other abnormalities include anemia, neutropenia, elevated transaminases, hyperglycemia, and hyperlipidemia.
The current pediatric antiretroviral therapy recommendation consists of three drugs: two nucleoside reverse transcriptase inhibitors and one protease inhibitor. An existing treatment regimen is altered when toxicity becomes an issue or disease progression occurs. Ultimately, HIV treatment requires a multidisciplinary approach with input from nutritionists, social workers, and pediatric HIV and mental health specialists. In addition to periodic monitoring of viral activity and prophylaxis against opportunistic infection, close monitoring of growth, development, and emotional health is important in pediatric HIV disease management. Immunizations should be kept current, with all vaccines administered per the recommended pediatric schedule, excluding live vaccines such as measles-mumps-rubella (MMR) and varicella for symptomatic HIV-infected children with a CD4 count less than 15%.
4.1 A 15-year-old adolescent girl has a 1-month history of urinary frequency without dysuria and the complaint of a recent onset of an itchy rash beneath both breasts. She has been gaining weight over the past year and regularly complains of fatigue. She is a febrile with a weight greater than the 99th percentile and has an erythematous, macular rash beneath both breasts characterized by satellite lesions. Urinalysis is significant for 2+ glucosuria, but no pyuria. Which of the following is the best next step in your evaluation?
A. HIV RNA level
B. Hemoglobin A1c
C. CD4 cell count
D. Herpes simplex virus-1 IgG
E. Thyroid stimulating hormone
4.2 A mother notes her 6-week-old son’s umbilical cord is still attached. His activity and intake are normal; he has had no illness or fever. Delivery was at term without problems. His examination is notable for a cord without evidence of separation and a shallow, 0.5-cm ulceration at the occiput without discharge or surrounding erythema. Mother declares that the “sore,” caused by a scalp probe, has been slowly healing since birth and was deemed unremarkable at his 2-week checkup. Which of the following is consistent with this child’s likely diagnosis?
A. Defective humoral response
B. Functional leukocyte adherence glycoproteins
C. Marked neutrophilia
D. Normal wound healing
E. Purulent abscess formation
4.3 A 6-month-old girl is seen after an emergency room visit for decreased intake, emesis, and watery diarrhea for the past 3 days. She was diagnosed yesterday with “stomach flu” and given IV fluids. She is doing better today with improved intake and resolution of her emesis and diarrhea. The father is concerned about her thrush since birth (despite multiple courses of an oral antifungal), and that she has been hospitalized twice for pneumonia over the past 4 months. Her weight has dropped from the 50th percentile on her 4-month visit to the 5th percentile today. She has no findings consistent with dehydration, but she does appear to have some extremity muscle wasting. Her examination is remarkable for buccal mucosal exudates and hyperactive bowel sounds. Vital signs and the remainder of her examination are normal. You suspect severe combined immunodeficiency (SCID). Which of the following is consistent with the diagnosis?
A. Autosomal dominant inheritance
B. Persistent lymphocytosis
C. Defective cellular immunity
D. Normal vaccine immune response
E. No curative therapy
4.4 You are called urgently to examine a term, 2-hour-old newborn with temperature instability, difficulty with feeding, and a suspected seizure. He has atypical facies (wide-set eyes, a prominent nose, and a small mandible), a cleft palate, and a holosystolic murmur. A chest radiograph reveals a boot-shaped heart. Which of the following is consistent with this infant’s likely diagnosis?
B. Chromosomal duplication
C. Parathyroid hyperplasia
E. Thymic aplasia
4.1 B. The obese adolescent in this case has findings of diabetes mellitus. An elevated hemoglobin A1c (glycosylated hemoglobin) is a good diagnostic tool for diabetes. This patient’s cutaneous candidiasis is likely an indication of secondary immunosuppression related to hyperglycemia. In diabetes, hyperglycemia promotes neutrophil dysfunction, and circulatory insufficiency contributes to ineffective neutrophil chemotaxis during infection. HIV infection is possible and testing might be reasonable, but this scenario is most consistent with hyperglycemia.
4.2 C. You suspect leukocyte adhesion deficiency (LAD) as the etiology of this child’s problem. LAD is an inheritable disorder of leukocyte chemotaxis and adherence characterized by recurring sinopulmonary, oropharyngeal, and cutaneous infections with delayed wound healing. Neutrophilia is common with WBC counts typically more than 50,000 cells/mm3. Severe, life-threatening infection is possible with Staphylococcus species, Enterobacteriaceae,and Candida species. Good skin and oral hygiene are important; broad-spectrum antimicrobials and surgical debridement are early considerations with infection.
4.3 C. Severe combined immunodeficiency (SCID) is an autosomal recessive or X-linked disorder of both humoral and cellular immunity. Serum immunoglobulins and T cells are often markedly diminished or absent. Thymic dysgenesis is also seen. Recurring cutaneous, gastrointestinal, or pulmonary infections occur with opportunistic organisms such as cytomegalovirus (CMV) and Pneumocystis pneumonia(PCP). Death typically occurs in the first 12 to 24 months of life unless bone marrow transplantation is performed.
4.4 E. The child in the question has typical features of DiGeorge syndrome, caused by a 22q11 microdeletion. This syndromic immunodeficiency is characterized by decreased T-cell production and recurring infection. Findings include characteristic facies and velocardiofacial defects such as ventricular septal defect and tetralogy of Fallot. Thymic or parathyroid dysgenesis can occur, accompanied by hypocalcemia and seizures. Developmental and speech delay are common in older patients.
Primary immunodeficiency is an inheritable disorder characterized by weakened immunity and recurring, serious infection early in life.
A variety of illnesses can provoke secondary immunodeficiency; malignancy, malnutrition, hepatic disease, and HIV infection are known to adversely influence both humoral and cellular immunity.
Pediatric HIV disease can be deterred by appropriate testing and treatment of pregnant females and judicious antiretroviral prophylaxis in the exposed neonate. Exposed patients should be closely followed by clinicians and a team approach used in the management of active disease.
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