case studies 2

scid

Mr and Mrs Causubon had a normal daughter 3 years after they were married. Two years later they had a son and named him Martin. He weighed 3.5 kg at birth and seemed to be perfectly normal. At 3 months of age, Martin developed a runny nose and a persistent dry cough. One month later he had a middle ear infection (otitis media) and his pediatrician treated him with amoxicillin. At 5 months of age Martin had a recurrence of otitis media. His cough persisted and a radiological examination of his chest revealed the presence of pneumonia in both lungs. He was treated with another antibiotic, clarithromycin. Mrs Causubon noticed that Martin had thrush (Candida spp.) in his mouth (Fig. 5.6) and an angry red rash in the diaper area. He was not gaining weight; he had been in the 50th centile for weight at age 2 months, but by 6 months he had fallen to the 3rd centile. His pediatrician had given him diphtheria–pertussis–tetanus (DPT), hemophilus, pneumococcus, and inactivated polio vaccine at 2, 4, and 6 months, according to the calendar. Martin’s pediatrician referred him to the Children’s Hospital for further studies. On admission to the hospital, he was fretful and had tachypnea (fast breathing). A red rash was noted in the diaper area as well as white flecks of thrush on his tongue and buccal mucosa. His tonsils were very small. He had a clear discharge from his nose, and cultures of his nasal fluid grew Pseudomonas aeruginosa. Coarse, harsh breath sounds were heard in both lungs. His liver was slightly enlarged. Martin’s white blood count was 4800 cells μl –1 (normal 5000–10,000 cells μl –1) and his absolute lymphocyte count was 760 cells μl –1 (normal 3000 lymphocytes μl –1). None of his lymphocytes were stained by an antibody to CD3, and it was concluded that he had no T cells. Ninety-nine percent of his lymphocytes bound antibody against the B-cell molecule CD20, and 1% were natural killer (NK) cells reacting with anti-CD16. His serum contained IgG at a concentration of 30 mg dl–1, and IgM at 12 mg dl–1. Serum IgA were undetectable. His blood mononuclear cells were completely unresponsive to phytohemagglutinin (PHA), concanavalin A, and pokeweed mitogen (Fig. 5.7), as well as to specific antigens to which he had been previously exposed by immunization or infection—tetanus and diphtheria toxoids, and to Candida antigen. His red cells contained normal amounts of adenosine deaminase and purine nucleoside phosphorylase. Cultures of sputum for bacteria and viruses revealed the abundant presence of respiratory syncytial virus (RSV). At this point a blood sample was obtained from Martin’s mother to examine her T cells for random inactivation of the X chromosome (a diagnostic test explained in the answer to Question 1 in Case 1). It was found that her T cells exhibited complete nonrandom X-chromosome inactivation. Search for mutations in the IL2RG gene revealed deletion of a single A nucleotide in exon 2, leading to a frameshift. HLA typing showed that Martin’s sister had no matching HLA alleles. His parents, as expected, each shared one HLA haplotype with Martin. Martin was treated with intravenous gamma globulin at a dose of 0.5 g kg–1 body weight every 3 weeks, and his serum IgG level was maintained at 600 mg dl–1 by subsequent IgG infusions. He was given aerosolized ribavirin to control his RSV infection and trimethoprim-sulfamethoxazole for prophylaxis against Pneumocystis jirovecii. Without any chemotherapy, Martin was given 5 × 106 kg–1 CD34+ cells that had been purified from his mother’s bone marrow. Three months after receiving the maternal bone marrow, Martin’s blood contained 600 maternal CD3+ T cells μl –1, which responded to PHA. His immune system was slowly reconstituted over the ensuing 3 months, but he remained unable to produce IgA and to make specific IgG antibodies. Therefore, Martin continues to require substitution therapy with intravenous immunoglobulin (400 mg kg–1 every 3 weeks).

aids

Martin Thomas is a 42-year-old police officer, who has always been in good health. He has been married for 10 years and has one child, an 8-year-old daughter. Six months ago he went to the emergency room at the local hospital complaining of a fever and a swollen right hand. He was admitted to the hospital for the hand infection, which was assumed to be the result of a cat scratch. His blood lymphocyte count was found to be very low, so a blood sample was sent to be tested for antibodies against the human immunodeficiency virus (HIV). The testing was done according to the algorithm illustrated in Fig. 10.2. ELISA (enzyme-linked immunosorbent assay) revealed the presence of anti-HIV antibodies and p24 antigen. Further testing using an FDA-approved immunoassay that differentiates HIV-1 from HIV-2 antibodies was positive for HIV-1 antibodies, indicating the presence of an HIV-1 infection. The results were reported to the patient’s physician and the state public health authorities, according to the guidelines in Fig. 10.3. Officer Thomas was referred to Dr Wright, an AIDS specialist, at the Massachusetts General Hospital. Mr Thomas told Dr Wright that he had had several sexual encounters with both women and men before his marriage 10 years ago. He had always been in good health until 6  months before the present consultation, when he began to have drenching night sweats several times a week. Over this period his body weight had gone down from 94.5 kg to 90 kg. He could not remember having any infections other than the one in his hand, nor any rashes, gastrointestinal problems, cough, shortness of breath, or any other symptoms. His mother had been 84 years old when she died of a heart attack, and his father had died at age 87 from cirrhosis of the liver, cause unknown. His wife and child were both in good health and his wife, pregnant with their second child, had recently tested negative for anti-HIV antibodies. Mr Thomas told Dr Wright that he did not smoke or use intravenous drugs. He drank large amounts of beer on weekends. A cat and a dog were the only pets in the house. On physical examination his blood pressure was 130/90, his pulse rate 92, and temperature 37.5ºC (all normal). Nothing abnormal was found during the physical examination. His white blood cell count was 5800 μl –1 (normal), his hematocrit was 31.3 (slightly low), and his platelet count was 278,000 μl –1 (normal). His CD4 T-cell count was low at 170 μl –1 (normal 500–1500 μl –1) and his HIV-1 RNA viral load was 67,000 copies μl –1. Mr Thomas was prescribed trimethoprim-sulfamethoxazole for prophylaxis against Pneumocystis jirovecii pneumonia (see Case 5). He was also given a combination antiretroviral agent consisting of tenofovir (TDF), emtricitabine (FTC), and efavirenz (Sustiva). He was counseled not to have sexual contact with his wife until his HIV viral load was suppressed, and to always use barrier protection thereafter. Because of her pregnancy, he was asked to immediately share his diagnosis with his wife and for her to see her obstetrician and an infectious disease specialist urgently to be HIV tested by viral load. She did so and was negative. After 5 weeks of this therapy, Mr Thomas’s HIV-1 viral load declined to 400 copies of RNA μl –1 and after 8 weeks to <20 copies of RNA μl –1, in other words, to suppressed levels. In the meantime his CD4 T-cell count rose to 416 μl –1. The prophylaxis for Pneumocystis was discontinued. Mr Thomas remains well and active and works full time; his wife delivered a healthy baby boy and remains uninfected.

gvhd

John was healthy until he was 7 years old, when his mother noticed that he had become very pale. She also noticed small hemorrhages (petechiae) on the skin of his arms and legs and took John to the pediatrician. Apart from the pallor and skin petechiae, a physical examination showe d nothing unusual. The pediatrician ordered blood tests, which revealed that John was indeed very anemic. His hemoglobin was 7 g dl–1 (normal 10–15 g dl–1) and platelet count was 20,000 μl –1 (normal 150,000–300,000 μl –1). His white blood cell count was also lower than normal. The pediatrician sent John to a hematology consultant for a bone marrow biopsy. The biopsy showed that John’s bone marrow had very few cells and that red cell, platelet, and white cell precursors were almost completely absent. Aplastic anemia (bone marrow failure) of unknown cause was diagnosed. Aplastic anemia is ultimately fatal but can be cured by a successful bone marrow transplant. Fortunately, John had an HLA-identical 11-year-old brother who could be the bone marrow donor. John was admitted to the Children’s Hospital and given a course of horse anti-thymocyte globulin (ATG), fludarabine, and cyclophosphamide to eradicate his own lymphocytes. He was then given 2 × 108 nucleated bone marrow cells per kg body weight obtained from his brother’s iliac crests. He was also started on cyclosporin A (CsA) to prevent GVHD. John did well for 3 weeks after the bone marrow transplant. However, in spite of GVHD prophylaxis with CsA, on the 24th day after the transplant he developed a skin rash and watery diarrhea consistent with acute GVHD. He had a patchy red rash on palms and soles, scalp, and neck. He had no fever and was not jaundiced. His lungs were clear and the heartbeat normal. The liver and spleen were not enlarged. John was treated with corticosteroids. His skin rash faded, but the intestinal symptoms did not abate and the diarrhea became more profuse. He was given rabbit ATG for two consecutive days. This brought about a 90% decrease in the volume of his stool and the intestinal bleeding stopped. Two weeks later, John was sent home, with continuing treatment with low doses of corticosteroid, and his GVHD remained under control.

ra

Ariadne Underwood teaches a class of sixth-graders. When she was 30 years old, Ariadne developed stiffness in her shoulders, hands, knees, and hips. The stiffness lasted for about an hour every morning, and increased in intensity over the course of several months. After her wrists and fingers began to swell, she saw her primary care physician. Her medical history indicated that a maternal aunt had rheumatoid arthritis, a disease that led to markedly deformed hands, wrist swelling that required surgical fusion for pain control, and bilateral total knee replacements. Based on these findings, the primary care doctor suspected that Ms Underwood had rheumatoid arthritis and advised her to take four aspirin tablets a day. He also obtained a blood sample, which was positive for RF. The patient was referred to a rheumatologist, Dr Shaw. On physical examination, the patient’s blood pressure, pulse, and respiratory rate were all normal, and she had no fever. Dr Shaw felt spongy swelling indicating thickening of the synovium in both elbows, as well as swelling and decreased flexion and extension of her wrists, second and third metacarpophalangeal (MCP) joints, and second and third proximal interphalangeal (PIP) joints. Her hemoglobin was 11.4 g dl–1, and her hematocrit was 33.4% (she was slightly anemic). Her white blood cell count was 4720 μl –1 (slightly low). Her sedimentation rate was 87 mm h–1 (very high). A test for recent parvovirus infection was negative, while anti-cyclic citrullinated peptide (CCP) antibodies were positive (see below). A urinalysis was normal. X-rays of her hands and feet revealed erosions in several joints. Dr Shaw confirmed the diagnosis of seropositive, erosive rheumatoid arthritis (“seropositive” indicates positive tests for RF and/or CCP). Treatment was initiated with ibuprofen, a nonsteroidal anti-inflammatory drug (NSAID), 600 mg every 6 hours; prednisone, a glucocorticoid preparation, 10 mg every morning; and methotrexate, a disease-modifying antirheumatic drug (DMARD), 20 mg weekly. At her follow-up visit one month later, the patient reported substantial relief from pain, but joint swelling and tenderness persisted. Three months after initiation of treatment, joint inflammation (synovitis) was still evident on examination. Dr Shaw initiated treatment with weekly subcutaneous etanercept (Enbrel), a TNF-α antagonist. Ms Underwood experienced rapid improvement in her pain and morning stiffness, and 9 months after diagnosis her joint exam normalized and she was able to discontinue NSAIDs and steroids altogether. Over the next several years, she was able to continue all her usual activities, and serial X-rays revealed no further joint erosion, although she experienced occasional disease flares managed with NSAIDs or short courses of prednisone. She was unable to taper off either methotrexate or etanercept.

lupus

Nicole Chawner was a healthy 16-year-old until this summer. A few days after excessive exposure to the sun on the beach, Nicole developed a red rash on her cheeks. She saw her family doctor, who recognized that the butterfly rash on her cheeks and bridge of her nose was typical of systemic lupus erythematosus (SLE) (Fig. 36.3). He referred Nicole to the Children’s Hospital, where she was asked about any other problems she might have noticed. Nicole said that when she woke up in the morning her fingers and knees were stiff, although they became better as the day progressed. Nicole had also noticed some symmetric swelling in her fingers. A blood sample was taken from Nicole to ascertain whether she had anti-nuclear antibodies (ANA). These were positive, at a titer of 1:1280 (low titers of ANA are found in more than 10% of otherwise healthy people). Because of this result, further tests were performed for antibodies characteristically found in SLE. An elevated titer of antibodies against double-stranded DNA was also found. Her serum C3 level was 73 mg dl–1 (normal 100–200 mg dl–1). Her platelet count was normal at 225,000 μl –1, and her direct and indirect Coombs tests were negative, as was a test for anti-phospholipid antibodies. A urine sample was also found to be normal. Nicole was advised to take an antimalarial agent, hydroxychloroquine sulfate (Plaquenil), avoid direct sunlight, and apply protective sun cream. She did well for a while but, after a month, the morning stiffness in her fingers and knees worsened. She developed a fever of 39ºC each evening accompanied by shaking chills. Enlarged lymph nodes were felt behind her ears and in the back of her neck. She also lost 4.6 kg over the course of the next 2 months. When she returned to the hospital for a check-up, it was noted that her butterfly rash had disappeared. She had diffuse swelling of the proximal joints in her fingers and toes. Blood was drawn at this time, and the titer of anti-DNA antibodies had increased further. The serum C3 level had dropped to 46 mg dl–1. Nicole was advised to take 10 mg of prednisone twice a day, as well as 250 mg of the nonsteroidal antiinflammatory drug naproxen twice a day. This quickly controlled her symptoms, and she remained well. At her next visit, her serum C3 level was 120 mg dl–1.

crohns

Dorian was a healthy 8-year-old when he developed painful swelling and redness of his right elbow. The following day, he developed mouth ulcers (aphthous ulcers) that persisted for several days. He was taken to the pediatrician, who thought that the ulcers could be due to a Coxsackie virus infection. X-rays of the elbow were done and showed no fracture or injury. Over the next 2 months, Dorian developed frequent poorly localized abdominal pain. Passing stools was particularly difficult, and his parents would often find Dorian crying in the bathroom. He had difficulties with constipation, passing three hard stools per week, but had no bloody stool or sensation of incomplete bowel evacuation. The severity of Dorian’s abdominal pain, elbow swelling, and oral ulcers seemed to wax and wane over the next 2 months. Dorian developed daily low-grade fevers, at times as high as 39ºC. His abdominal pain became more severe and he passed stools more frequently. Dorian was fatigued and listless and was unable to attend school. His appetite was very poor and his parents noticed that he had lost about 3.5 kg over the previous 2 months. He was seen again by his pediatrician, who set up outpatient appointments to investigate Dorian’s illness. But when Dorian developed painful red lesions on his right shin and a pain in his jaw soon after this visit, his parents became concerned and brought him to the Children’s Hospital Emergency Department. The Grays were asked about the health of their family and told the staff that there was no history of inflammatory bowel disease or autoimmune illness. When examined, Dorian looked ill, tired, and pale. Numerous aphthous ulcers were present in his mouth. His abdominal examination showed no focal tenderness or masses. Two inflamed anal skin tags were found and the rectal exam showed no tenderness, fissures, or evidence of occult blood. Several raised, red skin lesions were present on Dorian’s shins and his right elbow was swollen and warm. The skin lesions were recognized as erythema nodosum—acute nodular erythematous eruptions that typically occur on the lower extremities.

Blood tests were sent to check for evidence of infection or inflammation. The white blood cell count was elevated at 14,700 μl –1 (normal 5,700–9,900 μl –1), and the platelet count was high at 759,000 μl –1 (normal 198,000–371,000 μl –1). The erythrocyte sedimentation rate (ESR), an index of systemic inflammation, was elevated at 80 mm h–1 (normal 0–20 mm h–1). The level of another acute-phase reactant, C-reactive protein (CRP), was also high at 2.2 mg dl–1 (normal less than 0.5 mg dl–1). Dorian was told to return for an upper and lower endoscopy the following week. On endoscopy, Dorian’s pediatric gastroenterologist found ulceration of the esophagus and small intestine, and a perianal fistula (Fig. 37.3). The pathologist found neutrophilic infiltration of the esophageal and ileal lesions, active colitis with rare crypt abscesses, but no granulomatous inflammation (Fig. 37.4). The arthritis, oral aphthous ulcers, erythema nodosum lesions on the shins, and the endoscopic findings were all consistent with a diagnosis of Crohn’s disease, and Dorian was started on a proton pump inhibitor to treat the esophageal lesions and oral corticosteroids as an initial anti-inflammatory treatment. Over subsequent months, additional immunosuppressive agents in combination with oral steroids were tried, including 6-mercaptopurine and infusions of antibodies (infliximab and adalimumab) that inhibit the proinflammatory cytokine tumor necrosis factor-α (TNF-α). Unfortunately, Dorian’s symptoms were not completely controlled. A year after receiving his diagnosis, Dorian developed worsening fever and abdominal pain, and an abdominal mass in the right lower quadrant could be felt. He was admitted to the Children’s Hospital; abdominal ultrasound and CT scans revealed a large abscess of the distal small intestine (ileum and cecum). He was treated with intravenous antibiotics and was taken to the operating room, where the ileum and cecum were resected (ileocecectomy) and multiple smaller abscesses were drained. Dorian recovered well from surgery, continues to take weekly adalimumab injections, and has been able to discontinue steroid therapy. Although the weekly injections are difficult for Dorian and his family, the abdominal, skin, and joint symptoms of his Crohn’s disease are all well controlled.

ms

Mrs Vivie Warren, a 29-year-old professional oboe player, was in good health until one morning she noticed a loss of vision in her left eye. Her physician referred her to a neurologist, who found that her eye movement was normal and not accompanied by any pain. The visual acuity in Vivie’s left eye was 20/100 and in her right eye 20/200. Her retina was normal, and a detailed neurologic examination also proved normal. The neurologist diagnosed optic neuritis (inflammation of the optic nerve). Her family history, however, revealed that her mother had severe MS and was permanently disabled, and a magnetic resonance imaging (MRI) brain scan was ordered. Vivie was given a 5-day course of intravenous corticosteroids, and her vision returned to normal over the next 3 weeks. The MRI scan revealed multiple lesions in the white matter of the brain under the cortex and around the ventricles (Fig. 38.2). Intravenous injection of gadolinium, a contrast agent that leaks from blood vessels in recently inflamed tissue, showed that some of the brain lesions were probably of recent origin (Fig. 38.3). The neurologist told Vivie that she had a high probability of developing MS and advised her to return for frequent neurologic examination. Vivie remained well for a further 3 years and then developed weakness of the muscles on the left side of her face that were innervated by the seventh cranial nerve. A repeat MRI scan with gadolinium enhancement showed new lesions in the left middle cerebellar peduncle and in the pons. CSF was obtained by lumbar puncture. It contained 28 mg dl–1 protein (normal) and 8 lymphocytes ml–1 (normal 0–3 ml–1). At this point a firm diagnosis of MS was made. Despite the normal level of protein in the CSF, the IgG content was raised. On electrophoresis, discrete bands of IgG were observed, indicating clonal expansion of restricted B-cell populations in the central nervous system (CNS). Another 5-day course of corticosteroids was administered intravenously, and Vivie’s symptoms improved. Weekly intramuscular injections of interferon (IFN)-β were started to prevent progression of the disease.

Vivie did well for 3 more years, after which she developed a weakness in her left leg and left hand. Her speech became slurred. She developed nystagmus (rapid uncontrolled horizontal jerking eye movements when attempting to fix the gaze on something) and ataxia (wide-based staggering gait). Vivie was given another course of corticosteroids, after which her symptoms improved, but 8 months later they recurred. The injections of IFN-β were stopped and she was put on high doses of cyclophosphamide and corticosteroids at monthly intervals. After 3 months of this therapy, the cyclophosphamide and corticosteroid injections were gradually reduced to every 12 weeks. Her neurological examination became normal and no new lesions were observed on gadolinium-enhanced MRI.

aiha

Gwendolen Fairfax was a healthy, unmarried 34-year-old who worked as a manager in a bank. She had never had any illness other than minor colds and the usual childhood infections. After developing a feverish cough her symptoms got progressively worse over the next few days and she decided to seek the advice of her physician, Dr Wilde. Dr Wilde noted that Gwendolen was extremely pale; this was particularly noticeable in the palms of her hands, which were completely white. (Look at your palms; they have a healthy reddish pink color, unless your hemoglobin level is less than 10 g dl–1). Her temperature was raised, at 38.5ºC, and her respiratory rate was 30 per minute (normal 20). On listening to her chest, the physician heard scattered rhonchi (harsh breath sounds) at the bases of both lungs. The physician ordered blood counts to be performed immediately. Gwendolen’s hematocrit and hemoglobin level were low—hematocrit 26% (normal 38–46%) and hemoglobin 9.5 g dl–1 (normal 13–15 g dl–1). Her white blood cell count was elevated at 11,300 μl –1, with 70% neutrophils, 24% lymphocytes, 6% monocytes, and 1% eosinophils, revealing an increased absolute neutrophil count, and the platelet count was 180,000 μl –1. The chest radiograph showed patchy infiltrates in both lower lungs (Fig. 39.2). Dr Wilde suspected a diagnosis of mycoplasma pneumonia (also known as atypical pneumonia because there was no complete opacity over a whole lobe of the lung such as typically occurs in pneumococcal and other bacterial pneumonias). He advised Gwendolen to go to Reading Hospital. In the hospital, a sputum sample proved negative for bacteria but contained abundant neutrophils. A blood sample was tested for the presence of antibodies against the red blood cells. In the presence of sodium citrate as an anticoagulant, the sample was chilled to 4ºC; the red cells became clumped and the blood looked as though it had clotted. When warmed to 37ºC, however, the red cells dispersed. Thus, the red cells were reversibly agglutinated in the cold. A blood sample was spun in a warmed centrifuge, and the red cells and plasma were separated. Gwendolen’s red cells were tested using direct and indirect Coombs tests for the presence of anti-red cell IgG antibody (see Fig. 44.2); these tests proved negative. Her red cells, however, were strongly agglutinated by an antibody against the complement component C3. When Gwendolen’s plasma, or dilutions of the plasma, were incubated in the refrigerator with red cells from type O normal blood, the red cells were strongly agglutinated; when the same test was performed with red cells obtained from an umbilical cord in the delivery room of the hospital, agglutination was weaker, or negligible. Gwendolen was started on erythromycin. In 3 days her symptoms had abated; she had no fever and her cough had greatly improved. Her hemoglobin had risen to 12 g dl–1. She was discharged from the hospital, and advised to continue erythromycin orally and to avoid exposure to cold weather. When she returned to Dr Wilde’s office 2 weeks later for a check-up, her fever had not returned, her cough had gone, and her hemoglobin was now a normal 14.5 g dl–1.

mg

Mr Weld, a 71-year-old retired engineer, had been in good health and active all his life. He developed double vision (diplopia). Initially, he did not want to seek medical attention because the double vision sometimes improved spontaneously. However, it gradually worsened over the course of 4 months and he finally scheduled an appointment with his physician. On examination, the doctor noticed that Mr Weld had ptosis of both eyelids so that they covered the upper third of the irises of his eyes. When the doctor asked Mr Weld to look to the right and then to the left, he noticed limitations in the ocular movements of both eyes, as shown in Fig. 40.3. The remainder of the neurological examination was normal. No other muscle weakness was found during the examination. A radiological examination of the chest was performed, and it was normal. There was no evidence in the radiograph of enlargement of the thymus gland. A blood sample was taken from Mr Weld, and his serum was tested for antibodies against the acetylcholine receptor. The serum contained 6.8 units of antibody against the acetylcholine receptor (normal less than 0.5 units). Mr Weld was told to take pyridostigmine, an inhibitor of cholinesterase. His double vision improved steadily but he developed diarrhea from the pyridostigmine, and this limited the amount he could take. Three years later, Mr Weld developed a severe respiratory infection. Soon afterward, his ptosis became so severe that he had to lift his eyelids by taping them with adhesive tape. His diplopia recurred and his speech became indistinct. He developed difficulty in chewing and swallowing food. He could only tolerate a diet of soft food and it would take him several hours to finish a meal. On examination the neurologist noted that Mr Weld now had weakness of the facial muscles and the tongue, and the abnormality in ocular movements again became apparent. Because of the diarrhea Mr Weld was only able to tolerate one-quarter of the prescribed dose of pyridostigmine. He also developed difficulty in breathing. His vital capacity (the amount of air he could exhale in one deep breath) was low, at 3.5 liters. He was admitted to hospital and treated with azathioprine. Thereafter he showed steady improvement. His ptosis and diplopia improved remarkably and he was able to eat normally. His vital capacity returned to normal and was measured to be 5.1 liters.

celiac

Demeter O’Reilly was a healthy baby who grew normally until 12 months old, when her parents noticed that she became irritable and stopped gaining weight. She was observed closely by her pediatrician for the next 3 months during which time she developed a distended abdomen, passed large, foul-smelling stools, and lost nearly 2 kg in weight. Her parents also noticed that Demeter was becoming progressively weaker. At birth, Demeter weighed 3.8 kg, was 52 cm long, and had a head circumference of 36 cm (all within the normal range). Both of her parents were of Irish American ancestry and were healthy, as was her 3-year-old sister. There was no known history of metabolic, neurologic, or gastrointestinal disease in children in the family. There was no history of autoimmune diseases, including type 1 diabetes mellitus or autoimmune thyroid disease. Given the progression of her symptoms and the weight loss, Demeter was referred to the Children’s Hospital Emergency Room at 15  months. When she arrived she appeared pale and chronically ill. She weighed 8.5 kg (5th centile), her height was 77.5 cm (50th centile), and her head circumference was 46 cm (50th centile). The examination made Demeter fretful but she could be consoled. She was mildly dehydrated, and had a protuberant abdomen and significant muscle wasting in her buttocks, legs, and arms (Fig. 42.1). No enlargement of liver, spleen, or lymph nodes was evident. Laboratory tests revealed anemia, with a hemoglobin level of 10  g  dl–1 (normal 12–14 g dl–1). Her white-cell count and platelets were normal. She had a mild elevation of liver enzymes (transaminitis), with aspartate aminotransferase at 48 U l–1 (normal range 2–40 U l–1) and alanine aminotransferase at 46 U l–1 (normal range 3–30 U l–1). Her albumin was normal at 3.7 g dl–1. No evidence of metabolic disease was found. Serologic samples for testing for celiac disease were sent to the laboratory. Demeter tested positive for anti-endomysium IgA antibodies (autoantibodies against the connective tissue that sheathes muscle—the endomysium) at a titer of 1:2560 and for anti-tissue transglutaminase (TTG) IgA antibodies at a level greater than 118 U ml–1 (greater than 25 U ml–1 is considered positive). Given Demeter’s symptoms and the positive serologic results, the decision was made to perform a biopsy of her gastrointestinal tract. An upper gastrointestinal endoscopy revealed edema and flattening of the mucosal folds in the duodenal bulb. Multiple biopsies were taken from the distal duodenum and duodenal bulb. Review of the pathology of the tissues showed subtotal to total villous atrophy, crypt hyperplasia and increased intraepithelial lymphocytes (Marsh type 3 lesion) (Fig. 42.2). The clinical presentation, serology, and biopsy results confirmed the diagnosis of celiac disease.

Demeter’s family received extensive nutritional counseling and she was started on a gluten-free diet. At the 6-month follow-up, she was doing extremely well, with an excellent energy level. She had normal bowel movements once a day and had no abdominal pain or vomiting. Her weight was now in the 75th centile and her height was at the 50th centile for her age. She appeared a robust and healthy toddler with a normal abdomen and muscle bulk. Serologic tests revealed no anti-endomysium and anti-TTG antibodies. Her family had availed themselves of the many sources of advice and support available to families with celiac disease, and felt comfortable with her gluten-free diet.

mono

Emma Bovary was a healthy 15-year-old when she suddenly developed a very sore throat accompanied by fever and malaise. Her throat was so swollen she had difficulty swallowing. Over the next few days the fever waxed and waned, her sore throat became worse, and she became progressively more tired and anorectic (lost her appetite). On the third day of illness her pediatrician noted severe pharyngitis and took a throat culture for β-hemolytic streptococci; the culture proved negative. Emma’s symptoms persisted, and she was unable to eat because she could hardly swallow. She said she had no difficulty breathing but that her left upper abdomen felt slightly uncomfortable. Emma’s 1-year-old brother became ill at the same time, but did not have such severe symptoms. He was merely listless and felt warm. He had no particular physical symptoms, and seemed to recover completely after a few days. On physical examination on the tenth day of illness, Emma appeared very ill. She had a high temperature (38.2ºC), a pulse rate of 84 min–1, a respiratory rate of 18 min–1, and a blood pressure of 85/55 mmHg. Her mouth was dry and her tonsils were red and enlarged. They met in the midline, leaving a passage of only about 2 cm × 2 cm. Palatal petechiae (very small hemorrhages under the mucosa) could be seen. Her anterior and posterior cervical lymph nodes were swollen and tender (lymphadenopathy); the largest nodes were 2 cm × 2 cm. Her abdomen felt soft and the liver was enlarged, the edge being palpable 2  cm below the right costal margin. The spleen was also enlarged; the tip was easily palpable under the left costal margin. A blood test gave a white blood cell count of 18,590 μl –1, with 39% neutrophils, 27% lymphocytes, 22% atypical lymphocytes (very high), and 11% monocytes (high); her hematocrit was 45% and the platelet count 397,000 μl –1. Serum electrolytes were normal. Another throat culture was obtained, and blood tests for Epstein–Barr virus (EBV) were ordered. In the meantime a presumptive diagnosis of acute infectious mononucleosis was made with complications including partial pharyngeal obstruction and mild dehydration. Emma was admitted to the hospital and received 1 liter of normal saline intravenously followed by 20 mg of methylprednisolone (a corticosteroid) intravenously every 12 hours. Her throat culture again proved negative for streptococcus but her blood serum was positive for IgM and IgG antibodies against EBV capsid antigen. Emma improved quickly with the symptomatic treatment and was discharged on the second day after admission to complete her recovery at home.

leprosy

Ursula first sought medical advice when she was 18 years old, having left her home in Colombia to attend Harvard University on a scholarship. From the age of 16 years, she had started to notice a gradual loss of sensation on the backs of her hands and had developed hypopigmented lesions over both arms. The lesions progressively became worse and she noticed that she was losing her eyelashes and hairs from her eyebrows. She also experienced recurrent nosebleeds. A month after first noticing the hair loss she decided to seek medical help. On examination at the physician’s office, Ursula seemed to be well, apart from her immediate symptoms. She reported a history of mild asthma, which required treatment with inhaled β2-adrenergic agents on an as-needed basis. Multiple hypopigmented macules (coin-sized raised lesions with ill-defined borders) were evident on her skin, along with cutaneous nodules 1 cm in diameter. These lesions were predominantly on her elbows, wrists, and hands (Fig. 46.3) and showed traces of dried blood; she also had similar lesions on her knees, ears, and buttocks. The absence of eyelashes and the ends of her eyebrows was obvious. Cardiovascular and abdominal examinations were normal; a neurological examination was negative except for a decreased response to pinprick on the outer edges of the right and left hands and the right fourth and fifth fingers. There was a flexion contracture of the fourth and fifth fingers of both hands so that she could not straighten these fingers completely. On blood test, Ursula’s hematocrit was 35.1%; her white blood count was 7100 μl –1, with 68% neutrophils, 23% lymphocytes, 5% monocytes, and 4% eosinophils (all normal values). Serum electrolytes were normal. Because her symptoms were becoming more severe, Ursula was referred to a dermatologist. She told him that she had grown up in a small village on the Caribbean coast of Colombia where many people, including her mother, had leprosy. The dermatologist performed a biopsy of the lesions on her left arm and right forearm, which revealed numerous acid-fast bacilli in clumps. A routine hematoxylin and eosin stain of lesion tissue showed up numerous Virchow’s cells (highly vacuolated cells of the macrophage lineage, also known as foam cells) and few lymphocytes (Fig. 46.4). Cultures for acid-fast bacilli were negative. The suspected diagnosis of lepromatous leprosy led to a more extensive immunologic work-up. Delayed hypersensitivity skin tests with intradermal injections of candida, mumps, and tuberculin antigens showed no reactions when the injection sites were inspected 48 and 72 hours later. Ursula’s serum IgG was mildly elevated at 1800 mg dl–1 (normal 600–1100 mg dl–1); her IgA and IgM levels were normal. A diagnosis of lepromatous leprosy was made on the basis of the presence of acidfast bacilli in the biopsy and Ursula’s progressive neurologic symptoms. She was placed on a multiple drug regime consisting of dapsone, clofazamine, and rifampin, drugs that kill M. leprae. Her skin lesions gradually flattened and improved.

asthma

Frank Morgan was referred by his pediatrician to the allergy clinic at 14 years of age because of persistent wheezing for 2 weeks. His symptoms had not responded to frequent inhalation treatment (every 2–3  hours) with a bronchodilator, the β2-adrenergic agonist albuterol. This was not the first time that Frank had experienced respiratory problems. His first attack of wheezing occurred when he was 3 years old, after a visit to his grandparents who had recently acquired a dog. He had similar attacks of varying severity on subsequent visits to his grandparents. Beginning at age 4 years, he had attacks of coughing and wheezing every spring (April and May) and toward the end of the summer (second half of August and September). A sweat test at age 5 years to rule out cystic fibrosis, a possible cause of chronic respiratory problems, was within the normal range. As Frank got older, gym classes, basketball, and soccer games, and just going outside during the cold winter months could bring on coughing and sometimes wheezing. He had been able to avoid wheezing induced by exercise by inhaling albuterol 15–20  minutes before exercise. Frank had frequently suffered from a night-time cough, and his colds had often been complicated by wheezing. Frank’s chest symptoms had been treated as needed with inhaled albuterol. During the previous 10 years, Frank had been admitted to hospital three times for treatment of his asthma with inhaled bronchodilators and intravenous steroids. He had also been to the Emergency Room many times with severe asthma attacks. He had maxillary sinusitis at least three times, and each episode was associated with green nasal discharge and exacerbation of his asthma. Since he was 4 years old, Frank had also suffered from intermittent sneezing, nasal itching, and nasal congestion (rhinitis), which always worsened on exposure to cats and dogs and in the spring and late summer. The nasal symptoms had been treated as needed with oral antihistamines with moderate success. Frank had had eczema as a baby, but this cleared up by the time he was 5 years old. Family history revealed that Frank’s 10-year-old sister, his mother, and his maternal grandfather had asthma. Frank’s mother, father, and paternal grandfather suffered from allergic rhinitis. When he arrived at the allergy clinic, Frank was thin and unable to breathe easily. He had no fever. The nasal mucosa was severely congested, and wheezing could be heard over all the lung fields. Lung function tests were consistent with obstructive lung disease with a reduced peak expiratory flow rate (PEFR) of 180 liter min–1 (normal more than 350–400 liter min–1), and forced expiratory volume in the first second of expiration (FEV1) was reduced to 50% of that predicted for his sex, age, and height. A chest radiograph showed hyperinflation of the lungs and increased markings around the airways (Fig. 47.4). A complete blood count was normal except for a high number of circulating eosinophils (1200 μl –1; normal range less than 400 μl –1). Serum IgE was high at 1750 ng dl–1 (normal less than 200 ng dl–1). Radioallergosorbent assays (RAST) for antigen-specific IgE revealed IgE antibodies against dog and cat dander, dust mites, and tree, grass, and ragweed pollens in Frank’s serum. Levels of immunoglobulins IgG, IgA, and IgM were normal. Histological examination of Frank’s nasal fluid showed the presence of eosinophils.

Frank was promptly given albuterol nebulizer treatment in the clinic, after which he felt better, his PEFR rose to 400 liter min–1, and his FEV1 rose to 65% of predicted. He was sent home on a 1-week course of the oral corticosteroid prednisone. He was told to inhale albuterol every 4 hours for the next 2–3 days, and then to resume taking albuterol every 4–6  hours as needed for chest tightness or wheezing. He was also started on fluticasone propionate (Flovent), an inhaled corticosteroid, and montelukast (Singulair), a leukotriene receptor antagonist for long-term control of his asthma. To relieve his nasal congestion, Frank was given the steroid fluticasone furoate (Flonase) to inhale through the nose, and was advised to use an oral antihistamine as needed. He was asked to return to the clinic 2 weeks later for follow-up, and for immediate hypersensitivity skin tests to try to detect which antigens he was allergic to (Fig. 47.5). On the next visit Frank had no symptoms except for a continually stuffy nose. His PEFR and FEV1 were normal. Skin tests for type I hypersensitivity were positive for multiple tree and grass pollens, dust mites, and dog and cat dander. He was advised to avoid contact with cats and dogs. To reduce his exposure to dust mites the pillows and mattresses in his room were covered with zippered covers. Rugs, stuffed toys, and books were removed from his bedroom. He was also started on immunotherapy with injections of grass, tree, and ragweed pollens, and cat, dog, and house dust mite antigens, to try to reduce his sensitivity to these antigens. A year and a half later, Frank’s asthma continued to be stable with occasional use of albuterol during infections of the upper respiratory tract and in the spring. His rhinitis and nasal congestion now require much less medication.

poison ivy

Paul Stein was 7  years old and had enjoyed perfect health until 2  days after he returned from a hike with his summer camp group, when itchy red skin eruptions appeared all along his right arm. Within a day or two, the rash had spread to his trunk, face, and genitals. His mother gave him the antihistamine Benadryl (diphenhydramine hydrochloride) orally to suppress the itching, but this gave only partial relief. The rash did not improve, and a week after it first appeared he attended the Dermatology Clinic at the Children’s Hospital. Physical examination revealed large patches of raised, red, elongated blisters, oozing scant clear fluid, on his body and extremities (Fig. 49.3). Paul also had swollen eyelids and a swollen penis. There was no history of fever, fatigue, or any other symptom. A contact sensitivity reaction to poison ivy was diagnosed. He was given a corticosteroid-containing cream to apply to the skin lesions three times a day, and Benadryl to take orally three times a day. He was asked to shampoo his hair, wash his body thoroughly with soap and water, and cut his nails short. Two days later, his parents reported that, although no new eruptions had appeared, the old lesions were not significantly better. Paul was then given the corticosteroid prednisone orally, which was gradually decreased over a period of 2 weeks. The topical steroid cream was discontinued. Within a week, the rash had almost disappeared. Upon stopping the prednisone there was a mild flare-up of some lesions, and this was controlled by application of topical steroid for a few days. Paul was shown how to identify poison ivy in order to avoid further contact with it, and told to wear long pants and shirts with long sleeves on any future hikes in the woods.