Chromosomes 19 and 22, for example, are gene rich, whilst chromosomes 4 and 18 are gene poor. These genes are often clustered, as with the globin gene clusters on chromosomes 11 and 16. In these tandem repeats the number of times that the core sequence is repeated varies among different people, giving rise to hypervariable regions. This approach revolutionised the predictive tests available for mendelian disorders such as Duchenne muscular dystrophy and cystic fibrosis before the genes were isolated and the disease causing mutations identified. Chromatin fibre Double helix Nucleosomes Metaphase chromosome Loops of chromatin Figure 15. At the first meeting the total number of autosomal genes whose chromosomal location had been identified was 64. The corresponding number of mapped genes had risen to 928 by the ninth meeting in 1987 as molecular techniques replaced those of traditional somatic cell genetics. The total number of mapped X linked loci also rose, from 155 in 1973 to 308 in 1987. The number of mapped genes has continued to increase rapidly since then, reflecting the development of new molecular biological techniques and the institution of the Human Genome Project. The database has evolved in the face of an explosion of information on human genetics into a freely available online resource, which is being continually updated and revised. The human genome project consortium used a hierarchical shotgun approach in which overlapping bacterial clones were sequenced using mapping data from publicly available maps. The first draft of the human sequence covering 90% of the gene-rich regions of the human genome was published in a historic article in Nature in February 2001 (Volume 409, No 6822). As a result of this monumental work, the overall size of the human genome has been determined to be 3. The consortium has estimated that there are approximately 32 000 human genes (far fewer than expected) of which 15 000 are known and 17 000 are predictions based on new sequence data. The Human Genome Sequencing Project has been complicated by the involvement of commercial organisations. Celera Genomics started sequencing in 1998 using a whole genome shotgun cloning method and published its own draft 82 Established 8486 genes or phenotype loci Phenotypic 769 descriptions Other loci or 2342 phenotypes Total 11 597 62 166 685 0 3 37 23 0 60 Table 16. Access to its information is restricted and Celera expect gene patent rights arising from use of its data. Despite the huge milestone achieved by these human genome sequencing projects, the data generated represent only the first step in understanding the way genes work and interact with each other. The human genome sequence needs to be completed and coupled with further research into the molecular pathology of inherited diseases and the development of new treatments for conditions that are, at present, intractable. With the advent of molecular techniques the first step in isolating many genes for human diseases was to locate their chromosomal position by gene mapping studies. In other disorders, the likely position of the gene was suggested by identification of a chromosomal rearrangement in an affected individual in whom it was likely that one of the chromosomal break points disrupted the gene. In Duchenne muscular dystrophy, several affected females had been reported who had one X chromosome disrupted by an X:autosome translocation with the normal X chromosome being preferentially inactivated. Prior to identifying specific gene mutations, this can provide information about carrier risk and enable prenatal diagnosis in certain situations. The closer the marker is to a gene, the less likely it is that recombination will occur. Linkage studies using intragenic markers provide much more accurate prediction of genetic state, but this approach is only used now when mutation analysis is not possible, as in some cases of Duchenne muscular dystrophy, Marfan syndrome and neurofibromatosis type 1. Alternatively, candidate genes can be identified by their function or expression patterns or by sequence homology with genes known to cause similar phenotypes in animals. The gene for Waardenburg syndrome, for example, was localised to chromosome 2q by linkage studies and the finding of a chromosomal abnormality in an affected subject. Identification of the gene was then aided by recognition of a similar phenotype in splotch mice. Deletion A C G T T G A A C G T G A Types of mutation Duplication In a few genetic diseases, all affected individuals have the same mutation. The majority of mendelian disorders are, however, due to many different mutations in a single gene. In cystic fibrosis, for example, over 700 mutations have been described, but one particular mutation, F508, accounts for about 70% of all cases in northern Europeans.
If the D-dimer is normal and the probability for embolism is low, then no further workup may be necessary. Ventilation-perfusion scans may revealing defects in perfusion without matching ventilation defects, but they are difficult to perform in young children. Children with pulmonary embolism without an obvious cause should be evaluated for hypercoagulable states, the most common of which is factor V Leiden. Treatment Once a pulmonary embolism is suspected, the patient should be anticoagulated, usually with low-molecular-weight heparin. All patients should receive supplemental O2, and it is important to treat the predisposing factors. Occasionally an inferior vena caval filter needs to be placed to prevent recurrent emboli. Abnormal airway secretions make the airway more prone to colonization with bacteria. This all leads to chronic airway infections and eventually to bronchial damage (bronchiectasis). Many infants currently are diagnosed based on newborn screening, which has been available in all 50 states and the District of Columbia since 2010. Older children commonly present with pulmonary manifestations such as poorly controlled asthma and chronic respiratory infections. This leads to a relative dehydration of airway secretions, which results in airway obstruction and impaired mucociliary transport. This, in turn, leads to endobronchial colonization with bacteria, especially Staphylococcus aureus and Pseudomonas aeruginosa. Chronic bronchial infection results in persistent or recurrent cough that is often productive of sputum, especially in older children. Chronic airway infection leads to airway obstruction and bronchiectasis and, eventually, to pulmonary insufficiency and premature death. Pulmonary infections with virulent strains of Burkholderia cepacia are difficult to treat and may be associated with accelerated clinical deterioration. Minor hemoptysis is usually due to airway infection, but major hemoptysis is often caused by bleeding from bronchial artery collateral vessels in damaged/ chronically infected portions of the lung. The most common mutation is a deletion of three base pairs resulting in the absence of phenylalanine at the 508 position (F508). The altered chloride ion conductance in the sweat gland results in excessively high sweat sodium and chloride levels. This is the basis of the sweat chloride test, which is still the standard diagnostic test for this disorder. Fat malabsorption manifests clinically as steatorrhea (large foul-smelling stools), deficiencies of fat-soluble vitamins (A, D, E, and K), and failure to thrive. Protein malabsorption can present early in infancy as hypoproteinemia and peripheral edema. In older patients, intestinal obstruction may result from thick inspissated mucus in the intestinal lumen (distal intestinal obstruction syndrome). In adolescent or adult patients, progressive pancreatic damage can lead to enough islet cell destruction to cause insulin deficiency. The failure of the sweat ducts to conserve sodium and chloride may lead to hyponatremia and hypochloremic metabolic alkalosis, especially in infants. Inspissation of mucus in the reproductive tract leads to reproductive dysfunction in both males and females. In males, congenital absence of the vas deferens and azoospermia are nearly universal. In females, secondary amenorrhea is often present as a result of chronic illness and reduced body weight. The inspissation of mucus and subsequent destruction of the pancreatic ducts result in the inability to excrete pancreatic enzymes into the intestine. Identification of carriers (heterozygotes) and prenatal diagnosis of children with the F508 and other common mutations is offered at most medical centers. Other supportive tests include the measurement of bioelectrical potential differences across nasal epithelium (not widely available) and measurement of fecal elastase levels.
An average child has three to six common colds per year, with the most affected being younger children and children attending day care. Infection is suggested by the presence of sore throat, fever, and poor appetite, especially with a history of exposure to others with colds. Chronic infectious rhinosinusitis, or sinusitis, should be suspected if there is mucopurulent nasal discharge with symptoms that persist beyond 10 days (see Chapter 104). Classic signs of acute sinusitis in older children include facial tenderness, tooth pain, headache, and fever. Classic signs are usually not present in young children who may present with postnasal drainage with cough, throat clearing, halitosis, and rhinorrhea. The character of the nasal secretions with infectious rhinitis varies from purulent to minimal or absent. Coexistence of middle ear disease, such as otitis media or eustachian tube dysfunction, may be additional clues of infection. Nonallergic, noninfectious rhinitis (formerly known as vasomotor rhinitis) can manifest as rhinorrhea and sneezing in children with profuse clear nasal discharge. Exposure to irritants, such as cigarette smoke and dust, and strong fumes and odors, such as perfumes and chlorine in swimming pools, can trigger these nasal symptoms. Nonallergic rhinitis with eosinophilia syndrome is associated with clear nasal discharge and eosinophils on nasal smear and is seen infrequently in 284 Section 14 u Allergy flunisolide, fluticasone, mometasone, and triamcinolone. They are effective for symptoms of nasal congestion, rhinorrhea, itching, and sneezing but less helpful for ocular symptoms. Deleterious effects on adrenal function or nasal membranes have not been reported when these agents are used appropriately. The most common adverse effects include local irritation, burning, and sneezing, which occur in 10% of patients. Antihistamines are the medications used most frequently to treat allergic rhinitis. They are useful in treating rhinorrhea, sneezing, nasal itching, and ocular itching but are less helpful in treating nasal congestion. First-generation antihistamines, such as diphenhydramine and hydroxyzine, easily cross the blood-brain barrier, with sedation as the most common reported adverse effect. Use of first-generation antihistamines in children has an adverse effect on cognitive and academic function. In very young children, a paradoxical stimulatory central nervous system effect, resulting in irritability and restlessness, has been noted. Other adverse effects of first-generation antihistamines include anticholinergic effects, such as blurred vision, urinary retention, dry mouth, tachycardia, and constipation. Second-generation antihistamines, such as cetirizine, loratadine, desloratadine, fexofenadine and levocetirizine, are less likely to cross the blood-brain barrier, resulting in less sedation. Azelastine and olopatadine, topical nasal antihistamine sprays, are approved for children older than 5 years and older than 6 years, respectively. Decongestants, taken orally or intranasally, may be used to relieve nasal congestion. Oral medications, such as pseudoephedrine and phenylephrine, are available either alone or in combination with antihistamines. Adverse effects of oral decongestants include insomnia, nervousness, irritability, tachycardia, tremors, and palpitations. For older children participating in sports, oral decongestant use may be restricted. Topical nasal decongestant sprays are effective for immediate relief of nasal obstruction but should be used for less than 5 to 7 days to prevent rebound nasal congestion (rhinitis medicamentosa). Topical ipratropium bromide, an anticholinergic nasal spray, is used primarily for nonallergic rhinitis and rhinitis associated with viral upper respiratory infection. Rhinitis medicamentosa, which is due primarily to overuse of topical nasal decongestants, such as oxymetazoline, phenylephrine, or cocaine, is not a common condition in younger children. Adolescents or young adults may become dependent on these over-the-counter medications. Treatment requires discontinuation of the offending decongestant spray, topical corticosteroids, and, frequently, a short course of oral corticosteroids. The most common anatomic problem seen in young children is obstruction secondary to adenoidal hypertrophy, which can be suspected from symptoms such as mouth breathing, snoring, hyponasal speech, and persistent rhinitis with or without chronic otitis media.
The reasons for this difference are not clear considering that normally about 50% of the final thoracic volume grows around puberty. A possible explanation is that congenital anomalies may be associated with molecular abnormalities that may affect the lungs directly. For example, the various chondrodysplasias are associated with genetic mutations affecting the transmembrane receptors, and the various spondyloepiphyseal dysplasias are associated with abnormalities involving the proteins involved in the matrix of the cartilage. Another possible explanation is that infancy is the period of rapid lung development with the appearance of new bronchioles and alveoli and therefore any process that limits this development will have a much worse outcome than a process that limits the full inflation of the lung after all the internal divisions have been completed. This is a relatively common finding among patients with pectus excavatum or scoliosis. Effects on the Airway Function Chest wall abnormalities do not usually affect the airway function directly. In fact, because of the restrictive lung defect that tends to be associated with most of them, the expiratory flow-rates (measured by spirometry and maximal expiratory flow-volume curves) tend to be very high relative to the lung volume, reflecting the rapid emptying of the lungs. The flow-volume curves have a very characteristic tall and narrow appearance (although in milder cases it may resemble a ``miniature' normal curve). Even more striking are the changes in the inspiratory flow-volume curves that lose their characteristic ``half-circle' shape and instead they resembles a mirror image of the expiratory flow-volume curve. On occasion patients with severe scoliosis may develop a flattening of the proximal portion of the flow-volume curve that suggests large/central airway obstruction. A possible explanation is that the obstruction is due to the asymmetry of the two hemithoraces that leads to the hyperinflation of one lung and hypoinflation of the other. Both conditions have the potential of ``pulling' the main stem bronchi forward or backward causing some ``kinking' that is relieved when the rib cage becomes more symmetric. This has been described in a substantial number of patients with pectus excavatum [3] as well as in patients with neuromuscular disorders possibly due to development of chronic airway inflammation secondary to poor airway clearance. Maximal flow-volume curves in a patient with severe restrictive lung defetct due to chest wall anormality. Note the characteristic tall and narrow shape of the flow-volume curve and the ``mirror-image' of the inspiratory flow-volume curve. Effects on the Ventilation and perfusion Under normal circumstances the right lung of an adult contributes approximately 55% and the left lung approximately 45% of the overall ventilation and perfusion. In chest wall abnormalities, because of the scoliosis that is invariably present, there is asymmetry between the two hemithoraces and as a result one of the lungs is always considerably bigger than the other. One would expect that this asymmetry would alter the normal the normal ratio and that the bigger lung would contribute the bulk of the ventilation and perfusion. Using ventilation/perfusion scans it has been found that the ratio indeed changes and it can increase up to 80% contribution from one lung. It is not known whether these changes in the ratio are reversible after surgical repair. This information could have clinical implications and specifically it might influence the decision for and/or the extent of the repair. Interestingly, the lung that contributes most in the ventilation/perfusion calculation does not seem to correlate directly with the Cobb angle. Thus, one may have to consider more extensive evaluation with the use of V/Q scans and then proceed with an operation that preserves the functioning lung. Severe scoliosis (primary or secondary) is associated with significant alterations in the breathing patterns at rest, on exertion and during sleep. The respiratory rate tends to be higher than normal whereas the tidal volume may be normal, higher than normal or lower than normal. The expiratory flow-volume curve shows extensive ``flattening' of its proximal portion consistent with central airway obstruction. Repeat testing after surgical repair of the scoliosis shows significant resolution of the central airway obstruction. These mechanisms are normally reserved for conditions of increased metabolic demands such as during exercise. However, when they are used for regular breathing they increase significantly the risk of respiratory muscle fatigue and eventual respiratory failure. Although these problems can be expected to be more common and/or more severe among patients with severe scoliosis, there is no direct correlation between them and the degree of scoliosis. In severe cases of scoliosis (angle >100o), patients are at an increased risk of developing chronic respiratory failure and pulmonary hypertension (the latter being the product of chronic atelectasis, chronic hypoxemia and chronic hypercapnia).
Clinically evident jaundice, dark urine resulting from bilirubin pigments, hemoglobinuria when hemolysis is intravascular, and decreased haptoglobin levels are common during hemolytic episodes. Early on, the hemolysis usually exceeds the ability of the bone marrow to compensate, so the reticulocyte count may be low for 3 to 4 days. Maintaining hydration and urine alkalization protects the kidneys against damage from precipitated free hemoglobin. Hemolysis is prevented by avoidance of known oxidants, particularly long-acting sulfonamides, nitrofurantoin, primaquine, dimercaprol, and moth balls (naphthalene). Fava beans (favism) have triggered hemolysis, particularly in patients with the Mediterranean variant. Some individuals have a true deficiency state, and others have abnormal enzyme kinetics. Pyruvate kinase deficiency is usually an autosomal disorder, and most children who are affected (and are not products of consanguinity) are double heterozygotes for two abnormal enzymes. Hemolysis is not aggravated by oxidant stress due to the profound reticulocytosis in this condition. Most patients have amelioration of the anemia and a reduction of transfusion requirements after splenectomy. The biochemical basis of hereditary spherocytosis and hereditary elliptocytosis are similar. Both conditions appear to have a defect in the protein lattice (spectrin, ankyrin, protein 4. In hereditary spherocytosis, pieces of membrane bud off as microvesicles because of abnormal vertical interaction of the cytoskeletal proteins and uncoupling of the lipid bilayer from the cytoskeleton. Hereditary elliptocytosis is a disorder of spectrin dimer interactions that occurs primarily in individuals of African descent. The transmission of the two variants is usually autosomal dominant, but spontaneous mutations causing hereditary spherocytosis are common. Hereditary spherocytosis varies greatly in clinical severity, ranging from an asymptomatic, well-compensated, mild hemolytic anemia that may be discovered incidentally to a severe hemolytic anemia with growth failure, splenomegaly, and chronic transfusion requirements in infancy necessitating early splenectomy. The less common variant is associated with spherocytes, ovalocytes, and elliptocytes with a moderate, usually compensated, hemolysis. The clinical diagnosis of hereditary spherocytosis should be suspected in patients with even a few spherocytes found on the blood smear because the spleen preferentially removes spherocytes. An incubated osmotic fragility test confirms the presence of spherocytes and increases the likelihood of the diagnosis. The osmotic fragility test result is abnormal in any hemolytic disease in which spherocytes are present-for example, in antibody-mediated hemolysis. Splenectomy should be considered for any child with symptoms referable to anemia or growth failure, but should be deferred until age 5 years, if possible, to minimize the risk of overwhelming postsplenectomy sepsis and to maximize the antibody response to the polyvalent pneumococcal vaccine. In several reports, partial splenectomy seems to improve the hemolytic anemia and maintain splenic function in host defense. B, An IgG antibody is too small to bridge the zeta potential and cause agglutination. Examples are antibodies to the A, B, and Rh D antigens; other Rh antigens; and the Kell, Duffy, and other blood groups. Anti-A and anti-B hemolysis is caused by the placental transfer of naturally occurring maternal antibodies from mothers who lack A or B antigen (usually blood type O). There may be no clinical manifestations, or the infant may exhibit jaundice, severe anemia, and hydrops fetalis. Autoimmune hemolytic anemia is usually an acute, selflimited process that develops after an infection (Mycoplasma, Epstein-Barr, or other viral infections). Autoimmune hemolytic anemia may also be the presenting symptom of a chronic autoimmune disease (systemic lupus erythematosus, lymphoproliferative disorders, or immunodeficiency).
Although in most areas it is rare for these animals to have rabies, rabies must be considered in many situations due to the potential devastating consequences of human exposure to the rabies virus. It is important to err on the side of caution when determining whether to declare an animal a "rabies suspect. If an animal is suspected of having rabies, the following must be carried out by the attending veterinarian: 1. The owner should be told about the potential for zoonotic transmission, that the animal will be tested for rabies if it dies/is euthanized and rabies is still considered a possible diagnosis, and that the owner should make a list of individuals that have been in contact with the animal recently. The owner should be asked whether the animal has bitten anyone in the past 10 days. The animal must be placed under strict isolation with a clear warning sign that the animal is not to be handled unless otherwise directed by the attending veterinarian. Entry into isolation and treatment of the patient should be limited to the minimum number of personnel necessary. The names of all personnel coming into contact with the animal must be recorded on this sheet. If additional diagnostics or treatments are required, all staff must be informed that the animal is a rabies suspect. Invasive procedures and procedures likely to result in contact with bodily fluids should be avoided. Anyone handling the animal must wear protective barrier clothing including gloves, gown and face protection. Ensure that any areas of broken skin are securely protected by a bandage or other clothing. Rabid animals can have very unpredictable behavior, therefore additional precautions such as the use of catch poles and heavy gloves should be employed to reduce the risk of bite injury occurring. Do not euthanize the animal unless it is in extremis, or authorized to do so by the owner and the appropriate authorities. If an individual is exposed through a bite or potential salivary contamination of a wound or mucous membrane, a. The wound should then be disinfected using a compound of proven lethal effect for rabies virus. The individual must then immediately seek medical attention in order to receive post-exposure prophylaxis as soon as possible. If rabies is ultimately confirmed, public health personnel will determine need for rabies post-exposure prophylaxis for each individual who had contact with the animal, depending on the circumstances for each. Local and national requirements regarding potential rabies cases may vary, however every veterinary clinic must be aware of proper procedure in its area, which should be prominently displayed for clinic staff, and include current contact information for the appropriate authorities. Staff members should not be allowed to work outside of these activities until they understand and have been appropriately trained in the infection control protocols pertaining to their added job activities. Area of Competency Detailed Core Competency Critical assessment skills Critical assessment skills related to exposure to infectious agents, awareness of zoonotic infections, and use of infectious disease specific protocols Basic rationale for routine Understands basic microbiology and how infections can be transmitted in veterinary practices clinic settings Personal safety Knows how to appropriately manage sharps, and body fluids. Routine Practices and Additional Precautions for Preventing the Transmission of Infection in Health Care. Compendium of Veterinary Standard Precautions: Zoonotic Disease Prevention in Veterinary Personnel. Best Practices for Cleaning, Disinfection and Sterilization in All Health Care Settings. Literature search terms used for this revision are below and include literature from January 1, 2004, through May 31, 2014. Hand searching of identified articles and work group submission was also undertaken. Lifestyle changes such as nutrition therapy, weight loss, increased exercise, and appropriate education and self-management strategies are pivotal to improved outcomes.
Diseases
Angiomyolipomas may cause abdominal pain, with or without haematuria, and multiple cysts can lead to renal failure. These can cause outflow tract obstruction or arrhythmias, but tend to resolve with age. First degree relatives of an affected individual need careful clinical examination to detect minor features of the condition. The value of other investigations in subjects with no clinical features is not of proven benefit. Current strategies for mutation analysis do not identify the underlying mutation in all cases. However, when a mutation is detected, this aids diagnosis in atypical cases, can be used to investigate apparently unaffected parents of an affected child, and enables prenatal diagnosis. In some familial cases, the diagnosis may have gone unrecognised in previously affected relatives because of mild presentation and the absence of complications. The main features of Marfan syndrome involve the skeletal, ocular and cardiovascular systems. Up to 80% of affected individuals have dislocated lenses (usually bilateral) and there is also a high incidence of myopia. Cardiovascular manifestations include mitral valve disease and progressive dilatation of the aortic root and ascending aorta. Regular monitoring of aortic root dimension by echocardiography, medical therapy (betablockers) and elective aortic replacement surgery have contributed to the fall in early mortality from the condition over the past 30 years. Clinical diagnosis is based on the Gent criteria, which require the presence of major diagnostic criteria in two systems, with involvement of a third system. Minor features indicating involvement of other symptoms include striae, recurrent or incisional herniae, and spontaneous pneumothorax. Clinical features of Marfan syndrome evolve with age and children at risk should be monitored until growth is completed. Neonatal Marfan syndrome represents a particularly severe form of the condition presenting in the newborn period. Pregnancy in women with Marfan syndrome should be regarded as high risk and carefully monitored by obstetricians and cardiologists with expertise in management of the condition. Fibrillin is the major constituent of extracellular microfibrils and is widely distributed in both elastic and non-elastic connective tissue throughout the body. Most Marfan syndrome families carry unique mutations and more than 140 different mutations have been reported. Screening new cases for mutations is not routinely available, and diagnosis depends on clinical assessment. The incidence of cystic fibrosis is approximately 1 in 2000, with 1 in 22 people in the population being carriers. Clinical manifestations are due to disruption of exocrine pancreatic function (malabsorption), intestinal glands (meconium ileus), bile ducts (biliary cirrhosis), bronchial glands (chronic bronchopulmonary infection with emphysema), sweat glands (abnormal sweat electrolytes), and gonadal function (infertility). Clinical presentation is very variable and can include any combination of the above features. Some cases present in the neonatal period with meconium ileus, others may not be diagnosed until middle age. Presentation in childhood is usually with failure to thrive, malabsorption and recurrent pneumonia. Decreased fluid and salt secretion is responsible for the blockage of exocrine outflow from the pancreas, accumulation of mucus in the airways and defective reabsorption of salt in the sweat glands. Family studies localised the gene causing cystic fibrosis to chromosome 7q31 in 1985 and the use of linked markers in affected families enabled carrier detection and prenatal diagnosis. Direct mutation analysis now forms the basis of both carrier detection and prenatal tests (see chapter 18). Within affected families, mutation analysis enables carrier detection and prenatal diagnosis.
Infections of the central nervous system or the eye necessitate treatment with antimicrobials that penetrate and achieve therapeutic levels in these sites. Limited renal function (as in premature infants or those with renal failure) requires increasing dosing intervals to allow time for excretion of certain drugs. The larger volume of distribution of certain hydrophilic antimicrobials and increased renal clearance. Weight-based dosage regimens may result in overdoses in obese children due to significantly smaller volumes of distribution for hydrophilic drugs. Drug-drug interactions must be considered when multiple antimicrobial agents are used to treat infection. Use of two or more antimicrobial agents may be justified before organism identification or for the benefit of two drugs with different mechanisms of action. The use of a bacteriostatic drug, such as a tetracycline, along with a -lactam agent, effective against growing organisms only, may result in antibiotic antagonism, or less bacterial killing in the presence of both drugs than if either is used alone. There is a normal diurnal variation, with maximum temperature in the late afternoon. Normal body temperature is maintained by a complex regulatory system in the anterior hypothalamus. Development of fever begins with release of endogenous pyrogens into the circulation as the result of infection, inflammatory processes, or malignancy. Microbes and microbial toxins act as exogenous pyrogens by stimulating release of endogenous pyrogens, including cytokines such as interleukin-1, interleukin-6, tumor necrosis factor, and interferons. These cytokines reach the anterior hypothalamus, liberating arachidonic acid, which is metabolized to prostaglandin E2. Elevation of the hypothalamic thermostat occurs via a complex interaction of complement and prostaglandin-E2 production. Antipyretics (acetaminophen, ibuprofen, aspirin) inhibit hypothalamic cyclooxygenase, decreasing production of prostaglandin E2. Aspirin is associated with Reye syndrome in children and is not recommended as an antipyretic. The response to antipyretics does not distinguish bacterial from viral infections. The pattern of fever in children may vary, depending on age and the nature of the illness. Fever to this degree is unusual in older children and adolescents and suggests a serious process. The fever pattern does not reliably distinguish fever caused by infectious microorganisms from that resulting from malignancy, autoimmune diseases, or drugs. Children with fever without a focus present a diagnostic challenge that includes identifying bacteremia and sepsis. Bacteremia, the presence of bacteria in the bloodstream, may be primary or secondary to a focal infection. Sepsis is the systemic response to infection that is manifested by hyperthermia or hypothermia, tachycardia, tachypnea, and shock (see Chapter 40). Children with septicemia and signs of central nervous system dysfunction (irritability, lethargy), cardiovascular impairment (cyanosis, poor perfusion), and disseminated intravascular coagulation (petechiae, ecchymosis) are Chapter 96 readily recognized as toxic appearing or septic. These younger infants usually exhibit only fever and poor feeding, without localizing signs of infection. Differentiation between viral and bacterial infections in young infants is difficult. Febrile infants <3 months of age who appear ill, especially if follow-up is uncertain, and all febrile infants <4 weeks of age should be admitted to the hospital for empirical antibiotics pending culture results. After blood, urine, and cerebrospinal fluid cultures are obtained, broad-spectrum parenteral antibiotics (typically ampicillin with cefotaxime or gentamicin) are administered. The choice of antibiotics depends on the pathogens suggested by localizing findings. Well-appearing febrile infants 4 weeks of age without an identifiable focus and with certainty of follow-up are at a low risk of developing a serious bacterial infection (0. Fecal leukocyte testing and chest radiograph can be considered in infants with diarrhea or respiratory signs.
A diffuse, erythematous rash develops in approximately 80% of mononucleosis patients treated with amoxicillin. The most common manifestation of toxoplasmosis is asymptomatic cervical lymphadenopathy, but approximately 10% of cases of acquired toxoplasmosis develop chronic posterior cervical lymphadenopathy and fatigue, usually without significant fever. Cat-scratch disease typically presents with a cutaneous papule or conjunctival granuloma at the site of bacterial inoculation, followed by lymphadenopathy of the draining regional nodes. Less common features of cat-scratch disease include erythema nodosum, osteolytic Initial laboratory tests of regional lymphadenopathy include a complete blood count and inflammatory markers. Infectious mononucleosis is characterized by lymphocytosis with atypical lymphocytes; thrombocytopenia and elevated hepatic enzymes are common. Isolation of group A streptococci from the oropharynx suggests, but does not confirm, streptococcal cervical lymphadenitis. A blood culture should be obtained from children with systemic signs and symptoms of bacteremia. Heterophil antibody is also diagnostic but is not reliably positive in children younger than 4 years with infectious mononucleosis. Extended diagnostic workup for lymphadenopathy is guided by the specific risk factors in the history and physical examination findings. Genital tract evaluation and specimens should be obtained with regional inguinal lymphadenopathy (see Chapter 116). Screening for tuberculosis can be performed using the standard tuberculin skin test or an interferon gamma release assay; both may be positive with atypical mycobacterial infection. Aspiration is indicated for acutely inflamed, fluctuant cervical lymph nodes, especially those larger than 3 cm in diameter or not responding to antibiotic treatment. Ultrasound or computed tomography may help in establishing the extent of lymphadenopathy and defining whether the mass is solid, cystic, or suppurative with abscess formation. Pus from fluctuant lesions should be examined by Gram and acid-fast stains and cultured for aerobic and anaerobic bacteria and mycobacteria. Biopsy should be performed if lymphoma is suspected because of firm, matted, nontender nodes and other systemic findings. If the diagnosis remains uncertain and lymphadenopathy persists despite empirical antibiotic therapy for presumed S. Biopsy material should be submitted for histopathology as well as Gram, acid-fast, Giemsa, periodic acid-Schiff, Warthin-Starry silver (B. Cultures for aerobic and anaerobic bacteria, mycobacteria, and fungi should be performed. The titers are geometric mean values expressed as reciprocals of the serum dilution. The differential diagnosis for generalized lymphadenopathy includes juvenile idiopathic arthritis; systemic lupus erythematosus; and serum sickness and other adverse drug reactions, especially with phenytoin and other antiepileptic medications, allopurinol, isoniazid, antithyroid medications, and pyrimethamine. Leukemia, lymphoma, and occasionally neuroblastoma may have lymph nodes that are usually painless, uninflamed, matted, and firm (see Chapters 155 and 156). A syndrome of periodic fever, aphthous stomatitis, pharyngitis, and adenitis is an occasional cause of recurrent fever and cervical lymphadenitis (see Chapter 103). The recommended treatment of cervical lymphadenitis caused by nontuberculous mycobacteria is complete surgical excision. Antimycobacterial drugs are necessary only if there is recurrence or inability to excise infected nodes completely, or if M. In children most cases of cervical lymphadenopathy, without other signs of acute inflammation, require no specific therapy and usually regress within 2 to 3 weeks. Progression to lymphadenitis or development of generalized lymphadenopathy requires further evaluation. The specific treatment of cervical lymphadenitis depends on the underlying etiology. For patients with hypersensitivity to -lactam antibiotics, or if community-acquired methicillin-resistant S. Response to empirical antibiotic therapy for suppurative cervical lymphadenitis obviates the need for further evaluation. Absence of a clinical response within 48 to 72 hours is an indication for further laboratory evaluation and possible excisional biopsy and culture. Cat-scratch disease usually does not require treatment because the lymphadenopathy resolves in 2 to 4 months without sequelae.
If diazoxide therapy is unsuccessful, long-acting somatostatin analogs can be tried. Often medical therapy for persistent hyperinsulinemic hypoglycemia of the newborn is unsuccessful, and subtotal (90%) pancreatectomy is required to prevent long-term neurologic sequelae of hypoglycemia. In children hyperinsulinemia is a rare condition characterized by a voracious appetite, obesity, and accelerated linear growth and usually results from an islet cell adenoma. Computed tomography, magnetic resonance imaging, or radioisotope imaging of the pancreas should be attempted, but visualization of an adenoma is usually difficult. This diagnosis should be suspected if extremely high insulin concentrations are detected (>100 U/mL). C-peptide concentrations are low or undetectable, which confirms that the insulin is from an exogenous source. Hypopituitarism results from congenital hypoplasia or aplasia of the pituitary or, more commonly, from deficiency of hypothalamic releasing factors (see Chapter 173). Clues to this diagnosis in infants include the presence of hypoglycemia in association with midline facial or neurologic defects. Figure 172-1 Regulation of serum 582 Section 23 u Endocrinology glucose-6-phosphatase deficiency, which is characterized by severe hypoglycemia, massive hepatomegaly, growth retardation, and lactic acidosis. In contrast, deficiencies in the glycogen phosphorylase enzymes may cause isolated hepatomegaly with or without hypoglycemia. The diagnosis of glycogen storage disease is suggested by a finding of hepatomegaly without splenomegaly. Confirmation of the diagnosis requires specific biochemical studies of leukocytes or liver biopsy specimens. Treatment involves frequent high-carbohydrate feedings during the day and continuous feedings at night via nasogastric tube. Feedings of uncooked cornstarch overnight are sufficient to maintain serum glucose concentrations in some patients. Deficient cortisol secretion also can occur in primary adrenal insufficiency, resulting from a variety of causes. In infants it often results from congenital adrenal hyperplasia, most frequently as a result of 21-hydroxylase deficiency (see Chapters 177 and 178). In older children, primary adrenal insufficiency is seen most frequently in Addison disease and other disorders (see Chapter 178). Treatment involves supplementation of the deficient hormones in physiologic doses. Deficiencies in these stores are a common cause of hypoglycemia in neonates who are small for gestational age or premature (see Chapter 60). Beyond the early neonatal period, energy stores are usually sufficient to meet the metabolic requirements except in malnourished children. Defects in gluconeogenesis are uncommon and include fructose-1,6-diphosphatase deficiency and phosphoenolpyruvate carboxykinase deficiency. Affected patients exhibit fasting hypoglycemia, hepatomegaly, lactic acidosis, and hyperuricemia. Treatment involves frequent high-carbohydrate, low-protein feedings (see Chapter 52). Patients have symptoms of hypoglycemia after a period of prolonged fasting, often in the setting of an intercurrent illness with decreased feeding. Children with this disorder are often thin and small and may have a history of being small for gestational age. Defective mobilization of alanine from muscle to fuel gluconeogenesis is thought to be the cause, although the condition may derive mostly from having lower fuel reserves. Because there are no specific diagnostic tests for this disorder, ketotic hypoglycemia is a diagnosis of exclusion. Treatment involves avoidance of fasting and frequent feedings of a high-protein, high-carbohydrate diet. Fatty acid oxidation disorders of ketogenesis include the fatty acid acyl-coenzyme A (CoA) dehydrogenase deficiencies; long-chain, medium-chain, and short-chain acyl-CoA dehydrogenase deficiencies; and hereditary carnitine deficiency (see Chapter 55). Of these disorders, medium-chain acyl-CoA dehydrogenase deficiency is the most common; it occurs in 1 in 9000 to 15,000 live births. Patients often are well in infancy and have the first episode of hypoglycemia at 2 years of age or older. Episodes of hypoglycemia usually occur with prolonged fasting or during episodes of intercurrent illness.
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