TODD A. FLORIN
HISTORY OF PRESENT ILLNESS
The patient is a 2-year-old girl who presented with a 1-month history of fevers and a nonproductive cough. Six weeks prior to presentation she developed fevers and a dry cough. Soon after, she was admitted to the hospital with the diagnosis of an otitis media and pneumonia. After a 2-day hospitalization, during which she received intravenous antibiotics, she was discharged home. Her parents felt that her symptoms had not improved. Her fevers continued and occurred every few days with maximum temperatures of 103-106oF. She was treated with nebulized albuterol without improvement in her cough.
She had a decreased appetite for the last month with a 2 kg weight loss. She also had nonbloody, nonbilious emesis occurring 3-4 times each day. Her parents reported 3-4 loose bowel movements each day. In her doctor’s office, a stool sample was obtained and was tested positive for microscopic blood.
The patient was full term at birth with a birth weight of 2800 g. She has had four episodes of otitis media in the past and two episodes of sinusitis. Her only medication is albuterol as needed. Her family history is significant for having two aunts with asthma.
T 40.0°C; P 140 bpm; RR 44/min; BP 98/60 mmHg; Oxygen saturation 90%-92% in room air; Weight 5th to 10th percentile
In general, she presented with very mild increase in her work of breathing. Her chest examination revealed good aeration throughout with bilateral end-expiratory wheezes present in the left upper lobe and right anterior lung field. No rales or rhonchi were noted. The remainder of her physical examination was within normal limits.
The complete blood count revealed a white blood cell count of 8800 cells/mm3 with 66% segmented neutrophils, 27% lymphocytes, and 7% monocytes. Her hemoglobin was 12.2 gm/dL and her platelet count was 268 000/mm3. Erythrocyte sedimentation rate was 24 mm/h. Electrolytes and liver function tests were within normal limits. Prothrombin and partial thromboplastin times were elevated at 15.1 seconds and 33.5 seconds, respectively. Blood and urine cultures did not reveal any growth.
COURSE OF ILLNESS
A chest roentgenogram was performed which revealed diffuse peribronchial thickening as well as subsegmental atelectasis in the right middle lobe. CT scan of her sinuses revealed extensive maxillary sinus disease with some ethmoidal opacification. A chest CT revealed subcarinal and hilar adenopathy.
Ultimately, a diagnostic procedure was performed which revealed the diagnosis.
DISCUSSION CASE 4-5
As with all other age groups, the most common etiology for a cough in the toddler is an infectious process. Viruses, M. pneumoniae, and pertussis should all be considered as possible infectious causes. Given her symptoms and the findings on chest radiograph, pneumonia, and bronchiolitis remain on the list of potential diagnoses. Almost equally as important in this age group is the possibility of a foreign body ingestion, which is often revealed during a thorough analysis of medical history. Another clue to foreign body ingestion is a focal finding on chest auscultation, as was seen in this patient, with localized wheezing. If there is a concern for a foreign body ingestion, inspiratory and expiratory chest roentgenograms may reveal the diagnosis. If the child is too young for these maneuvers, bilateral decubitus chest roentgenograms can be obtained. In the case of foreign body ingestion, these films may reveal persistent hyperinflation on the side where the foreign body has lodged.
Other concerning findings in this patient’s history are her relatively poor growth, her diffuse sinus disease, and her history of frequent stooling. With this constellation of symptoms, one should include some rarer causes of cough in the differential diagnosis, including congenital immunodeficiencies, human immunodeficiency virus infection, and cystic fibrosis (CF).
Because of her poor growth, sinus disease, chronic cough, and frequent stooling, a sweat test was performed. The results revealed sweat chloride levels of 96 mEq/L and 88 mEq/L (normal <40 mEq/L), thus revealing the diagnosis of cystic fibrosis.
INCIDENCE AND EPIDEMIOLOGY
Cystic fibrosis is the most common lethal inherited disease in the Caucasian population. The incidence is approximately 1/2500 in Caucasians, 1/17 000 in African-Americans, and 1/90 000 in Asians. It is inherited in an autosomal recessive pattern with a carrier rate of 1/25. Life expectancy for patients with cystic fibrosis has improved dramatically during the last 50 years. In the 1950s, median survival was less than 5 years of age. The current predicted median age of survival for a person with CF is in the late 30s.
The gene for cystic fibrosis was discovered in 1989 and is located on chromosome 7. The gene product is a cyclic-AMP-activated chloride channel called the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR is expressed in multiple organs including the pancreas, sweat glands, gastrointestinal tract, reproductive tract, and respiratory tract. Defective CFTR function results in dysfunctional electrolyte transport at the affected epithelial surfaces leading to dehydration of the luminal surfaces. This causes the development of thick, viscid secretions that result in obstruction, inflammation, and progressive scarring of affected organs.
Given that CFTR gene expression is so diffuse, the clinical presentation of cystic fibrosis is quite diverse. The most common and life-threatening manifestations are related to respiratory disease, though extrapulmonary manifestations of cystic fibrosis are common (Table 4-8).
TABLE 4-8. Clinical manifestations of cystic fibrosis.
Chronic sinus and/or pulmonary disease
Persistent colonization and/or infection with CF pathogens (Staphylococcus aureus, nontypeable Haemophilus influenzae, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, and Burkholderia cepacia)
Persistent changes on chest radiograph
Sinus changes, including recurrent sinusitis, nasal polyps
Signs of airway obstruction, such as wheezing
Prolonged neonatal jaundice
Distal intestinal obstruction syndrome
Recurrent acute or chronic pancreatitis
Genitourinary and renal
Acute salt depletion
Chronic metabolic alkalosis
Failure to thrive
Hypoproteinemia with associated edema
Fat-soluble vitamin deficiencies
Source: Adapted, with permission, from Farrell PM, Rosenstein BJ, White TB, et al. Guidelines for diagnosis of cystic fibrosis in new-borns through older adults: Cystic Fibrosis Foundation consensus report. J Pediatr. 2008;153:S4-S14.
The initial presentation of cystic fibrosis can occur in a variety of ways. Increasing numbers of patients are being diagnosed before the onset of symptoms due to expanding newborn screening programs for CF (Figure 4-7). Symptoms present in infancy may include meconium ileus (present in 10%-15%), failure to thrive, rectal prolapse, and chronic cough. Failure to thrive due to intestinal malabsorption is the most common early manifestation of CF. Other presenting features in childhood can include nasal polyps, cough, frequent episodes of wheezing, frequent respiratory infections, liver disease, recurrent sinusitis and/or pancreatitis, and infertility.
FIGURE 4-7. Diagnostic approach to cystic fibrosis. (Reproduced, with permission, from Farrell PM, Rosenstein BJ, White TB, et al. Guidelines for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation consensus report. J Pediatr. 2008;153:S4-S14.)
The respiratory complications are the greatest cause of morbidity and mortality in CF. The classic pulmonary triad in CF is inflammation, impaired mucociliary clearance, and chronic airway infection. Recurrent acute pulmonary infections are common as a result of this triad, and may present similarly to recurrent viral infections or asthma. Common CF pathogens include Staphylococcus aureus, Haemophilus influenzae, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, and Burkholderia cepacia. Eventually, the recurrent pulmonary infections will lead to lung tissue destruction and bronchiectasis. Complications in CF patients can include allergic bronchopulmo-nary aspergillosis (detected by chronic wheeze, lung function decline, chronic cough, and transient infiltrates on CXR), hemoptysis, and pneumothorax.
Gastrointestinal disease is also common in CF, and will often include pancreatic insufficiency. Therefore, failure to thrive is a common presentation, along with frequent bulky or malodorous stools indicative of fat malabsorption. Other gastrointestinal complications can include liver disease, CF-related diabetes, gastroesophageal reflux, and rectal prolapse. Thick mucoid impaction in the distal small bowel can result in distal intestinal obstruction syndrome (DIOS).
Fertility is commonly affected in both males and females with CF. Ninety percent of men with CF will have congenital bilateral absence of the vas deferens. Women will also have significantly decreased fertility due to nutritional, respiratory, and cervical mucous abnormalities.
Sweat test. Quantitative pilocarpine iontophoresis is the gold standard in diagnosing cystic fibrosis (Figure 4-7). The chloride levels in collected sweat are measured. Levels ranging from 0 to 40 mmol/L are considered normal, 40-60 mmol/L are borderline (30-59 mmol/L for infants <6 months), and levels greater than 60 mmol/L are considered positive. If sweat chloride levels are borderline, the diagnosis of CF can be made with the presence of two disease-causing CFTR mutations. Elevated sweat chloride levels have been reported with other entities (untreated adrenal insufficiency, malnutrition, hypothyroidism, nephrogenic diabetes insipidus, ectodermal dysplasia, mucopolysaccharidosis, and panhypopituitarism), but most of those other conditions differ clinically from cystic fibrosis.
Genetic mutation analysis. Currently, more than 1000 different mutations in the CFTR gene have been identified. Standard genetic testing will usually screen for around 20-70 mutations. Testing for a discrete group of approximately 40 of the most common disease-causing mutations will detect more than 90% of cases. Expanded sequence analysis of many more mutations is costly and may detect novel polymorphisms and mutations of unknown significance. Testing can be performed on blood or a buccal swab.
Chest roentgenogram. While a chest roentgenogram cannot be used to diagnose CF, it can certainly have suggestive features. These may include significant peribronchial thickening, hyperinflation, and bronchiectasis. Progressive pulmonary disease in patients with CF leads to nodular pulmonary infiltrates and apical cystic lesions that predispose to pneumothoraces.
Sputum culture. Initially, the majority of patients with cystic fibrosis are colonized with Staphylococcus aureus and Haemophilus influenzae. By young adulthood, nearly 80% of patients are colonized with Pseudomonas aeruginosa.
Treatment for cystic fibrosis is multidisciplinary and targets the varied manifestations of the disease. An aggressive therapeutic strategy is essential to maximizing pulmonary function. As part of chronic pulmonary therapy, inhaled daily recombinant human deoxyribonuclease, or dornase alfa, and inhaled tobramycin have received the highest recommendations in moderate to severe disease. Other agents recommended by the Cystic Fibrosis Foundation include inhaled hypertonic saline, macrolide antibiotics, ibuprofen, and inhaled beta-agonists for specific populations. Airway clearance techniques are widely supported as part of the treatment regimen for patients with CF. There are many clearance options, including percussion and postural drainage, positive expiratory pressure devices, and airway and chest wall oscillating devices. Studies have not shown one method to be superior; thus selection of technique is dependent on each patient’s preferences. Finally, attention to nutritional status has been shown to be vital for long-term survival and lung health. Any patient who has pancreatic insufficiency clinically or subclinically, as evidenced by low fecal elastase concentrations, should receive supplementation with pancreatic enzymes, in addition to fat-soluble vitamins.
Aggressively treating pulmonary exacerbations improves outcomes. Treatment includes antibiotics, increased airway clearance, and optimizing nutrition. Generally, antibiotic treatment should consist of combination therapy with 2-3 antibiotics with different mechanisms of action for approximately 14 days. Given the high prevalence of Pseudomonas in patients with CF, a combination of a beta-lactam and aminoglycoside can be considered appropriate.
For patients with end-stage pulmonary disease, lung transplantation is considered the final treatment option. The 5-year survival rate for children after transplant is approximately 50%, and success depends on a variety of factors. Ultimately, mutation-specific and gene therapies targeting the specific mutations and genes involved in CF are areas of current research that are still in the early stages of development.
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