TODD A. FLORIN
HISTORY OF PRESENT ILLNESS
A 4-month-old African-American boy was well until 9 days prior to admission when he developed fever to 38.9°C and a cough. Seven days prior to admission he was evaluated by his primary physician and treated with ranitidine for suspected gastroesophageal reflux. Four days prior to admission he developed tachypnea and grunting and received nebulized albuterol. On the day of admission he had continued fever and worsening cough. His oral intake was poor. He drank only 2-3 ounces of breast milk every 4 hours during the past day. His urine output was also decreased. Multiple family members had upper respiratory infections.
The boy was born at 40 weeks gestation after an uncomplicated pregnancy. He had received all of the appropriate immunizations for age, including the second dose of DTaP. There was no family history of asthma or sickle cell disease.
T 37.0°C; P 120 bpm; RR 76/min; BP 102/72 mmHg; SpO2 93% with 3 liters O2 by nasal cannula
Weight 10-25th percentile; Length 10th percentile; Head circumference 10th percentile
The patient was awake and alert. The anterior fontanelle was open and flat. He had flaring of the alae nasi. There were moderate intercostal, subcostal, and supraclavicular retractions. Scattered rhonchi were present with diminished breath sounds at the bases bilaterally. There was no focal wheezing. The heart sounds were normal. The spleen was palpable just below the left costal margin. The remainder of the examination was normal.
The white blood cell count was 10 200/mm3 with 15% band forms, 68% segmented neutrophils, and 12% lymphocytes. The hemoglobin was 10.3 g/dL and the platelet count was 277 000/mm3. Arterial blood gas (ABG) revealed the following: pH, 7.42; PaCO2, 30 mmHg; and PaO2, 90 mmHg. Hepatic function panel revealed a total bilirubin of 0.3 mg/dL; alanine aminotransferase, 55 U/L; aspartate aminotransferase, 82 U/L; and lactate dehydrogenase, 3280 U/L. No antigens to respiratory syncytial virus, parainfluenza types 1, 2, and 3, influenza A and B, and adenovirus were detected by immunofluorescence of nasopharyngeal aspirate. Serum immunoglobulin results were as follows: IgG, 24 mg/dL (normal range, 27-73); IgM, 528 mg/dL (normal range, 37-124); and IgG, 650 mg/dL (normal range, 292-816).
COURSE OF ILLNESS
The patient was treated with nebulized albuterol and a racemic mixture of epinephrine without significant improvement in his respiratory status. An echocardiogram showed normal cardiac anatomy. The patient required endotracheal intubation for worsening respiratory distress. A chest radiograph suggested a diagnosis (Figure 1-8).
FIGURE 1-8. Chest radiograph of 4-month-old boy with fever and cough.
DISCUSSION CASE 1-6
The most common cause of progressive respiratory distress during infancy is bronchiolitis, most often caused by respiratory syncytial virus, adenovirus, human metapneumovirus, influenza viruses A and B, and parainfluenza viruses types 1, 2, and 3. The differential diagnosis of perihilar or diffuse infiltrates includes Bordetella pertussis or Bordetella parapertussis, Chlamydia trachomatis, and Myco-plasma pneumoniae. Herpes simplex virus and cytomegalovirus (CMV) may cause pneumonia in the young infant. CMV pneumonia is frequently associated with hepatosplenomegaly, thrombocytopenia, and lymphocytosis. Pneumocystis jiroveci (formerly P. carinii) pneumonitis (PCP) should be considered, particularly if there are maternal risk factors for human immunodeficiency virus (HIV) infection. The differential diagnosis of HIV-associated pneumonia is found in Table 1-5. Other conditions predisposing to PCP include primary B-cell defects, primary T-cell defects, and combined defects. The immune disorders most likely to present with PCP include severe combined immunodeficiency, DiGeorge anomaly or other 22q11 deletion syndromes (as a result of impaired thymus development), Wiskott-Aldrich syndrome, X-linked agammaglobulinemia, and hyper-IgM syndrome.
TABLE 1-5. Differential diagnosis of pneumonia in patients with HIV infection.
Noninfectious causes of pneumonia include gastroesophageal reflux associated with pulmonary aspiration, aspiration owing to foreign body or inhaled irritants, autoimmune diseases (e.g., sarcoidosis), and malignancies. Occasionally, an anatomic defect, such as tracheoesophageal fistula, may predispose to aspiration; of these, an H-type tracheoesophageal fistula is most likely to present after the neonatal period. Primary cardiac abnormalities (e.g., ventricular septal defect), pulmonary vascular abnormalities, and impaired lymphatic flow (e.g., congenital lymphangiectasia) may cause tachypnea and progressive respiratory distress in a 4-month-old child. Cystic fibrosis can masquerade as any of the above conditions.
Chest radiograph (Figure 1-8) revealed hazy ground-glass opacities bilaterally. There was no pleural effusion. The diagnosis of P. jiroveci pneumonia was confirmed by Gomori methenamine silver staining of a specimen obtained by bronchoalveolar lavage (BAL, Figure 1-9). The patient was treated with intravenous trim-ethoprim-sulfamethoxazole (TMP-SMX; 20 mg/kg/day trimethoprim component) and prednisone. He required ventilatory support for 5 days with gradual recovery. HIV DNA was detected in the patient’s blood by polymerase chain reaction (PCR), confirming the underlying diagnosis of HIV.
FIGURE 1-9. Gomori methenamine silver staining of a specimen obtained by bronchoalveolar lavage.
INCIDENCE AND EPIDEMIOLOGY
Pneumocystis jiroveci is an opportunistic parasite with some features of protozoa, but greater genetic homology to fungi. Asymptomatic infection occurs early in life; up to 85% of immunocompetent children have antibodies by 4 years of age. Immuno-compromised infants and children develop severe PCP as a result of primary infection.
The risk of PCP is related to the extent of T-cell deficiency or defect, immunosuppression and the use of chemoprophylaxis. PCP occurs in children with advanced HIV infection (25%-50%), primary immunodeficiencies (most notably severe combined immunodeficiency syndrome, 25%-50%), lymphoid malignancies such as acute lymphocytic leukemia (10%-20%), allogeneic bone marrow transplant (5%), and organ transplant (2%-10%) when no chemoprophylaxis is given. Patients with collagen vascular disorders, particularly Wegener’s granulomatosis, are at risk for PCP if they are lymphopenic or receiving multiple immunosuppressive agents. Use of TMP-SMX prophylaxis reduces the PCP rate to less than 5% in HIV-infected children. Children receiving agents that impair cell-mediated immunity, including corticosteroids and cyclosporine, are at even higher risk of developing PCP. Patients with a history of PCP are at high risk for recurrence.
Severe PCP infection usually occurs in the first year of life in HIV-infected children not receiving TMP-SMX prophylaxis with the highest incidence between 3 and 6 months of life. A bronchiolitis-like illness occurs with gradually worsening tachypnea and accessory muscle use. Physical examination reveals the absence of fever and a paucity of findings on auscultation despite significant hypoxia. Rales and cyanosis develop as the illness progresses.
In older HIV-infected children, the spectrum of clinical manifestation varies. The classic symptom triad is fever, cough, and dyspnea. The symptoms may initially be mild and slowly progressive, delaying the diagnosis. High fevers are common. Findings on lung auscultation are often unimpressive compared to the degree of dyspnea, tachypnea (80-100/min), and hypoxia. Scattered rales, rhonchi, or wheezes may be heard as the illness resolves. Pneumothorax may occur in 2% to 4% of patients. In children with an underlying non-AIDS-associated PCP, the onset of symptoms occurs more abruptly over days rather than weeks as in HIV-infected children, but physical examination findings are similar.
PCP should be considered in any immunocompromised patient with respiratory symptoms, fever, and an abnormal chest radiograph. The diagnosis should also be considered in any patient with risk factors for HIV infection. If the patient does not have a known predisposing condition, testing to exclude HIV and congenital immune deficiencies should be performed.
Chest roentgenogram. Chest radiograph most commonly shows diffuse bilateral interstitial infiltrates, beginning in the perihilar region and progressing to the periphery. The lung apices are least affected. The infiltrates are classically described as granular, reticular, or ground-glass. Chest radiograph is normal in up to 40% of cases.
Examination of lower respiratory tract specimens. Pneumocystis jiroveci cannot be cultivated in culture, and thus identification of the organism in respiratory specimens, such as pulmonary parenchyma or lower respiratory tract secretions, is required for definitive diagnosis. Specimens can be stained using Gomori’s methenamine silver, toluidine blue O, or Wright-Giemsa stains, or fluorescein-labeled monoclonal antibody stains. Monoclonal antibody stains are more sensitive than the general stains, and unlike many of the general stains, are able to stain both trophic and cystic forms of the organism. For these reasons, monoclonal antibodies have become the diagnostic “gold standard” at many institutions.
The diagnostic yield of various procedures follows: Induced sputum (children over 5 years of age), 20%-40%; BAL, 75%-95%; transbronchial biopsy, 75%-95%; and open lung biopsy, 90%-100%. The optimal procedure used to obtain a specimen depends on many factors, including the age and clinical status of the patient. The traditional algorithm involves examination of induced sputum in those over 5 years of age followed by BAL if the sputum sample is negative. Open lung biopsy is reserved for patients with a nondiagnostic BAL. Children less than 5 years should undergo BAL initially.
PCR, though still under investigation, may allow diagnosis with fewer invasive procedures. PCR assays seem to be more sensitive, but less specific, than traditional diagnostic methods, with PCR analysis of oral washes demonstrating a sensitivity of 80% compared to concomitantly obtained BAL. Sensitivity of PCR declines after initiation of treatment, and thus specimens should be collected before antibiotics.
Serum lactate dehydrogenase. Rising serum LDH reflects lung injury. Elevated serum LDH, while common in children with PCP, is a nonspecific finding.
Other studies. Additional studies should be performed to diagnose alternate or concomitant respiratory conditions. Nasopharyngeal aspirates, sputum, or BAL specimens should be sent for detection of respiratory viruses by PCR or immunofluorescent viral antigen detection (respiratory syncytial virus, influenza, parainfluenza, human metapneumovirus, and adenovirus), CMV quantitative PCR, and Mycoplasma pneumoniae PCR.
Extrapulmonary involvement due to P. jiroveci is rare; potential sites of dissemination include the lymph nodes, spleen, retina, thyroid, gastrointestinal tract, and adrenal glands. Routine radiologic imaging to exclude extrapulmonary manifestations of P. jiroveci is not necessary.
TMP-SMX (15-20 mg/kg/day of TMP) remains the treatment of choice for PCP in children. The oral route can be used in mild cases if patients can reliably take and retain oral medication. Most children require treatment intravenously. The course of treatment is 14-21 days. If no improvement is demonstrated in 5-7 days, treatment should be changed to pentamidine. Pentamidine, atovaquone, or primaquine plus clindamycin may be used for children unable to tolerate TMP-SMX. Adjunctive therapy with corticosteroids within 72 hours of diagnosis reduces the occurrence of respiratory failure and improves oxygenation in moderately ill adults with PCP. Limited data in children suggest similar benefit.
Children with an episode of PCP require post-treatment prophylaxis with TMP-SMX (5 mg/kg/day of TMP) either daily or three times per week for the duration of risk (indefinitely for those with HIV). Chemoprophylaxis agents for those unable to tolerate TMP-SMX include oral atovaquone, aerosolized or intravenous pentamidine, or oral dapsone. Because of the high risk of acquiring PCP during the first year of life, all infants born to HIV-infected mothers require PCP prophylaxis from 4 weeks to 12 months of age, regardless of CD4+ lymphocyte counts; prophylaxis can be discontinued sooner if HIV infection had been excluded. After 12 months of age, prophylaxis is required if the CD4 percentage is less than 15% or if the CD4+ count is less than 500 cells/microliter (less than 200 cells/microliter in those over 5 years of age). Prophylaxis should also be considered in patients with AIDS-defining illnesses and oropharyngeal candidiasis. Patients in other high-risk groups including those with severe combined immune deficiency, lymphoproliferative malignancies, organ transplants, prolonged high-dose corticosteroid use, and those receiving intensified immuno-suppression with T-cell depleting therapies also require PCP prophylaxis.
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