Persistent and Recurrent Pneumonia

Pathogen-Related Causes

Unresolved or untreated acute infection usually is responsible for persistent pneumonia ( Table 35.1 ). In a patient receiving empiric antibiotic therapy, the cause is (1) infection by an organism not eliminated by the chosen antibiotic, either because of antimicrobial resistance of a common bacterial pathogen (penicillin-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus [MRSA], β-lactamase-producing Haemophilus influenzae , Prevotella melaninogenica , resistant gram-negative bacilli); or (2) more commonly, infection with organisms for which the chosen antimicrobial therapy was ineffective ( Mycobacterium tuberculosis , Mycoplasma pneumoniae , Chlamydophila spp., Coxiella burnetii , Francisella tularensis , fungi, viruses, helminths). Complications of appropriately treated bacterial pneumonia, such as necrotizing pneumonia, pleural effusion, and progression to lung abscess or empyema, or bronchiectasis also must be considered. The clinical, radiographic, and other imaging findings, as well as the context of the patient’s illness, help prioritize possible causes ( Fig. 35.1 ).

Tuberculosis always should be considered in children with persistent pneumonia or subacute presentation, even if exposure is not obvious. Immigration from or travel to a region of the world with a endemic tuberculosis (Asia, Middle East, Africa, Latin America, countries of the former Soviet Union) or contact with individuals at high risk for tuberculosis (immigrants from regions in which tuberculosis is endemic; homeless persons; individuals with history of drug abuse or imprisonment; or persons with HIV infection) heightens the likelihood of tuberculosis. A history of weight loss, cough, or fever is not always present. The radiographic abnormality generally is more impressive than the limited clinical findings, although occasional patients can manifest hectic fever, respiratory distress, and toxicity simulating acute pyogenic pneumonia. The presence of enlarged thoracic lymph nodes is a suggestive, but inconsistent, finding.

C. burnetii (Q fever) and Chlamydia psittaci infections are considered in patients with persistent fever, malaise, and myalgia, hacking cough, persistent parenchymal infiltrate, and exposure to farm animals or psittacine birds. Systemic illness usually overshadows pulmonary symptoms in young children with Q fever; psittacosis is rare in young children.

The likelihood of fungal pneumonia in a previously healthy child depends on place of residence or unusual environmental exposure. Nodular or miliary densities are more common than lobar consolidation, but not consistently. Histoplasma capsulatum is endemic to the Midwest and to the St. Lawrence River valley in Canada. Subacute presentation with fatigue and a persistent cough is usual, and hilar lymphadenopathy is a clue. Blastomyces dermatitidis is a rare cause of persistent pneumonia in children. Endemic areas partially overlap those of histoplasmosis, including parts of the Mississippi, Ohio, Missouri, and St. Lawrence waterways. Older children with Blastomyces pneumonia may produce purulent sputum and often fail at least one course of treatment with an antibacterial agent before the etiology is identified correctly. Coccidioides immitis is endemic to the southwestern United States, including west Texas, Arizona, New Mexico, California, Utah, and Nevada, as well as northern Mexico and parts of Central and South America. Erythematous rashes and erythema multiforme are frequent early in the course, and erythema nodosum (also seen in Blastomyces or Histoplasma infection) can accompany pneumonia. Because environmental exposure often is a cause of fungal pneumonia, clusters of cases within the same family or in other persons exposed simultaneously can occur with Histoplasma, Blastomyces, and Coccidioides spp. infections. Rarely, a previously healthy child with or without undue exposure to dust, pigeon excreta, model terrarium, construction, or home renovation develops pneumonia due to Cryptococcus or Aspergillus spp. that leads to a protracted infection.

In adolescents at risk for HIV infection, Pneumocystis jirovecii should be considered, especially when persistent pneumonia is bilateral, interstitial, and associated with hypoxemia disproportionate to the severity of clinical illness or physical findings. Risk factors for HIV infection (injection drug use, multiple sexual partners, bisexual partner) need to be evaluated. In the infant with HIV infection, Pneumocystis pneumonia (PCP), especially when not properly treated, is rapidly progressive and has a high mortality.

Diffuse lower respiratory tract inflammation caused by some respiratory viruses can predispose to bacterial superinfection, especially in patients hospitalized with influenza or RSV infection requiring intensive care. For children with laboratory-confirmed viral respiratory infection for whom symptoms persist or progress, a viral-bacterial coinfection deserves consideration. Several viruses, including influenza, can cause a rapidly progressive pneumonia nonresponsive to antibacterial therapy. Hantavirus can act similarly and also can involve other organs. Adenovirus can cause a necrotizing pneumonia (bronchiolitis obliterans).

Host-Related Causes

Multiple congenital or acquired anatomic abnormalities also are considered in children whose pneumonia (1) fails to resolve, (2) responds symptomatically to antimicrobial therapy but does not resolve radiographically, or (3) resolves and then recurs at the same site (see Table 35.1 ). Atelectasis (parenchymal volume loss) should be differentiated from persistent infiltrate or consolidation (without volume loss). Atelectasis occurs commonly with RSV bronchiolitis, airway hyperreactivity in infants and toddlers, asthma, and complete bronchial obstruction from intrinsic or extrinsic causes. Except with fixed obstructing lesions, atelectasis is expected to be transient or migratory; if atelectasis persists, the affected lung segment can become infected secondarily.

Bronchiectasis, with dilation of the bronchi, arises most commonly from damage to bronchial walls by infection or chronic inflammation. The bronchial wall then is susceptible to further dilation and distortion during breathing. Severe acute viral, bacterial, or fungal infection or recurrent infection related to CF, immunodeficiency, or local obstruction are known causes of bronchiectasis. Adenovirus and measles virus infections, retained foreign body, and tuberculosis are associated most commonly with segmental bronchiectasis in the healthy host. In children with untreated or poorly controlled HIV infection or congenital immunodeficiency, lymphocytic interstitial pneumonia or recurrent bronchitis or pneumonia can progress to bronchiectasis. After bronchiectasis has developed, impaired ciliary function and bronchial mechanics predispose to recurrent pneumonia. Children with extensive bronchiectasis often are fatigued easily, may have slower growth, and commonly have digital clubbing.

Intraluminal Obstructing Lesions

In otherwise healthy children, aspirated foreign body (or granulation tissue resulting from presence of a foreign body) is the most common cause of incompletely resolved or recurrent pneumonia at the same site. ^, The diagnosis is apparent if history of an event is elicited or if a foreign body is visualized radiographically. Neither finding is present in most cases, but frequently older children remember the event after the object is retrieved at bronchoscopy. Spontaneous hemorrhage from the lower respiratory tract suggests foreign body (or pulmonary sequestration) and can be life threatening.

Pneumonia at a single anatomic site can be related to particular positional vulnerability in children who are relatively immobile and who aspirate oropharyngeal material because of impaired neuromuscular function or coordination. A dependent segment or segments of lung are involved usually. Other intraluminal bronchial obstructions can cause associated single-site pneumonia, including bronchial adenoma, lipoma, papilloma, foreign body granuloma (e.g., peanut, other vegetable matter), granuloma of M. tuberculosis or nontuberculous Mycobacterium spp., or segmental bronchomalacia or bronchial stenosis.

The right middle lobe is predisposed to persistent atelectasis and subsequent infection or delayed resolution of pneumonia because of the acute angle and length of its bronchus, the proximity of its bronchus to hilar nodes, and poor to absent collateral ventilation compared with other regions of the lung. The right middle lobe also is a site of aspiration in the upright position. Recurrent right middle lobe pneumonia and atelectasis make up the so-called right middle lobe syndrome. Right middle lobe syndrome in children can have an intraluminal cause secondary to a primary ventilation disorder and chronic inflammation; asthma and foreign body aspiration are two such causes. Extraluminal compression from anatomic abnormalities and compression through lymph nodes from infectious causes, such as fungi and M. tuberculosis , also can be responsible. Evaluation of children with recurrent abnormalities of the right middle lobe should include bronchoscopy with direct visualization of the airway and sampling for cultures and cytology.

Extrinsic Obstructing Lesions

Extrinsic airway compression most commonly is due to lymph node enlargement. Tuberculosis is most common, causing hilar, carinal, and other superior mediastinal airway compression, leading to secondary bacterial pneumonia. Pulmonary histoplasmosis, blastomycosis, and coccidioidomycosis also are important causes of hilar adenopathy. Tumors can cause compression of the airway directly or through lymph node involvement. Congenital or acquired heart disease associated with an enlarged heart can cause compression of left lower lobe bronchus especially, leading to pneumonia. Shunting procedures that cause excessive pulmonary blood flow can lead to airway compression or segmental congestion and impaired drainage, predisposing to localized infection.

Congenital Abnormalities of the Respiratory Tract

Congenital abnormalities of airways, pulmonary parenchyma, or the diaphragm can cause localized persistent or recurrent pneumonia ( Fig. 35.2 ). Tracheal bronchus, an abnormal bronchus arising from the trachea, leads to impaired drainage of the right upper lobe and persistent collapse. Congenital cystic anomalies of the tracheobronchial tree include congenital pulmonary airway malformation (CPAM; previously termed congenital cystic adenomatoid malformation or CCAM), congenital lobar hyperinflation, and bronchogenic cysts ( Fig. 35.3 ).

CPAM is the most common congenital lung anomaly, representing 30%–40% of cases. CPAM and congenital lobar hyperinflation manifest early in infancy with respiratory distress (and cystic abnormality on radiographs) but can come to attention later as recurrent infection in the same segment of lung. Pulmonary sequestrations are the second most common congenital pulmonary anomaly and are composed of dysplastic pulmonary tissue that contains no connection or an aberrant connection to the tracheobronchial tree and receives a systemic vascular supply. Bronchogenic cysts are a form of foregut duplication cyst resulting from defective foregut budding. Bronchogenic cysts and pulmonary sequestrations, particularly intralobar sequestrations, can manifest as chronic or recurrent pneumonia later in childhood. Radiographically, bronchogenic cysts usually appear as round or oval well-circumscribed lesions typically in the paratracheal, hilar, and subcarinal areas. Pulmonary sequestrations appear as a focal opacity or mass in the lower lobe, usually on the left. With recurrent infection, intralesional necrosis can develop, and a more cystic appearance with or without air-fluid levels can be seen.

Approach to Diagnosis

The history of illness, associated symptoms, environmental or contact exposures, judgment about adherence to prescribed therapy, possibility of partial improvement, and reevaluation of the appropriateness of prescribed therapy usually identify children with incompletely or inadequately treated uncomplicated acute pneumonia. Continued therapy or change in therapy with follow-up to document resolution is appropriate in many situations.

A tuberculin skin test or, for children ≥2 years, an interferon γ release assay (IGRA) should be performed for children with persistent pneumonia without a clear etiology. Because of their higher specificity and lack of cross-reaction with bacille Calmette-Guérin (BCG), IGRAs are preferred in children ≥2 years who have received BCG. In infants and young children with suspicion of tuberculosis, serial first-morning gastric aspirates are obtained for testing . Sputum is obtained from older children and adolescents. HIV testing is indicated for all individuals in whom tuberculosis is diagnosed.

Serologic tests for Q fever, psittacosis, mycoplasmal infection, histoplasmosis, coccidioidomycosis, or blastomycosis are useful when the setting and clinical findings are compatible. The diagnosis of histoplasmosis is improved by testing for both antibody and antigen. Molecular-based methods, such as polymerase chain reaction assays, are available for some organisms. Fungal pneumonia due to Candida , Cryptococcus , or Aspergillus spp. can be difficult to diagnose. Testing for cryptococcal, galactomannan, and β-D-glucan antigens can be helpful. Bronchoalveolar lavage (BAL) usually is the next diagnostic specimen obtained for persistent pneumonia and has been reported to confirm the etiology of persistent pneumonia (including Blastomyces and Histoplasma spp., viruses, bacteria, and obstructing lesions) in 30% of immunocompetent children, 27% of children with cancer, and in 70% of children with AIDS.

If P. jirovecii pneumonia is suspected in an adolescent, diagnosis can be attempted through identification of the organism with methenamine silver staining, fluorescent antibody staining, or PCR of an induced sputum specimen. If the result is negative or a specimen cannot be obtained, BAL is performed. If PCP is confirmed, an underlying immunodeficiency must be investigated.

Patients with documented recurrent pneumonia, segmental bronchiectasis, suspected anatomic or obstructing lesions, or pneumonia that persists >8 weeks of appropriate therapy require further evaluation. Poor weight gain, weight loss, digital clubbing, polycythemia, or anemia validates a history of chronicity and the need to proceed aggressively. Bronchoscopy is performed to (1) exclude, or detect and remove, a foreign body; (2) detect extrinsic compression or intraluminal anomaly; (3) obtain a biopsy specimen of a mass; or (4) obtain a specimen for microscopy and culture.

CT is useful to evaluate more distal airways (including for bronchiectasis), mass lesions, tracheal bronchus, and congenital cystic anomalies and to define precise relationships of cysts with surrounding structures before surgical excision. ^, Additionally, CT is better than chest radiography to detect parenchymal lung complications (cavitary necrosis, abscess, bronchopleural fistula) and can better define pleural versus parenchymal disease. For children with moderate to large parapneumonic effusions, imaging with chest ultrasound or CT is warranted to assess for loculation. Multidetector CT with three-dimensional reconstruction generally is used for confirmation of pulmonary sequestration and presurgical planning.

Causes of Dense Focal or Multifocal Infiltrates

Primary pulmonary and a variety of nonpulmonary disorders can predispose to a diagnosis of recurrent and persistent pneumonia affecting multiple areas of the lungs ( Table 35.2 ). Primary pulmonary disorders include inflammatory diseases (such as asthma), congenital and acquired causes of epithelial dysfunction (ciliary dyskinesia, CF, viral infection), and congenital and acquired structural abnormalities (laryngeal and tracheal anomalies, chronic lung disease in infancy). Nonpulmonary disorders that cause pneumonia are myriad, comprising (1) conditions that impair or overcome normal pulmonary clearance mechanisms, such as impaired cough or gag reflex, neuromuscular disorders, and gastroesophageal reflux; and (2) conditions that increase the risk for infections in the lung, such as congenital and acquired immunodeficiency states and sickle cell hemoglobinopathies.