Lung infection in the immunocompromised child
Ernst Eber, MD
Correspondence
Prof. Dr. Ernst Eber
Respiratory and Allergic Disease Division
Paediatric Department
Medical University of Graz
Auenbruggerplatz 30
A-8036 Graz, AUSTRIA
Tel.: +43 316 385 12620
Fax: +43 316 385 14621
ernst.eber@medunigraz.at
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Summary
Lung infections are a frequent cause of morbidity in immunocompromised children.
This group of patients includes children with congenital defects of host defense and
defects in cell-mediated and humoral immunity, and – much more frequently –
children treated for malignancy and autoimmune diseases, patients after bone
marrow or solid organ transplantation, and children with acquired immunodeficiency
syndrome (AIDS). Thus, the paediatric population at risk for opportunistic infections
has significantly increased in the recent past and the number of organisms causing
lung infections in these patients is extensive and ever-growing. The clinical
presentations of lung infections in immunocompromised children are often nonspecific, and the clinical management is complex due to the availability of many
diagnostic tools and the broad range of antimicrobial agents potentially needed for
treatment, implicating an increased risk of adverse drug effects. The diagnostic workup is complicated by many non-infectious processes that simulate infection in the
populations at risk. A rapid and often invasive diagnostic approach followed by early
initiation of effective treatment is crucial for the clinical outcome.
Key words
Bronchoalveolar lavage (BAL), imaging, immunodeficiency, lung biopsy, opportunistic
pathogen, Pneumocystis, pneumonia, treatment
Clinical presentation and important pathogens
The clinical presentations of lung infections in immunocompromised children are
often non-specific, and thus not helpful for establishing specific diagnoses. Patients
may either be infected with a common pathogen (e.g. respiratory syncytial virus,
adenovirus, and varicella zoster virus) and then present with an atypical disease
course, or with an opportunistic pathogen (e.g. Pneumocystis jirovecii) presenting
with very variable clinical courses, depending on the degree of residual immunity. It is
vital to identify unusual patterns of common infections and rare infections which
suggest immunodeficiency in order to enable early diagnosis and appropriate (i.e.
aggressive) treatment to prevent sequelae such as bronchiectasis and respiratory
failure. The underlying disorders (malignancy, bone marrow and solid organ
transplantation, primary immunodeficiencies, and acquired immunodeficiency
syndrome – AIDS) are each associated with specific respiratory pathogens; further,
the types of pulmonary complications seen in bone marrow transplantation vary with
the time after transplantation. Combined immunodeficiencies often present with
persistent viral infection, whereas antibody deficiencies present with recurrent
bacterial infection. The most important bacterial pathogens are Haemophilus
influenzae, Streptococcus pneumoniae, Staphylococcus aureus, Klebsiella
pneumoniae,
Pseudomonas
aeruginosa,
Mycobacterium
tuberculosis,
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Mycobacterium avium-intracellulare, Legionella sp. and Listeria monocytogenes.
Cytomegalovirus, varicella zoster virus, herpes simplex virus, and Epstein-Barr virus
are frequent viral, and P. jirovecii, Aspergillus sp., Candida sp., and Cryptococcus
neoformans frequent fungal pathogens. In addition, parasitic infections (e.g.
Toxoplasma gondii, Cryptosporidium parvum) may cause pulmonary complications. A
number of non-infectious complications (e.g. drug-induced lung injury, radiation
pneumonitis, and lymphocytic interstitial pneumonitis) have to be considered as
differential diagnoses in the diagnostic work-up of immunocompromised children
presenting with respiratory signs and symptoms.
Diagnostic studies
Imaging
Plain chest radiographs are insensitive and usually not helpful in establishing a
specific diagnosis; they often show atypical features, and in some cases they may be
normal. High-resolution computed tomography (HRCT) is much more sensitive, thus
improving diagnostic accuracy and allowing for earlier diagnosis. In addition, it can be
of help in planning invasive procedures such as flexible bronchoscopy or lung biopsy.
The radiological appearance of lung infection in the immunocompromised child varies
and includes diffuse alveolar and/or interstitial pneumonitis (common causative
pathogens include P. jirovecii and cytomegalovirus), lobular or lobar pneumonitis
(with S. pneumoniae, S. aureus, and H. influenzae as typical pathogens), and solitary
or multiple nodular infiltrates, cavitary lesions or lung abscess (causative pathogens
include Aspergillus sp. and Mycobacteria). However, the radiographic findings as a
product of both the pathogen and the response of the child may not adequately
reflect pulmonary involvement, in particular in patients with pronounced neutropenia.
Bronchiectasis is a common complication in the immunocompromised child; typical
radiologic features include hyperinflation and bronchial wall thickening, with or
without dilatation.
Methods for pathogen detection
Blood cultures
While a blood culture should be obtained in immunocompromised children suspected
of having lung infection, a positive result is unusual.
(Induced) Sputum
Sputum analysis may be helpful when pathogens which do not normally colonise the
upper respiratory tract are isolated (e.g. M. tuberculosis or Legionella sp.). In
particular, induced sputum has a role for the diagnosis of P. jirovecii in AIDS patients.
However, non-invasive methods only rarely allow to establish a specific diagnosis in
immunocompromised children with lung infection.
Tracheal aspirates, non-bronchoscopic bronchoalveolar lavage (BAL)
In intubated patients, tracheal aspirates and non-bronchoscopic samples are easy to
obtain and have a favourable diagnostic yield as compared with non-invasive
methods.
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Flexible bronchoscopy and BAL
In immunocompromised children, flexible bronchoscopy and BAL represent a very
useful technique, and – in experienced hands – a safe procedure, even in patients
with reduced platelet counts and in most ventilated patients with stable
haemodynamic and ventilatory parameters. BAL is carried out in the most-affected
area; in diffuse lung disease, the middle lobe or lingula are used.
In children with acute onset of tachypnoea, dyspnoea, and hypoxaemia, and with
radiographic findings of diffuse alveolar and/or interstitial pneumonitis BAL should be
performed before antibiotic therapy is commenced. If antibiotic therapy has been
started already, BAL should be performed in those children who do not improve.
Further, BAL should be repeated in children with a specific BAL diagnosis but who
deteriorate clinically in spite of appropriate treatment. Additional indications for BAL
include children with acute focal infiltrates which do not respond to standard broad
spectrum antibiotic therapy within 48 hours, and (in association with transbronchial
lung biopsy) lung transplant recipients as part of a routine surveillance programme or
in case of clinical and/or radiological pulmonary deterioration.
Microbiological studies must be interpreted with care. The identification of primary
pathogens not usually found in the lung in BAL fluid is diagnostic. Such pathogens
include P. jirovecii, M. tuberculosis, L. pneumophila, Nocardia, Histoplasma,
Blastomyces, Mycoplasma, influenza virus, and respiratory syncytial virus.
Conversely, the identification of herpes simplex virus, cytomegalovirus, Aspergillus,
atypical mycobacteria, bacteria, and Candida in BAL fluid from immunocompromised
children does not necessarily establish a diagnosis of infection, since these
organisms may be present as airway contaminants or commensals.
In AIDS patients with acute interstitial pneumonitis or lower respiratory tract disease,
infectious agents may be identified in the majority of cases, with P. jirovecii being the
most frequent pathogen, followed by cytomegalovirus. In other immunocompromised
children and in patients receiving Pneumocystis prophylaxis, however, the number of
P. jirovecii organisms is usually low, and BAL may be falsely negative. Further, in
immunocompromised children on broad-spectrum antimicrobial therapy, the yield of
BAL probably will also be low. The wide variation in diagnostic rates reported may be
due to the heterogeneity of patient selection, the delay between onset of lung
disease and BAL, the BAL technique used, and the techniques used for detection of
organisms.
Open lung biopsy
In immunocompromised children, open lung biopsy represents the “gold standard”
technique for pathogen detection, and may be performed via video-assisted thoracic
surgery (VATS) or a mini-thoracotomy. With current techniques, open lung biopsy is
a procedure with low morbidity. In contrast, for both transbronchial biopsy and
percutaneous CT-guided needle lung biopsy there is a considerable risk of bleeding
and pneumothorax. In immunocompromised children, the reported yield of open lung
biopsy for a specific diagnosis varies widely, but in general supports its utility. Timing
of the biopsy is often difficult; usually, a patient not clearly responding to therapy
chosen on the basis of results obtained by other techniques or chosen empirically will
benefit from a specific diagnosis by open lung biopsy. For both BAL and open lung
biopsy it is very important to liaise closely with microbiology and virology laboratories
to ensure that appropriate tests are performed.
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Treatment
Pathogen-specific treatment is most desirable in immunocompromised children with
lung infection. However, while awaiting the results of the diagnostic work-up,
empirical treatment has to be initiated; the latter should address both the most
common and the most serious infections conceivable. Thus, the initial treatment
typically is a broad spectrum antibacterial regimen, aimed at both gram-positive and
gram-negative pathogens. In addition, other pathogens should be considered
depending on the patient population and the local epidemiological situation. In
neutropenic patients with lung infiltrates, Pseudomonas coverage and an antifungal
regimen with efficacy against Aspergillus is strongly recommended. A positive
tuberculin skin test, a positive history of tuberculosis, or a recent documented
exposure to tuberculosis may be an indication for empirical antimycobacterial
treatment in an immunocompromised child with pulmonary infiltrates. Empirical
treatment of P. jirovecii pneumonia and antiviral treatment for cytomegalovirus
disease should be considered in AIDS patients with low CD4 cell counts and other
high-risk patients. Pneumocystis-prophylaxis significantly reduces but does not
eliminate the risk of Pneumocystis pneumonia. In general, treatment should be
continued for a minimum of two weeks, but may be required for much longer periods,
in particular in the case of antifungal therapy.
Viral infections
For cytomegalovirus pneumonitis, a combination of ganciclovir and intravenous
immunoglobulin is recommended. Similarly, acyclovir and intravenous
immunoglobulin are the mainstay of treatment of herpes simplex / varicella zoster
virus. For adenovirus pneumonitis, cidofovir has been shown to be of benefit.
Fungal infections
For both Aspergillus pneumonitis and Candida infections, amphotericin B has been
the drug of choice, sometimes in combination with flucytosine. Newer antifungal
agents such as voriconazole and caspofungin have now replaced conventional
amphotericin.
Patients at risk for P. jirovecii infection should receive prophylaxis, preferably with
oral trimethoprim-sulphamethoxazole or, alternatively, with aerosolised and
intravenous pentamidine and dapsone. Pneumocystis pneumonia can be treated with
several medications including trimethoprim-sulphamethoxazole and pentamidine.
Prognosis
The prognosis for immunocompromised children with lung infection depends on
several factors such as the underlying disorder and the degree of residual immunity,
the infectious agent, and the points in time the diagnosis is established and effective
treatment is started; thus, the prognosis is highly variable.
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