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Pneumonia with a slow resolution of radiographic
infiltrate or clinical symptoms despite adequate
antibiotic treatment (generally 10 to 14 days).
Is usually due to:
Defects in immune defense mechanisms
Presence of unusual organisms
Resistant bacteria
Diseases that mimic pneumonia.
Clinics in chestmedicine 2005
 Non-resolving pneumonia is a clinical syndrome in
which infiltrates occurring in association with acute
pulmonary infection fail to improve /worsen [despite
at least 10 days of antibiotic therapy] clinically /
radiologically (non-resolution within 12 weeks of the
onset of pneumonia.)
Problem statement

• Amberson introduced the term non resolving pneumonia 1943.

• Early studies show that 13% to 25% of patients with

community-acquired pneumonia had slowly resolving disease.

• The incidence of non-resolving pneumonia is 10% to 15% in

community-acquired and 30% to 60% in nosocomial
pneumonia (menendez R et al)

Problem statement
 In a large US teaching hospitals study, approximately 15% of
pulmonology consultations and 10% of diagnostic
bronchoscopies were performed for NRP.

 Mortality in non-resolving pneumonia increases 3-fold in

community-acquired and 5-fold in nosocomial pneumonia.
(Clinical pulmonary medicine, 2004 (vol. 11) (no. 5)

 Noninfectious causes were responsible for around 20% of cases

of nonresolving pneumonia in multicentric study
(Torres A et al, Thorax. 2004;59:960-965)
Patterns of normal resolution in
 Fever: Average duration is 2.5-4 days,
days after
starting appropriate treatment. Longest for legionella
6 to 7days
 Leukocytosis: TLC usually comes to normal by end
of 3-4 days but 20-40% cases it takes upto 7 days
(Halm et al)
 Cough: predominant symptom in most of the
studies (up to 93%). At 6wks 35% had cough in one
Table 1. Time to resolution of common pneumonias

Causative Radiographic Residual radiographic

organism clearing abnormalities

Bacteremic 3-5 mo 25%-35%

Nonbacteremic 1-3 mo Rare

Legionella 2-6 mo 10%-25%

Mycoplasma 2 wk-2 mo Rare

C. psittaci 1 -3 mo 10%-20%

Fein et al and Macfarlane et al

Factors associated with delayed
resolution of pneumonia
1. Age >50 yr
2. Smoking
3. Bacteremic pneumonia
4. Extent of disease.
5. Persistent fever or leukocytosis
 Chronic illness (COPD, alcoholism, DM,
renal failure,bronchiectasis)
Extent of disease
 Single vs multi lobar.
 Presence of absence of bacteremia.
 Pleural involvement.
 Cavities or abscess formation.
Table 3. Impaired immune defense mechanisms that may
lead to nonresolving pneumonia
Defense Cause of immune impairment

Nasal Use of endotracheal tube, tracheostomy


Oropharynge Severe illness, increased oral proteases, xerostomia

al bacterial malnutrition, viral illness, smoking, aging

Epiglottis Stroke, carcinoma of upper airway, use of feeding

tube, endotracheal tube, or sedating drugs
Impaired immune defense mechanisms that may
lead to nonresolving pneumonia
Defence mechanism Cause of immune impairment

Cough Use of sedating drugs, stroke, neuromuscular

illness, malnutrition, chronic bronchitis

Mucociliary Aging, smoking, chronic bronchitis,

transport bronchiectasis, dehydration, vitamin A
deficiency, endotracheal intubation alcohol use,
bacterial colonization

Immunoglobulins Malnutrition, aging, vitamin B6 or folate

deficiency, zinc deficiency, malignancy,
increased airway proteases
Impaired immune defense mechanisms that may
lead to nonresolving pneumonia
Defense mechanism Cause of immune impairment
Complement Normal with aging, consumed in sepsis

PMN cytotoxic therapy, diabetes, use of

corticosteroids or alcohol use, malnutrition.

T cells Aging, zinc deficiency

Bacterial Malnutrition, inflammatory proteases, viral

adherence illness, endotracheal intubation

Alveolar Viral illness, malnutrition, aging, use of

macrophages corticosteroids, cytotoxic therapy, alveolar
 Streptococcus Pneumonia

 Legionella

 Mycoplasma

 Staph aureus

 Gram negative bacteria

 Chlamydia psittaci
Alternative causative pathogens in
non-resolving pneumonia
 Mycobacterium tuberculosis
 Atypical mycobacteria
 Nocardia
 Actinomyces israelii
 Aspergillus
 Endemic fungi
Histoplasma capsulatum
Coccidioides immitis
Blastomyces dermatitidis
Coxiella burnetii (Q fever)
Noninfectious causes of
non-resolving resolving
Primary lung cancer (bronchioloalveolar cell ca)
Endobronchial metastasis
Bronchial adenoma
Carcinoiod syndrome
Radiation pneumonitis.
Immunologic causes non-
resolving pneumonia
 Wegener's granulomatosis

 Allergic bronchopulmonary aspergillosis

 Bronchiolitis obliterans with organizing


 Idiopathic pulmonary fibrosis.

 Eosinophilic pneumonia.
Miscellaneous Noninfectious
 Congestive heart failure
 Pulmonary embolism or infarction
 Drug toxicity
 Foreign body
 Sarcoidosis
 Radiation pneumonitis
 Alveolar hemorrhage syndromes
 Pulmonary alveolar proteinosis
 Lipoid pneumonia
 Rounded atelectasis
Drug-induced lung
 Nitrofurantoin crystals This drug can cause acute and
chronic pulmonary reactions that result in alveolar interstitial
 Amiodarone hydrochloride Toxic levels of this drug can
present acutely as focal alveolar infiltrate.
 Methotrexate. A chest radiograph usually shows bilateral
interstitial infiltrate that sometimes appears nodular or displays
an alveolar pattern.
 Bleomycin sulfate A chest radiograph shows reticular-nodular
infiltrate, which can progress to diffuse interstitial infiltrate.
 Mitomycin Toxic pulmonary levels of this drug usually are
observed when it is used with vinca alkaloids or cisplatin
(Platinol-AQ). A chest radiograph may show diffuse interstitial
Cancers and common infectious organisms linked to immune
defects that may lead to nonresolving pneumonia
Immune Cancers linked to Common organisms linked to
defect immune defect immune defect

B-cell defect ALL,CLL, multiple myeloma Streptococcus pneumoniae,

Haemophilus influenzae,
gram-negative bacilli

T-cell defect Hodgkin's disease, Pneumocystis carinii,

chemotherapy, high-dose mycobacteria,
corticosteroid therapy herpesvirus
Cryptococcus, other pathogenic

Granulocytic Myeloproliferative disorders, Staph aureus,

defect AML, cancer drug therapy gram-positive organisms,
with neutropenia gram-negative bacilli (including
opportunistic fungi
Organisms isolated in cases of
nonresolving pneumonia in cancer
 Bacteria (37%)
 Mixed organisms (20%)
 Viruses (15%)
 Fungi (14%)
 P carinii (8%)
 Nocardia asteroides (7%)
 M tuberculosis (1%)

Rosenow et al,Clin Chest Med

Pneumonia in elderly
 Several weeks may be required for even a
"typical" pneumonia to resolve in the elderly with
comorbid illness.
 20% NRP in elderly persons caused by Gram-
negative bacteria.
 Mortality very high in elderly with NRP
 Common bacterial causes of CAP elderly persons
include S pneumoniae, enteric gram-negative
bacilli, Legionella pneumophila, H influenzae, and
S aureus..
Fein m et al The approach to nonresolving pneumonia in the elderlySemin
Respir Infect,1993.
El-Solh et al. Etiology of severe pneumonia in the very elderly. Am J Respir Crit
Care Med 2001.
Which patients with prolonged pneumonia
should undergo further evaluation?
 What is the correct timing for diagnostic
Diagnostic considerations in
evaluation of nonresolving
 should begin with an assessment for risk factors that may
contribute to delayed resolution

 Is the clinical or radiographic course longer than what is expected,

given the presumptive diagnosis?

 Is the therapy appropriate?

 Patient compliance with treatment also should be assessed.

 Is an unusual pathogen or resistant organism present?

 Is the cause noninfectious?

(Menendez R. Evaluation of nonresolving and progressivepneumonia. Semin
Respir Infect. 2003 Jun;18(2):103-11)
 Most patients have a normal temperature and
decreased cough 3 to 5 days after beginning
 Radiographic resolution often lags behind
clinical improvement.
 Infiltrates resolved faster than pleural
effusions or pleural thickening.
 In general, resolution rates are slower in
those in ICUs .
 Most cases can be resolved without undue
complications and expense
When To Initiate An Invasive
Diagnostic Work-up For Nonresolving
 If pt present with classical features of CAP clinical
response to therapy is the most important
determinant for further diagnostic studies.
 Within the first few days, persistence or even
progression of infiltrates on chest radiographs is not
 Defervescence, or diminished symptoms, and
resolution of leukocytosis strongly support a response
to antibiotic therapy, even when chest radiographic
abnormalities persist.
When To Initiate An Invasive
Diagnostic Work-up For
Nonresolving Pneumonia
 Patient may be safely observed for 4-8
wks when
- The presentation is typical.
- Symptomatic improvement is present
- "At risk" factors are identified
 Investigate further when
- No risk factors are present for delayed resolution
- Suspicion of non-infectious aetiology
- Lack of at least partial resolution even in
asymptomatic patient at 6 wks.
Management of
 Reevaluation Of Epidemiologic Data
 Complete Microbiologic Investigation.
 Conventional And Invasive Respiratory
 Performance Of A New Radiographic
 Broadening bacteriologic coverage.

Evaluation of nonresolving and progressive pneumonia ,

Semin Respir Infect. 2003 Jun;18(2):103-11
 Chest radiograph
 CT Thorax
 Microbiologic investigations
 Bronchoscopy
 Transthoracic needle aspiration
 Transbronchial biopsy
 Thoracoscopic lung biopsy or open lung
Radiographic resolution of CAP.
Mittl et al. Am J Respir Crit Care Med 1994;149(3
Pt 1):630-5
 Studied 81 non-immunocompromised patients.
 Chest films were obtained every 2 weeks for the first 8
weeks and then monthly for 4 months or until
resolution of pneumonia.
 Mycoplasma and clamydia resolution is the earliest at
around 2-6 wks.
 Complete resolution
 At 2wks ->51percent
 By 4 wks->67percent and
 77% at 6 weeks.
 In hospitalized patients with community-acquired pneumonia
whose disease shows a good clinical response to treatment,
pre-discharge chest films are not necessary.
 Follow-up films should be obtained in young patients with
atypical features or persistent symptoms.
 Bartlett and colleagues recommend follow-up films 7 to 12
weeks after initiation of treatment to document resolution.
 Fein AM and his team recommend follow-up films 4 to 8
 Although CT is not recommended for the initial evaluation of
patients with pneumonia its an adjunct to conventional
 CT particularly the high-resolution type, is the primary
radiographic tool for assessing treatment failure in presumed

 Providing excellent anatomical details may narrow the differential

diagnostic considerations .

 Chest CT scans are useful in the evaluation of nonresolving

pneumonia because they can detect pleural disease, cavitary
lesions, and mediastinal abnormalities not visible on plain films.

 CT also detects sequestered foci of infection, such as lung

abscesses and empyema
 CT is extremely useful serving as a "road map" to direct fibreoptic
bronchoscopy toward the lesion
CT Air-bronchogram
• Endotracheal aspirates with quantitative
cultures (106 cfu/ml)
• Sampling of distal airways (mini-BAL, PTC)
• Bronchoalveolar lavage (104 cfu/ml)
• Protected specimen brushing (103 cfu/ml)
Fiberoptic bronchoscopy
 This procedure allows careful inspection of the bronchial tree for
endobronchial lesions and foreign bodies.
 Recovery of deep respiratory secretions, brushings, and biopsy
specimens useful in diagnosis of uncommon infectious pathogens,
neoplasms, and noninfectious causes.
 FOB with lung biopsy is most likely to yield a specific diagnosis.
 The ultimate diagnostic procedure is thoracotomy with lung biopsy.

(Utility of fiberoptic bronchoscopy in nonresolving pneumonia. Chest 1990)

Antibiotic therapy
 Inappropriate therapy is a major risk factor for
excess mortality and length of stay for patients with
 Antibiotic-resistant pathogens are most commonly
associated with inappropriate therapy
 In patients who have recently received an antibiotic,
use an agent from a different antibiotic class
 Initial appropriate antibiotic therapy should be given
promptly to avoid excess mortality caused by delays
in therapy

ATS/IDSA Guidelines. Am J Respir Crit Care Med

Reevaluate host factors

Review microbiological data



Non-invasive serological tests.
open lung biopsy
Histologic sections show obliteration of large portions of the alveolar
parenchyma by a monotonous population of small lymphocytes with round
to slightly irregular nuclei.Diagnosis NHL low-grade B lymphocyte lymphoma
Normal pattern resolution of common
pneumonias must be considered before
further evaluation.
 When the radiograph has failed to resolve
by 50% in 2 weeks or completely in 4
weeks, the pneumonia should be
considered to be nonresolving or slowly
Algorithm for evaluation of
Nonresolving pneumonia.
 defined as the presence of pulmonary
infiltrates associated with fever, sputum
production, malaise, chest pain, or
shortness of breath, which do not resolve
within an expected period given the
presumptive diagnosis
Pneumonia: Diagnosis
 Pneumonia is defined as an infectiPneumonia is defined as an
infection of the pulmonary parenchyma

• Cough
• Sputum
• Rales
• Pulmonary
Pathogens In Nonresolving
 Mycobacterium tuberculosis
 Atypical mycobacteria
 Nocardia
 Actinomyces israelii
 Aspergillus
 Coxiella burnetii
 Francisella tularensis
 Chlamydia psittaci
 Leptospira interrogans
 Burkholderia pseudomallei
 Anthrax
 If cultures show a resistant or
 unusual pathogen, thempy can be
modified appropriately.
Sputum culture
 For patients with severe CAP
 Chest January 2003
 Retrospective analysis of prospective data
 210 pts at two teaching hospitals in Spain
 106 intubated, 81 noninvasive mechanical
ventilation, median age 60 years
 Microbiologic Dx pneumonia in 117 patients
 Most common: S. pneumo, legionella, H. flu
 Pseudomas and legionella more common with
intubation, also more lethal
 41.6% patients required changes to antibiotic
Specificity and False Positives
False Positive (%)

50 ETA
40 BAL
30 PSB

103 104 105 106
Culture Threshold
Torres et al. ARRD. 1993: 952-57.
• Endotracheal aspirates with quantitative cultures (106
• Sampling of distal airways (mini-BAL, PTC)
• Bronchoalveolar lavage (104 cfu/ml)
• Protected specimen brushing (103 cfu/ml)
 If improvement is not seen at that time
and the patient has no risk factors for
delayed resolution, further workup with a
chest CT scan, fiberoptic bronchoscopy,
and other studies should be considered.
 Bacterial adherence to airway epithelium
 Mechanical Obstructions – foreign body, tumors
 Impaired immune defense mechanisms
• Immunoglobulins.
• Complement.
• Polymorphonuclear leukocytes.
• T cells .
• Alveolar macrophages.
The radiographic resolution of
Streptococcus pneumoniae
pneumonia. Jay SJ et al N EngI J Med 1995;293:798-
 patients with bacteremic pneumococcal pneumonia.

 In this group, 37 percent had residual consolidation at one


 In those older than age 50 years with both

COPD and alcoholism, 60 percent had abnormal
chestroentgenograms at 14 weeks.

 They, therefore, recommended that in pneumococcal

pneumonia, bronchoscopy be delayed for at least eight weeks
pending resolution.