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NON RESOLVING PNEUMONIA
BY DR.LOKESH.L.V
MODERATORs : DR MOHAN.RAO AND
DR UMAMAHESHWARI
DEFINITION
Pneumonia with a slow resolution of radiographic Pneumonia with a slow resolution of radiographic
infiltrate infiltrate oror clinical symptoms despite adequate clinical symptoms despite adequate
antibiotic treatment (generally 10 to 14 daysantibiotic 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
ALTERNATE DEFINITION 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.Amberson introduced the term non resolving pneumonia 1943.
• Early studies show that 13% to 25% of patients with Early studies show that 13% to 25% of patients with
community-acquired pneumonia had slowly resolving disease. community-acquired pneumonia had slowly resolving disease.
• The incidence of The incidence of non-non-resolving pneumonia is 10% to 15% in pneumonia is 10% to 15% in
community-acquired and 30% to 60% in nosocomial pneumonia community-acquired and 30% to 60% in nosocomial pneumonia
(menendez R et al) (menendez R et al)
CONTD……
In a large US teaching hospitals study, approximately 15% of In a large US teaching hospitals study, approximately 15% of
pulmonology consultations and 10% of diagnostic bronchoscopies pulmonology consultations and 10% of diagnostic bronchoscopies
were performed for NRP.were performed for NRP.
Mortality in non-resolving pneumonia increases 3-fold in community-Mortality in non-resolving pneumonia increases 3-fold in community-
acquired and 5-fold in nosocomial pneumoniaacquired and 5-fold in nosocomial pneumonia..
((Clinical pulmonary medicine, 2004 (vol. 11) (no. 5) 298-306Clinical pulmonary medicine, 2004 (vol. 11) (no. 5) 298-306))
Noninfectious causes were responsible for around 20% of cases of nonresolving pneumonia in multicentric study
(Torres A et al, Thorax. 2004;59:960-965)
Problem statement
Patterns of normal resolution in pneumonia
Fever: Average duration is 2.5-4 days2.5-4 days, after starting appropriate treatment. Longest for legionella 6 to 7days
Leukocytosis: TLC usually comes to normal by end of 3-4 days3-4 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 study.
Table 1. Time to resolution of common pneumonias
Causative organism
Radiographic clearing
Residual radiographic abnormalities
Pneumococcus
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 yr2. Smoking3. Bacteremic pneumonia 4. Extent of disease.5. Persistent fever or leukocytosis
6. 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 mechanism
Cause of immune impairment
Nasal filtration
Use of endotracheal tube, tracheostomy
Oropharyngeal bacterial adherence
Severe illness, increased oral proteases, xerostomia malnutrition, viral illness, smoking, aging
Epiglottis Stroke, carcinoma of upper airway, use of feeding tube, endotracheal tube, or sedating drugs
Defence mechanism Cause of immune impairment
Cough Use of sedating drugs, stroke, neuromuscular
illness, malnutrition, chronic bronchitis
Mucociliary transport
Aging, smoking, chronic bronchitis, 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 adherence
Malnutrition, inflammatory proteases, viral illness, endotracheal intubation
Alveolar macrophages
Viral illness, malnutrition, aging, use of corticosteroids, cytotoxic therapy, alveolar edema
Impaired immune defense mechanisms that may lead to nonresolving pneumonia
Etiology 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 capsulatumHistoplasma capsulatum
Coccidioides immitisCoccidioides immitis
Blastomyces dermatitidisBlastomyces dermatitidis Coxiella burnetiiCoxiella burnetii (Q fever (Q fever))
Noninfectious causes of non-resolving resolving pneumonia
Primary lung cancer (bronchioloalveolar cell ca)Endobronchial metastasisBronchial adenomaLymphomaCarcinoiod syndromeRadiation pneumonitis.
Noninfectious causes of non-resolving resolving pneumonia
Immunologic causes non-resolving pneumonia
Wegener's granulomatosis
Allergic bronchopulmonary aspergillosis
Bronchiolitis obliterans with organizing
pneumonia
Idiopathic pulmonary fibrosis.
Eosinophilic pneumonia.
Miscellaneous Noninfectious causes
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 disease Nitrofurantoin crystals This drug can cause acute and
chronic pulmonary reactions that result in alveolar interstitial pneumonitis.
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 infiltrate.
Cancers and common infectious organisms linked to immune defects that may lead to nonresolving pneumonia
Immune defect
Cancers linked to immune defect
Common organisms linked to immune defect
B-cell defect ALL,CLL, multiple myeloma Streptococcus pneumoniae, Haemophilus influenzae, gram-negative bacilli
T-cell defect Hodgkin's disease, chemotherapy, high-dose corticosteroid therapy
Pneumocystis carinii, mycobacteria, herpesvirusCryptococcus, other pathogenic fungi,
Granulocytic defect
Myeloproliferative disorders, AML, cancer drug therapy with neutropenia
Staph aureus, gram-positive organisms, gram-negative bacilli (including enteric, opportunistic fungi
Organisms isolated in cases of nonresolving pneumonia in cancer patients.
Bacteria (37%) Mixed organisms (20%) Viruses (15%) Fungi (14%) P carinii (8%) Nocardia asteroides (7%) M tuberculosis (1%)
Rosenow et al,Clin Chest Med 1990;11(1):55-64
Pneumonia in elderly persons 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 studies?
Diagnostic considerations in evaluation of nonresolving pneumonia
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)
IMPORTANT POINTS Most patients have a normal temperature and
decreased cough 3 to 5 days after beginning treatment.
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 Pneumonia. 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 unusual.
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 nonresponding
Reevaluation Of Epidemiologic Data Complete Microbiologic Investigation. Conventional And Invasive Respiratory
Samples. Performance Of A New Radiographic
Study. Broadening bacteriologic coverage.
Evaluation of nonresolving and progressive pneumonia , Semin Respir Infect. 2003 Jun;18(2):103-11
DIAGNOSTIC TOOLS USED IN NONRESOLVING PNEUMONIA
Chest radiograph CT Thorax Microbiologic investigations Bronchoscopy Transthoracic needle aspiration Transbronchial biopsy Thoracoscopic lung biopsy or open lung
biopsy.
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.
Radiography 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
weeks.
CT THORAX Although CT is not recommended for the initial evaluation of
patients with pneumonia its an adjunct to conventional radiography.
CT particularly the high-resolution type, is the primary radiographic tool for assessing treatment failure in presumed pneumonia.
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
MICROBIOLOGIC DIAGNOSISTECHNIQUES:A) NONBRONCHOSCOPIC:
• Endotracheal aspirates with quantitative cultures (106 cfu/ml)
• Sampling of distal airways (mini-BAL, PTC)
B) BRONCHOSCOPIC:• 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 HAP
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 2005;171:388–416
Repeat CXR
Review microbiological data
Reevaluate host factors
CT SCAN
REPEAT RESIRATORY SAMPLING 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 resolving.
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
LocalInflammatoryResponse
• Cough• Sputum• SOA• Rales• Pulmonary infiltrate
Alternative Causative Pathogens In Nonresolving Pneumonia Mycobacterium tuberculosis Atypical mycobacteriaAtypical 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
regimen
Bronchoscopy
0
10
20
30
40
50
60
70
80
Culture Threshold
Fal
se P
osit
ive
(%)
ETABALPSB
Specificity and False Positives
103 104 105 106
Torres et al. ARRD. 1993: 952-57.
MICROBIOLOGIC DIAGNOSIS OF VAP: TECHNIQUESA) NONBRONCHOSCOPIC:• Endotracheal aspirates with quantitative cultures (106 cfu/ml)• Sampling of distal airways (mini-BAL, PTC)B) BRONCHOSCOPIC:• 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;293:798-801
patients with bacteremic pneumococcal pneumonia.
In this group, 37 percent had residual consolidation at one month.
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.