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.