10-11, 12, 13, 14-10 Pneumonia Super Outline (Palmieri, Elswafi, Martin, Williams) - OutlineTotal lecture hours: 2 Palmieri/Elswafi, 3 Williams, 4 Martin (lots of redundancy) – 9 lecture hours in total

Anatomy Alveoli: concentrically arranged, free edge reinforced by thick bundles of connective tissue (entrance

rings)o Alveolar septal tissues include

epithelial type I cells epithelial type II cells capillary endothelial cells

o Note the thin alveolar septal tissue barrier over much of the surface.o The barrier for O2 diffusion across the thin portions of the septa into erythrocytes (EC) consists of

epithelium common basement membrane endothelium

Normal Flora (Respiratory)o The lower respiratory system is generally devoid of resident bacteriao Transient populations are effectively cleared by the host defenseso Successful pathogens are those that can persist despite the host defense systems

Bacterial Immune Defense (Immunology)

o Ciliated respiratory epitheliumo Cough reflexo Alveolar macrophageso Other immune cells (lymphocytes, neutrophils o Alveolar lining fluid which contains surfactant, various immunoglobins, complement

components, phospholipids, enzymes, albumin, transferrin.o Lymphoid tissue

Pathogen Defense (Virulence)o Ways pathogens avoid phagocytosis

Capsule production! Cytotoxicity Hiding (growing) in pulmonary or phagocytic cells Mimicry

o Ways pathogens survive phagocytosis Inhibition of lysosome/phagosome fusion Phagosome lysis or escape Growth in the phagolysosome

Pathogenso A HUGE variety of organisms have been implicated in LRT infections. The following is a list of the

most common/important agentso Bacterial: Most Common Agents

More common: Streptococus pneumoniae Haemophilus influenzae Klebsiella pneumoniae Staphylococcus aureus Gram-negative diplococci

Atypical Pneumonia: Mycoplasma pneumoniae Chlamydia pneumoniae Legionella pneumophila

Some others: Group A and B streptococci Mycobacterium tuberculosis Pseudomonas aeruginosa Bacillus anthracis and others Escherichia coli anaerobes (important in aspiration pneumonia)

Pathophysiology, Diagnosis, Treatmento Pneumonia

A clinical syndrome Streptococcus pneumonia (50%) Haemophilus influenzae (10%)

Type B, childhood vaccine requires X and V factors

Pneumonia develops when host defenses are overwhelmed by an infectious pathogen. This may occur because of :

inadequate immune response (often the result of underlying comorbid illness such as congestive heart failure, diabetes, renal failure, chronic obstructive lung disease, or malnutrition)

anatomic abnormalities (endobronchial obstruction, bronchiectasis) immune dysfunction associated with acute illness (sepsis, extrapulmonary

infection) therapy-induced dysfunction of the immune system (corticosteroids,

endotracheal intubation) Seeding

o Inhalation Aerosolized droplets accounts for the transmission of

respiratory viruses, such as influenza, which is highly contagious and often occurs in epidemics. Similar means of spread produce pneumonias

Mycobacterium tuberculosis is spread from person to person by aerosolized droplets.

Legionella pneumophila is the species most likely to be spread by inhalation of aerosolized organisms that originate in contaminated freshwater

o Aspiration Nasopharyngeal organisms occurs in nearly all persons during

sleep and is probably responsible for most bacterial pneumonias

The pulmonary consequences from the abnormal entry of fluid, particulate exogenous substances, or endogenous secretions into the lower airways.

There are usually two requirements to produce aspiration pneumonia:

Compromise in the usual defenses that protect the lower airways including glottic closure, cough reflex, and other clearing mechanisms

An inoculum deleterious to the lower airways by a direct toxic effect, a large enough bacterial inoculum, or obstruction of the airway

The term aspiration pneumonia usually reserved for pneumonitis resulting from the altered clearance defenses and usually refers to an infection caused by less common and often less virulent bacteria, primarily anaerobes and enterobacteriace, which are constituents of the normal flora in a susceptible host.

Primary Mechanism Microaspiration of colonized oropharyngeal

secretions Oral Colonization: Haemophilus influenzae and

Streptococcus pneumoniae Anaerobic Bacteria Elderly Patients: Enterobacteriaceae, Pseudomonas

aeruginosa, and Staphylococcus aureus. Recumbent Position

MC Site: Posterior segment of upper lobes and apical segments of lower lobes

Upright or Semirecumbent Position MC Site: Basal segments of the lower lobes

Risks Altered Consciousness

o Alcoholismo Seizureso Cerebrovascular Accidento Head Traumao General Anesthesiao Drug Overdose

Dysphagia o Esophageal Disorders: Strictrures,

neoplasm, diverticula, TE fistula, incompetent cardiac sphincter

Neurologic Disorderso Multiple Sclerosis, Parkinson’s Disease,

Myasthenia gravis, Pseudobulbar palsyo Stroke patients

Not protected by feeding tubes Mechanical disruption of the usual defense barriers

o Nasogastric tube, endotracheal intubation, tracheostomy, upper gastrointestinal endoscopy, bronchoscopy

Othero Protracted vomiting, gastric outlet

obstruction, large-volume nasogastric tube feedings, pharyngeal anesthesia, general debility, recumbent position

Types

Chemical Pneumonitiso The aspiration of substances that are toxic

to the lower airways, independent of bacterial infection (gastric acid).

This form of aspiration pneumonia commonly follows a fulminate course that may result in acute respiratory distress syndrome (ARDS)

o Hypoxemia results from pulmonary edema, reduced surfactant activity, reflex airway closure, atelectasis, alveolar hemorrhage, infiltration of polymorphoneculear leukocytes and fibrin and hyaline membrane formation.

o Lung function demonstrates decreased compliance, abnormal ventilation-perfusion, and reduced diffusing capacity.

The lung becomes grossly edematous and hemorrhagic with alveolar consolidation.

o Diagnosis — The diagnosis of acid pneumonitis is usually presumptive based upon the clinical features and course. After aspiration, chest x-ray changes are noted in as little as two hours.

Aspiration of gastric contents requires a pH of <2.5 to produce chemical pneumonitis.

o Abrupt onset of symptoms with prominent dyspnea

Fever, which is usually low-grade Cyanosis and diffuse crackles on

lung auscultation Severe hypoxemia and infiltrates

on chest radiograph involving dependent pulmonary segments

o Treatment — Patients with an observed aspiration should have immediate tracheal suction to clear fluids and particulate matter that may cause obstruction.

The major therapeutic approach is to support pulmonary function.

Demonstrated benefit from positive-pressure ventilation support

The use of corticosteroids in the treatment of chemical pneumonitis is controversial with mixed results reported.

o The acid-injured lung is highly susceptible to bacterial challenge with 13 to 26 percent of patients developing pulmonary superinfections within 7 days .

Antimicrobial agents are commonly given and must cover gram negative m/o as well as anaerobes.

Outcomes vary Bacterial Infection

o The most common forms of aspiration pneumonia are caused by bacteria that normally reside in the oral-pharyngeal area or stomach.

Anaerobic bacteria are the dominant organisms in the upper airways and most common cause of infection.

Major M/O include: Peptostreptococcus, Fusobacterium nucleatum, Prevotella, and Bacteroides spp.

Gram-negative bacilli, E. coli, Klebsella, Proteus spp., P. aurgenosa, Serratia spp., etc were the most common isolates (49 percent) followed by anaerobes (16 percent) and S. aureus (12 percent) due to difficulty in culturing and identifying anaerobic m/o.

patients with gram-negative bacilli isolated often also have anaerobes involved

o Highly variable depending upon the bacteria involved and the status of the host.

Compared to most cases of community-acquired pneumonia, the tempo of the disease in this type of aspiration pneumonia is often relatively slow.

o Most patients present with the common manifestations of pneumonia including cough, fever, purulent, sputum and dyspnea, but the process evolves over a period of several days or weeks instead of hours

Some patients have a relatively abrupt and more toxic course with chills and rigors onset suggestive of a pyrogenic pneumonia due to common bacterial pathogens, including Streptococcus pneumoniae, H. Influenza, S. aures, etc.

o Clindamycin is more effective for treatment than penicillin agents today due to development of resistance in the anaerobic m/o most commonly involved with micro-aspiration

o Beta-lactam beta lactamase combination anti-pseudomonal penicillins (piperacillin-tazobactam or ticarcillin-clavulanate)

Or o antipsuedomonal cephalosporin agents

such as cefepime or ceftadizime indicated for treatment of suspected gram negative

Oro Antipseudomonal carbapenem, (inipenem

or meropenem).o Aminoglycocide agents alternative for gram

negative agents including pseudomonas in combination with fluoroquinolones

o Fluoroquinolones, levofloxacin and gatifloxacin indicated but clinically moxifloxacin and trovafloxacin, have best anaerobic activity in addition to good gram negative coverage and are more appropriate.

o If MRSA suspected, linezolid or vancomycin employed

Mechanical obstructiono Aspiration pneumonia may involve fluid or

particulate matter, which are not inherently toxic to the lung, but can cause airway obstruction or reflux airway closure.

o Intratracheal instillation of fluids in limited quantities results in transient, self-limited hypoxemia. On occasion, this may trigger pulmonary edema, more severe hypoxemia, and reduced lung compliance .

o This reaction is reversible by vagotomy or administration of atropine or isoproterenol.

o This type of aspiration pneumonia is difficult to recognize clinically, but the appropriate treatment would be removal of the offending agents and positive-pressure breathing with 100 percent oxygen combined with isoproterenol.

o Particulate matter Money and toys Teeth Large food particles-such as

peanuts which are often not visible on x-ray

Medical deviceso Fluids

Saline , water, juices, etc Barium Gastric contents with a pH

exceeding 2.5o Bacterial superinfection is a frequent

complication when the obstruction or partial obstruction persists for more than one week, with anaerobic m/o being most common

o Hematogenous Causes pneumonia, accounts for occasional cases of

staphylococcal pneumonia in patients with tricuspid valve endocarditis or septic thrombophlebitis. This mechanism is also responsible for various gram-negative bacillary pneumonias in patients with bacteremi

Associated with spread of infectious agent via circulatory system to lung secondary to development of septacemia from distant infected site.

May have any organism that becomes bacteremic, from Candida septicemia, Klebsiella, E. coli, P. aurgenosa, etc.

Commonly associated with right heart disease and emboli of infected vegetations associated with endocarditis and valular heart disease

Most common organism is S. aures, associated with I.V. drug abusers which produces classic cannon ball defects on CXR

Spread from pulmonic and tricuspid value vegetations with any organism producing pathology, from S. viridians to Candida

o Environmental This category includes Hypersensitivity Lung Disease.

These conditions produce 15 to 20% of all COPD. Related to development of interstitial lung disease as

well as COPD, CA and pnuemonitis in patients. X-ray distribution and resp. changes provide some

clues to but not definitive etiology. Mineral dust more related to restrictive changes on PFT while

organic dust and chemical agents more associated with obstructive patterns seen with asthma and COPD.

Small, round, millenary opacities on CXR related more commonly with silicosis or coal workers pneumoconiosis

Linear opacities more associated with asbestosis The size of particles and composition of gaseous agent also

determine the presentation on X-ray and distribution of pathological agent:

Particles >10-15 um generally do not penetrate beyond upper respiratory tract.

Particles < 10um penetrate below larynx in larger airways

Particles 2.5 um-10um (associated with crustal elements like silica, iron and aluminum) tend to deposit high in the tracheo-bronchial tree

Particles < 2.5 um tend to penetrate to lower airways, bronchioles and alveoli

Particles < 1 um (ultrafine particles) have diffuse distribution in all areas of lung

The size of particles and composition of gaseous agent also determine the presentation on X-ray and distribution of pathological agent:

Water soluble gases like ammonia or sulfa oxide tend to cause upper airway bronchoconstrictive processes

Less soluble agents like phosgene or nitrogen dioxide penetrate to bronchioles and alveoli and are associated with more severe respiratory perfusion/ventilation damage and ARDS

Inorganic Dusts & Respiratory Response Asbestos (asbestosis)

o Pulmonary Fibrosis (PF), Lung CA, mesothelioma

o Asbestos is generic term for several mineral silicates

Widely distributed world wide, was widely utilized up to 1980 for insulation so extensive exposure

o Produces acute pneumonitis, pleural and pulmonary fibrosis, diffuse interstitial fibrosis as well as highly associated with Cancer of the lung and respiratory tract.

Produces restrictive pattern with decrease with decrease in both lung volume and diffusion

o CXR associated with pleural plaques in linear pattern, most commonly in lower lung fields.

Occasionally have pleural effusion in acute episodes, frequently bloody.

o On C.T., classic is cardiac margin occluding “ground glass” perihilar changes.

o Pneumonitis and interstitial pneumonia can be seen in few weeks or delayed for months and years.

o Lung CA delayed >15 years classically after prolonged exposure to agent.

Risk of lung CA greatly multiplied by concurrent or history of smoking!

Mesothelioma both pleural and peritonial , although less common than lung CA, occurs in association with asbestos and may be seen with short term exposure as much as 4 decades before

Risk of mesothelioma not related to smoking!

Silica (silicosis)o PF, CA, silcotuberculosis, COPD, PMFo Pulmonary fibrosis generally occurs after

years of exposure to silica although an acute syndrome is associated with large volume exposure.

May be rapidly progressive with fibrosis and interstitial pneumonitis in spite of removal from exposure.

o Characterized by diffuse milinary infiltration and consolidation (“crazy paving”)

Simple silicosis from long term (15-20 year) exposure presents as rounded opacities in upper lobes accompanied by hilar node calcification

o Silica is cytotoxic to alveolar macrophages and patients are at greater risk of lung infections from organism like M. tuberculosis, atypical mycobacterium and fungi.

Also associated with exacerbation of autoimmune connective tissue disorders such as RA, SLE and scleroderma

Coal Dust o PMF, COPD (Coal workers pneumoconiosis)o Seen in up to 50% of coal miners after 20

years of work in mines. Less common in miners of

bituminous coal found in the west than miners of anthracite coal found in Europe and Eastern US

o CXR resembles silicosis, small, round opacities more common in upper lobes.

Complicated CWP presents with large nodules (> 1cm up to involvement of entire lobe) seen primarily in upper lobe. More severe restrictive and obstructive lung disease associated.

o Highly associated with development of COPD.

Effects are synergistic and additive to effects of cigarette smoking

Berylliumo Lung CA, Acute pneumonitis, chronic

granulomatous diseaseo Beryllium is a light weight utilized in control

of nuclear reactions due to ability to quench neutrons and in production of electronics, ceramics, etc.

Exposure can produce an acute pneumonitis but more associated with a chronic granulomatous inflammatory disease similar to sarcoidosis

o Disease is secondary to cell mediated immune response.

o Test for beryllium disease is beryllium lymphocyte proliferation (BeLPT)

Presents on CXR similar to sarcoidosis with nodules along septal lines but has less hilar adenopathy.

PFT yield both restrictive and obstructive changes along with decreased diffusion capacity.

o Chronic beryllium disease is one of best examples of genetic-environmental interaction.

Susceptibility to CBD is highly associated with HLA-DP alleles that possess a glutamic acid in position 69 of the beta chain

Other metals o Pneumonitis, CA, asthma (Aluminum,

Chromium, Cobalt, Nickel, titanium, Tungsten)

Organic dusts & Respiratory response Hypersensitivity Pneumonitis (again)

o An inflammatory disorder of the lung involving the alveolar walls and terminal airways.

Induced by inhalation of a variety of organic agents that induce an immunologic reaction within the pulmonary parenchyma.

Immune complex-induced inflammatory reactions initiate acute lung injury then T cell-mediated hypersensitivity reactions perpetuate it and induce chronic inflammatory, granulomatous, and fibrotic responses in the interstitium of the lungs.

o Numerous inciting agents, with more than 300 identified, include but are not limited to, agricultural dusts, bioaerosols, fungi, bacterium, virus, and certain chemicals.

Klebsiella oxytoca, Mycobacterium avium complex (MAC), actinomycetes spores, aspergillus, micropolyspora faeni, Cladosporium cladosporioides, diphenylmethane diisocyanate (MDI), toluene diisocyanate, metalworking fluid aerosols, feather duvets, etc.

o EPIDEMIOLOGY — The prevalence and incidence are thought to be low but widely unknown.

Most knowledge has been derived from studies of chemical workers, farmers and bird fanciers.

The prevalence and incidence of HP varies considerably depending upon intensity of exposure to inciting antigens, season, geographical conditions, local practices and customs, proximity to certain industries, and host risk factors.

o Many persons with mild or subclinical HP escape detection or are misdiagnosed as suffering from viral illnesses or asthma, either of which may have nonspecific clinical findings which mimic HP.

Only a small proportion of exposed individuals develop clinically significant HP, and genetic factors have been postulated to play a major role in determining an individual's risk of disease.

o A wide range of occupations and avocations that result in contact with airborne organic antigens increase the risk of developing HP.

Farmer's lung is one of the most common forms of HP, affecting 0.4 to 7 percent of the farming population

Chemical workers lung, related in part to exposure with isocyanates in US in relatively rare.

Bird fanciers lung has variable occurrence as well with estimates range from 20 to 20,000 affected individuals per 100,000 persons at risk.

Bagassosis sugar cane workers response to fungal antigens.

o High rates noted with sporadic outbreaks of HP among other populations :

52 percent of exposed office workers with humidifier lung

37 percent of lifeguards exposed to a public swimming pool

27 percent of workers at an injection molding plant manufacturing polyurethane foam parts for automobiles

15 percent of office workers exposed to a contaminated forced air system

o Cigarette smoking is associated with a decreased risk of HP. These observations may reflect diminished antibody responses to inhaled antigens among smokers.

o Once the disease is established, however, smoking does not appear to attenuate its severity, and may predispose to a more chronic and severe course .

o Clinical picture is interstitial pneumonitiso Can be acute, sub-acute or chronic in

presentation Acute presents as cough, fever,

chills, malaise and dyspnea as quickly as 6 to 8 hours post exposure.

Sub acute presents over weeks with cough, dyspnea, progressing to cyanosis and hypoxia.

Acute and sub-acute signs, symptoms and manifestation disappear in days, weeks or month if exposure is removed.

Chronic only seen with continued exposure to antigen and may be indistinguishable from pulmonary fibrosis from a variety of causes with clubbing, chronic cyanosis, pulmonary hypertension and respiratory failure.

o Diagnosis See elevation in acute reactants,

ESR, C-reactive protein, rheumatoid factor, neutrophilia

It is on note that eosinophilia if not a feature of HP.

Serum precipitins against suspected agents (thermophilic actinomycetes, apsergillus, cladosporium spp, mycobacterium avium complex, isocyanates, etc) are suggestive but not diagnostic due to wide exposure among population.

CXR is non-specific with diffuse infiltrates or discrete nodular infiltrates both seen.

Differentiate from other interstitial lung disorders made often by history, drugs exposed to, history of collagen vascular disease like RA or Crohn’s, etc.

o Prevention Diminishing exposure to

provocative antigens. This may be accomplished by minimizing contact with potential inciting agents, reducing microbial contamination, or using protective equipment.

Indoor microbial contamination is usually related to problems with moisture control.

Stagnant water is prone to microbial overgrowth. humidity should be maintained below 60 percent, water damage cleaned aggressively, carpeting should be avoided if possible and kept dry if

not and water in heating, ventilating, and air conditioning systems should not be re-circulated and cleaned regularly.

o Treatment Antigen avoidance Glucocorticoids — accelerate initial

recovery from farmer's lung and bird fancier's lung, however, the long-term outcome appears unchanged by glucocorticoid treatment

The majority of persons with HP experience near total recovery of lung function, which in some cases may take several years after the inciting exposure ceases

Cotton Dust o byssinosis-(asthma like syndrome), COPD

Grain Dusto Asthma, COPD, HP

Other Ag. Dustso Asthma, COPD, HP

Toxic Chemicals have been demonstrated to produce COPD, hypersensitivity pneumonitis, pneumoconiosis, pulmonary edema, ARDS, and CA

o Infiltrates with Eosinophilia First described by Loeffler as migratory pulmonary infiltrates

and peripheral eosinoophilia of unknown cause. Idiopathic causes:

Loeffler’s syndrome Acute eosinophilic pneumonia Chronic eosinophilic pneumonia Allergic granulomatosis of Churg and Strauss Hypereosinophilic syndrome

Known etiologies: Allergic bronchopulmonary mycoses (aspergillus,

penicillium, candida, helminthosporium spp) Parasitic infestations Drug reactions Eosinophilia-myalgia syndrome

o Most common form of eosinophilic pneumonia.

Associated with bronchial asthma. Most common agent is A. fumigatus

Asthma due to IgE mediated hypersensitivity, while bronchiectasis associated form immune complex reaction in airways.

Parasite Most often with filarial infections but also seen with

Ascaris, Ancyclostoma, Toxocara, Strongyloides, Wuchereria bancrofti

Rare in US unless international travel but seen recently with Iraq and Afghanistan veterans.

Drug-Induced Most common cause of eosinophilic pulmonary

infiltrates in US. Most commonly associated with nitrofurantion with

onset 2 to 10 days after exposure to drug. Also seen with thiazides, penicillin, sulfonamides,

chlorpropamide, tricyclic antidepressants, gold salts, isoiazide, indomethacin, etc.

Recently reported with anti-TNF-alfa therapyo Contiguous Spread o Reactivation

Riskso Smoking

Smoking alters mucociliary transport, humoral and cellular defenses, and epithelial cells, and increases adhesion of Strep. pneumoniae and H. influenzae to the oropharyngeal epithelium. Accordingly, a large proportion of patients hospitalized with pneumonias are current smokers

o Age: >65 y.o.o COPDo Immunosuppressiono Respiratory therapyo Comorbidity

Neoplasm Neurological disease Alcoholism

Alcohol adversely affects many aspects of the respiratory tract defense mechanisms.

o facilitates bacterial colonization of theo oropharynx by Gram-negative bacillio impairs cough reflexeso alters swallowing and mucociliary transporto impairs the function of lymphocytes,

neutrophils,o monocytes, and alveolar macrophages.

Each of these alterations contributes to the reduced bacterial clearance from the airways found in these patients.

o Close contact with infected personso Institutionalization

Oropharyngeal colonization Strep. Pneumonia > Staph. Aureus > Gram-negative bacilli >

Haemophilus influenzaeo Miscellaneous

Soldiers Painters South African gold miners Recent hospitalization (especially S. pneumonia)

Defined as pneumonia that occurs more than 48 hours after hospital admission, excluding any infection incubating at the time of admission.

It has been suggested that this definition is no longer adequate because cases can occur within 48 hours of hospitalization, particularly as a consequence of emergency intubation, or cardiopulmonary resuscitation

Ventilator-associated pneumonia (VAP) can be regarded as a particular subgroup of HAP for which the incidence, etiology, investigation and outcome are somewhat different.

It should be remembered that patients recently discharged from hospital who develop pneumonia may have an illness with features more in keeping with hospital-acquired rather than community-acquired infection.

Pathogens with high rate of resistanceo Aerobic gram negative bacilli (Enterobacter

spp, Escherichia coli, Klebsiella spp, Proteus spp, Serratia marcescens, and Hemophilus influenzae)

o Gram-positive organisms such as Streptococcus pneumoniae and Staphylococcus aureus

Signs & Symptoms Respiratory

o Cougho Fevero Chest Paino Tachypneao Sputum

Non-respiratoryo Confusiono Headacheo Myalgiao Abdominal paino Nauseao Vomitingo Diarrhea

The classic signs of: consolidation dullness to percussion crackles

increased tactile fremitus bronchial breathing Found in only one third of adults admitted to hospital with radiographically

confirmed CAP o 5–10% of adults who have CAP in the community

Radiologic Findings Lobar

o Relatively homogeneous regions of increased lung opacity and air bronchograms

o The entire lobe need not be involved, and in fact, with early therapy, consolidation does not usually affect the entire lobe

o Pathologically, the infecting organism reaches the distal air spaces, resulting in edema filling the alveoli

o The infected edema fluid spreads centripetally throughout the lobe via communicating channels to adjacent segments

o Air bronchograms are common

Lobularo Characterized on x-ray by relatively homogeneous regions of increased

lung opacity and air bronchogramso The entire lobe need not be involved, and in fact, with early therapy,

consolidation does not usually affect the entire lobeo Pathologically, the infecting organism reaches the distal air spaces,

resulting in edema filling the alveoli The infected edema fluid spreads centripetally throughout

the lobe via communicating channels to adjacent segments. Air bronchograms are common

o Bronchopneumonia Results from inflammation involving the terminal and

respiratory bronchioles rather than the distal air spaces. Since the process focuses in the airways, the distribution is more segmental and patchy, affecting some lobules and sparing others

Interstitialo Looks awfulo Ground glass attenuation o Bilateral, patchy & diffuse o W /WO airspace consolidation o Geographic distribution with spared areas

Mixedo Mixed interstitial and alveolar opacities (ground-glass pattern) are

findings compatible with PCP in a HIV positive patiento Klebsiella pneumoniae

Enterobacteriaceae Extensive capsular polysaccharide

o Staphylococcus aureus Community acquired

Community-acquired pneumonia (CAP) affects approximately 4.5 million adults in the United States annually.

o About one third of these adults require hospitalization.o The mortality rate among hospitalized patients with CAP varies each

year and can reach 35 percent. Streptococcus pneumoniae causes up to 70 percent of CAP cases

o Atypical pathogens are responsible for 30 to 40 percent of cases and may be copathogens in other cases

Possible contradiction (Williams): S. aureus most likely pneumonia cause in 2006-2007 Flu Season

o Things to keep in mind: Flu first Then 2nd pneumonia – S. aureus “Don’t miss this” (I think this is a semantics problem, not a contradiction. Be

aware.) Determining the pathogen is difficult

o 50% of cases: pathogen is not identified Suggests atypical agent In a study of patients with a mean age of 41 years, for

example, Mycoplasma pneumoniae accounted for 22.8% of community-acquired pneumonias, Chlamydia pneumoniae for 10.7%, and influenza A for 2.7%

See “Atypical Pneumonia” below Most common cause of Community-Acquired Pneumonia Before antibiotics, S. pneumoniae was synonymous with pneumonia.

o Today S. pneumoniae accounts for about ½ the community acquired cases where agents are identified.

o The elderly and the very young are most at risk. Few virulence factors known besides polysaccharide capsule

o α-hemolytic, non-typeable (non-groupable) Rust-colored sputum

Often sequel to influenzao Gram-negative diplococci

Neisseria Moraxella catarrhalis

o Atypical Pneumonia Atypical organisms such as Mycoplasma pneumoniae, Chlamydia pneumoniae, and

Legionella pneumophila are implicated in up to 40 percent of cases of community-acquired pneumonia

Mycoplasma pneumoniae Smallest free-living organism, no cell wall

o Most common cause of atypical pneumonia Mycoplasma pneumoniae causes a wide range of respiratory infections,

including o Pneumoniao Tracheobronchitiso upper respiratory tract infection

Only 3 to 10 percent of persons infected with M. pneumoniae develop pneumonia.

Because M. pneumoniae infection becomes more common with increasing age, it is particularly important to consider this agent in elderly patients.

M. pneumoniae infection occurs throughout the year but can cause periodic outbreaks within small communities.

Transmission is by person-to-person contact, and infection spreads slowly, most often within closed populations (e.g., households, schools, businesses).

M. pneumoniae infection may be associated with several extrapulmonary manifestations.

Skin manifestations includeo erythema multiformeo erythema nodosumo maculopapular and vesicular eruptionso urticaria.

Neurologic derangements include o aseptic meningitiso cerebral ataxiao Encephalitiso Guillain-Barré syndromeo transverse myelitis.

S/So Onset is insidious, over several days to a week. o Constitutional symptoms, which usually are present, include headache

exacerbated by a cough, malaise, myalgias, and sore throat.o The cough is usually dry, paroxysmal, and worse at night.o The clinical course of pneumonia caused by M. pneumoniae is usually

mild and self-limited. o The mortality rate is approximately 1.4 percent.o However, pulmonary complications can be significant and include

effusion, empyema, pneumothorax, and respiratory The production of cold agglutinins can result in hemolytic anemia, especially

when M. pneumoniae titers are high. Finally, complications such as myocarditis, pancreatitis, pericarditis, and polyarthritis can occur.

Diagnosiso The WBC count is generally not helpful in mycoplasmal pneumonia

because results may be normal or elevated M pneumoniae is difficult to culture and requires 7-21 days to

grow; culturing is successful in only 40-90% of cases and does not provide information to guide patient management

o Hemolytic anemia has been described but is rare.o Sputum Gram stains and cultures are usually not helpful because M

pneumoniae lacks a cell wall and cannot be stained. o Elevated erythrocyte sedimentation rates may be present but are

nonspecific.o Serum cold agglutinins may be positive but are nonspecifico PCR can accurately identify the pathogen

Not practical or readily availableo Eosinophil cationic protein (ECP) measures damage to the respiratory

epithelium May be used more in the future for Dx

o High-resolution CT scans of the chest are more sensitive than chest radiography in elucidating lung disease.

o Radiographic findings vary, but abnormalities are usually more striking than the findings upon physical examination.

Bronchopneumonia often involves a single lower lobe. Lobar consolidation is rare.

Platelike atelectasis is noted as thin, flat areas of collapsed lung and is often seen on a lateral image of the chest.

Reticulonodular or interstitial infiltrates, primarily in the lower lobes, may resemble other diseases with granulomatous pathology, such as tuberculosis, mycoses, and sarcoidosis.

Hilar adenopathy is sometimes mistaken for malignancy. Pleural effusions develop in less than 20% of patients; when

present, they can be seen on lateral decubitus films. Treatment

Chlamydia pneumoniae Obligate intracellular pathogen Unusual life cycle (EB and RB forms) Chlamydia pneumoniae is an obligate intracellular organism capable of

persistent latent infection. Humans are the only known reservoir. Transmission results from contact with respiratory secretions, with an

incubation period of several weeks. By the age of 20 years, one half of persons in the United States have detectable

levels of antibody to C. pneumoniae. The antibody is present in 75 percent of elderly persons.C. pneumoniae infection is more likely to occur in older patients with comorbid diseases than in those who are otherwise healthy.

Patients with C. pneumoniae infection often present with sore throat, headache, and a cough that can persist for months if treatment is not initiated early.Sputum is usually scant or nonexistent, and a low-grade fever is usually present.

Chest radiographs tend to show less extensive infiltrates than are seen with other causes of pneumonia, although significant infiltrates have been reported.

Most cases of C. pneumoniae infection are mild,

Severe disease can occur, necessitating admission to an intensive care unit. The mortality rate has been estimated to be 9 percent, and death usually is associated with secondary infection and underlying comorbid disease

Legionella pneumophila Legionnaire’s disease

o water source reservoiro require iron and cysteine for growtho problematic in aged, smokers, drinkers, immunocompromised

Legionella species are intracellular organisms. Legionella pneumophila is the most pathogenic species, and several serotypes have been identified.

Serotype 1 has been associated with most reported human cases of pneumonia caused by L. pneumonphila.

Infection occurs from exposure to legionella organisms in the environment. Person-to-person spread has not been reported. Legionellae are found most commonly in freshwater and man-made water

systems. Risk factors for the development of legionellosis include

o overnight stays outside the home.o recent home plumbing worko renal or liver failureo Diabeteso Malignancyo Other conditions that compromise the immune system

The pathogens also can be found in moist soil, especially near streams and ponds.

Man-made systems for heating and cooling water can be prime environments for the proliferation of legionellae, because of conditions such as temperatures between 32°C (89.6°F) and 45°C (113°F), stagnation of water, and the presence of scale sediment and amebas.

Condensers, cooling towers, respiratory therapy equipment, showers, water faucets, and whirlpools have been associated with outbreaks of legion.

o Others Group A and B streptococci Mycobacteria

M. tuberculosis M. avium-intracellulare

o found in birdso TB-like disease in immunocompromisedo MAC is especially common in soil in the South-Eastern United Stateso Up to 40% of US patients with advanced AIDS have had MAC o Most common bacterial opportunistic infection (OI) in adults infected

with HIV in the developed world.o Most found in US – Rare in Africa.o Annual frequency in AIDS – 10-20%.o Occurs late in HIV infection.

Mean CD4+ Count ~ 10-30/μL. (TB occurs early.)o Inhaled or ingested from environment.o Spreads via lymphatics then hematogenously.o Taken up in reticuloendothelial organs.o Primary

None-tubercular pulmonary disease, more common than T.B. in US, endemic to most of N. America

Age > 50 Nonsmoking Women > Males No underlying disease identified absolutely Radiography reveal nodular bronchiectatic changes with

midzone involvement o Secondary

White Middle-Aged/Elderly Men 30-70 M>F Smokers &/or Alcoholics Resembles TB

Prior Bronchiectasis Healed TB Pneumoconisosis Cystic Fibrosis Prior Malignancy

o S/S Disseminated MAC

Fever Night Sweats Diarrhea Weight Loss and wasting syndrome in HIV patients Malaise Anemia Elevated LFTs Alkaline Phosphatase

Gastrointestinal MAC Chronic Diarrhea & Abdominal Pain Malabsorption Cholestatic Jaundice

o Diagnosis Repeated cultures of MAC from sputum or bronchial wash Positive blood cultures in severely compromised Imaging studies consistent with pulmonary disease

o Treatment: Clairthromycin daily (or Azithromycin) and ethambutol for 18

to 24 months Some recommend adding rifampin or floroquinolone

in those with secondary or more advanced disease Hypersensitivity-Pneumonitis due to NTM

“Hot Tub Lung” Treated with avoidance and glucocorticosteroids

Resistant MAC Treatment 4 Drug Therapy

o Rifabutin or rifampin +o Clarithromycin or azithromycin +o Ethambutol +o Streptomycin (f0r 2 months)

Treat for 18-24 Months Treat for 12 Months after sputum is negative for

MAC M. kansasii

Second most common cause of NTM in US Generally > 60 years of age Generally predisposing lung disease Closely resembles acute TB in S/S Treated with INH, rifampin and ethambutol. If resistant to rifampin, then clarithromycin or azithromycin may be subsituted.

Pseudomonas aeruginosa mucoid capsule; particularly difficult in cystic fibrosis patients

Bacillus anthracis Francisella tularemia Enterics and Anaerobes

Important in Aspiration Pneumoniao Aspiration of particulate material can produce acute airway

obstruction and death by asphyxiation; aspiration of smaller particles may produce atelectasis of a pulmonary segment or even an entire lung with dyspnea, wheezing, and cyanosis

Primary Mechanism Microaspiration of colonized oropharyngeal

secretions Risks

Altered Consciousness Dysphagia Neurologic Disorders Mechanical disruption of the usual defense barriers Other

o Because the concentration of aerobic bacteria in upper respiratory tract secretions is high, and that of anaerobic bacteria is about 10 times greater, aspiration of even small quantities of oropharyngeal secretions introduces an enormous bacterial challenge to the lungs

Prevotella (formerly oral strains of Bacteroides) e.g., P. melaninogenica

Fusobacterium nucleatum microaerophilic streptococci Peptostreptococcus

o Multiple organisms are recovered from most patients with aspiration (polymicrobial infections)

o Very high mortality with massive aspiration + Mendelson 70% 20% for aspiration + empyema Uncomplicated 5% mortality

Preventiono Bacterial pneumonia can be prevented in various ways,

reducing risk factors Smoking Alcoholism Vaccination

Influenza vaccine subjects over 65 years of age cases of chronic diseases medical and nursing home employees

Pneumococcal vaccine subjects older than 65 younger patients who have:

o cardiovascular or pulmonary diseaseso diabetes mellituso alcoholismo liver cirrhosiso cerebrospinal fluid leakso immunodepression (including human immunodeficiency virus

infection, chronic renal failure, organ transplant recipients, hematologic and lymphatic malignancies, asplenia, and sickle cell disease

Complicationso Abscess

Cavities develop when necrotic lung tissue is discharged into communicating airways, resulting in either necrotizing pneumonia (multiple small cavities, each <2 cm in diameter, in one or more bronchopulmonary segments or lobes) or lung abscess (one or more cavities >2 cm in diameter)

o Empyema Most empyemas evolve from parapneumonic effusions. Inadequate treatment of the

underlying infection results in bacterial invasion of the pleural space with accumulation of large volumes of pleural fluid

There is progressive thickening of the pleura and adjacent soft tissues with the development of a pleural peel, an inelastic fibrous membrane which encases the lung and restricts function

o Bronchiectasis Chronic bronchial dilatation with parenchymal infection and inflammatory reaction loss of parenchyma between the crowded airways, and the large caliber of the lumen

near the pleural surface, compared to airways in the lower lung Treatment

o Antibiotic treatment is empiric and includes coverage for both typical and atypical organisms. Doxycycline, a fluoroquinolone with enhanced activity against Streptococcus neumonia, or a macrolide is appropriate for outpatient treatment of immunocompetent adult patients

Viral Note: Martin likes coronavirus (SARS) and influenza for pneumonia

o “Considers them to be important” – hint hint Viral respiratory tract infections are the most common cause of symptomatic human disease among

children and adults. They account for more time lost from school and work than any other infection. Approximately 1-3 respiratory tract illnesses occur in adults, compared with 2-7 respiratory tract illnesses

in children, each year. These infections may cause a wide variety of diseases, from the common cold to severe pneumonia, and may result in significant morbidity and mortality.

The incidence of viral pneumonia has increased during the past decade. o The increase primarily is because of improved diagnostic techniques and the growing population

of patients who are immunocompromised. In the past, the diagnosis of viral pneumonia was made essentially on clinical grounds.

o Over the past 10 years, new biotechnology has greatly facilitated the diagnosis of viral pneumonias.

o Clinicians are able to obtain a virologic diagnosis with a high degree of sensitivity and specificity, often within a few hours of the diagnostic procedure.

o Furthermore, improved approaches to prevention and treatment of viral pneumonias have also become available

The 4 most frequent etiologies of viral pneumonia in adults are o influenza virus

enveloped, single-stranded, RNA viruses of the family Orthomyxoviridae and are the most common viral cause of pneumonia.

They are classified as types A, B, and C and are distinguished by the antigenic differences in the internal proteins.

Influenza virus is capable of undergoing minor or major changes in antigenicity, which allows the virus to evade the preexisting immunity in the population.

Influenza epidemics occur during the winter months and are associated with significant morbidity and mortality.

Patients at increased risk for severe disease, which can lead to death, include: Patients with chronic obstructive pulmonary disease (COPD) congestive heart failure hemoglobinopathies immunosuppression.

Influenza virus is transmitted from person to person primarily by droplet and aerosol exposure to the virus. The incubation period is 1-5 days after exposure.Two influenza types have emerged of particular importance

H5N1 avian influenza strain H1N1 swine influenza strain

o Respiratory syncytial virus (RSV) Second most common viral cause of pneumonia. It is a medium-sized virus of the Paramyxoviridae family but consists of only 1 serotype.

Structurally, RSV has 10 unique viral polypeptides, 4 of which are associated with virus envelope, and 2 of these (F and G) are important for infectivity and pathogenicity. Classic RSV infection causes syncytia formation in cell culture, giving the virus its name.

RSV is the most frequent cause of lower respiratory tract infection among infants and children and is highly contagious, spreading via droplet and fomite exposure.

Most children are infected before age 5 years, but the immunity is incomplete, and reinfection may occur later in life; the likelihood of more severe disease and pneumonia increases with advancing age.

RSV is a well-established cause of pneumonia in the elderly population and in adults who are immunocompromised.

Infection may occur seasonally during the winter months or as outbreaks in hospitals and nursing homes

o Adenovirus Enveloped DNA viruses that cause upper and lower respiratory tract infections. Pneumonia is less common in adults outside of military recruit camps and similar

facilities, but fulminant disease has been described in the immunocompromised population and can occur in apparently healthy hosts.

Although 51 serotypes exist, classified into 7 subgroups or species (A-G), pulmonary disease is predominantly caused by serotypes 1, 2, 3, 4, 5, 7, 14, and 21.

Adenoviruses are spread through droplet and fomite transmission; close living arrangements (eg, college campuses, military camps) are likely places for outbreaks.

newly identified, more virulent strain, serotype 14 (subgroup B), has been reported to cause severe respiratory illness and pneumonia.

In 2005, surveillance of civilian and military populations initially reported emergence of this strain, with outbreaks occurring subsequently at military training centers throughout the United States; in 2007, adenovirus serotype 14 caused a large, sustained outbreak of febrile respiratory illness among military trainees in Texas, in a residential care facility in Washington State more recently, and in a community-wide setting in Oregon.6,7,8,9

In the Oregon community outbreak, the median age was 52 years, and 76% required hospitalization, 47% required critical care, 24% required vasopressors, and 18% died; the majority of these patients were otherwise immunocompetent adults

o Parainfluenza virus (PIV) from the family Paramyxoviridae and is characterized by nucleocapsids, which develop

in the cytoplasm of infected cells, with hemagglutinin present in the virion envelope. These can be separated into 4 subtypes based on antigenic characteristics. This virus is

spread via droplet and fomite exposure. Parainfluenza is a common virus that infects most persons during childhood. PIV type 3

is endemic year round, and types 1 and 2 peak during the fall season. Immunity is short term, and recurrent upper or lower respiratory tract infections occur

throughout life. The infections vary from a mild illness to life-threatening croup, bronchiolitis, or

pneumonia. Infection in hosts who are immunocompromised can result in life-threatening pneumonia with lung injury and respiratory failure

o Human metapneumovirus relatively newly discovered respiratory pathogen, initially described in the Netherlands

in 2001. It is also in the Paramyxoviridae family (like RSV and PIV) and is a pleomorphic-shaped

virus surrounded by surface protein projections. This virus is a ubiquitous organism, and most surveys indicate that by age 5 years,

almost all children have been exposed to it. However, reinfection occurs throughout life, including in adults. This virus is spread via

droplet and fomite exposure. As with other viruses, the severity of infection increases with older age and with

comorbid (cardiopulmonary disease) or immunosuppressive conditions. The most common diagnoses associated with adult hospitalizations with hMPV infection

are COPD exacerbations Bronchitis and pneumonia.

In immunocompromised hosts (eg, hematologic malignancies), severe pneumonitis requiring intensive care or resulting in death has been reported

o Coronavirus Coronaviruses are from the family Coronaviridae and are single-stranded RNA viruses,

the surface of which is covered by crownlike projections, giving the virus its name. This virus is spread via droplet and fomite exposure. Long known to cause upper

respiratory infections, coronaviruses were not felt to significantly cause pneumonia until relatively recently; strains 229E and OC43 have been shown to cause pneumonia in adults.3

However, it was the severe acute respiratory syndrome (SARS) pandemic in 2003 that brought the ability of this virus to cause life-threatening pneumonia to worldwide attention.

The SARS coronavirus (SARS-CoV) quickly spread from China to the rest of the world, affecting more than 8000 patients in 29 countries and resulting in 774 deaths.

The mode of transmission was thought to be primarily via droplet and/or fomite. After intensive infection control measures by the World Health Organization, the global transmission was halted in June 2003.14

Viral isolation and genomic sequencing have revealed that this virus originated in the masked palm civet cat (Paguma larvata), raccoon dog (Nyctereutes procyonoides), and possibly the Chinese ferret-badger (Melogale moschata), with subsequent interspecies jumping, during which a partial loss of genome probably led to more efficient human-to-human transmission

o Cytomegalovirus Immune competent

“Mononucleosis”

High Fevers (6 weeks), Chills, Profound Fatigue, Malaise, Myalgias, Headache, Arthralgias

Rarely exudative pharyngitis and cervical lymphadenopathy Neonate

Pneumonitis Perinatal infection occurs with contact maternal cervicovaginal sections during

delivery or from breast milk ingestion after delivery. àinfection may become apparent as early as 3 weeks and as late as 3-6

months Sepsis-like syndrome commonly and associated with HSM abnormal blood

counts with lymphopenia, neutropenia, and thrombocytopenia, abnormal tranaminases and pneumonitis

Immunocompromised Fever , Leukopenia, Hepatitis, Pneumonitis, gastritis, colitis, retinitis Transplanted organ is often the targeted organ. Marrow transplant is associated with CMV pneumonia in 15-20% with a case

fatality of >80% CMV

o Also Varicella, Herpes Simplex associated with immunocompromised and viral pneumonia

Influenza virus types A and B are responsible for more than one of community-acquired viral pneumonia cases, particularly during influenza outbreaks.

RSV ranks second among the common causes of viral pneumonia in adults, followed by adenovirus and PIV

Fungal Endemic Infections

o Infection by organism, widely present but not normally a component of the host normal florao Generally, but not always, infection occurs only with compromise in immune function

Examples would include Coccidioidomycosis, Histoplasmosis, Blastomycosis, Cryptococcus

o Mucormycosis-Mucor, Rhizopus, rhizomucor Especially associated with uncontrolled DM patients Produces severe sinusitis as well as progressive lung tissue destruction with pneumonia Patient often critical rapidly Treated with Amp. B.

o Pneumocystis jirovecii Formally pneumocystis carinii

Treated with TMP-SMX or clindamycin + pirmiquin or pentamidine Manifest with cough, hypoxia, chest pain, high and undulating fever with frequently

night sweats Opportunistic Infections

o When infections are developed secondary to organism that are normally components of the hosts flora secondary to compromise in normal immune response

Examples: Candidia, Aspergillus Mycosis

o Yeast-normally present in rounded cellular form Candidia-cryptococcus

o Molds-normally present in environment in filamentous form as hyphae Aspergillus, rhizapus

o Dimorphic fungi are organism exist as yeast in tissue and molds with hyphae in environment Immunocompromised patient

o Cryptococcus is found world wide. The other major fungi are geographically restricted and are dimorphic, existing as a mold form in the environment and as a yeast form in tissue.

Widely disseminated, almost all adults have antibody to Cryptococcal neoformans antigens.

C. neoformans is associated with bird droppings and is found world-wide. C. gattii is also associated with eucalyptus trees and can be pathogenic. Cryptococcus exists only as a yeast form both in the environment and in the infected

person. There is no mycelial (mold) form. Treatment

Treatment: o Induction: Amphotericin B, Flucytosine o Consolidation: Fluconazole or Voriconazoleo Fluconazole is continued indefinitely in HIV patients unless CD4+ count

due to HAART rises to > 100 for > 6 months. Primary Prophylaxis: Not Recommended

o Incidence of Cryptococcal Disease has fallen due to HAART and daily fluconazole gave no survival advantage.

Treatment: Crytpococcal meningoencephalitis is uniformly fatal if untreatedo Medical therapy (2002 IDSA guidelines)o Amphotericin B (0.7 mg/kg daily) & flucytosine (100 mg/kg per day in

four divided doses) for two weeks of induction therapyàif clinical response during inductionàd/c ampho/flucytosine; start high-dose fluconazole (400mg/d if normal hepatic/renal fxn) for consolidation x 8 weeks; followed by fluconazole 200mg/d for long term chronic suppression

o Monitoring of treatment Amphoàserum creatinine and electrolytes. Infusion related reactions (fever/chills)àpretreatment w

acetaminophen, diphenhydramine, or corticosteroids Flucytosineàserum levels 2 hours after an oral dose; concern

bone marrow toxicity; caution w impaired renal fxn FluconazoleàLFTs

o H. capsulatum Most prevalent endemic mycosis in N. America General Range: Ohio & Mississippi Valleys Infection is by inhalation of wind blown earth in which the fungus lives. Dimorphic fungus; Mycelial form in soil and yeast form at body temperature Yeast within macrophage Temperate zones worldwide; specific endemic areas include the mississippi, ohio, and St

lawreence River valleys, the caribbean, southern mexico, central america Fungus is found in high concentrations in soil contaminated with bird or bat

excreta (associated with jobs/hobbies such as construction, spelunking, bird handling)

Occurs in 5-27% of patients with AIDS living in endemic areas Opportunistic pathogen, causing disseminated disease in patients with AIDS or

with other forms of impaired cellular immunity CD4 count <100 cells/microL AIDS defining illness in 50% of affected patients

Self-Limited Pulmonary Disease in Immune competent* Granuloma formtion and calcifications Mimicking “healed” or “latent” tuberculosis

*In the immune competent, this form of pulmonary Histoplasmosis needs no treatment.

Clinical Presentationo Isolated Pulmonary Involvement <5% of patientso Pulmonary Involvement in dissemenated disease 70%: cough and

dyspnea o Disseminated histoplasmosis: febrile, wasting illness. HSM,

adenopathy, skin and mucosal lesions, diarrhea, meningitis, cytopenias, and a sepsis-like syndrome

Immunocompromised: Active, Acute Infection with initial flu like symptoms progressive to more severe and persistent symptoms of cough, SOB, chest pain, fever, night sweatsin compromised.

Yields: Chronic Fibrocavitary Pulmonary Diseaseo Mimicking “active” tuberculosis

Untreated yields: Disseminated Diseaseo Febrile, wasting illness, anemia, thrombocytopenia, lympadenopathy,

hepatosplenomegaly, and abnormal liver function tests (LFTs) Diagnosis

Self-Limited Pulmonary Disease o Looks like TB but it isn’t and patient has been exposed in an Endemic

Area Chronic Fibrocavitary Pulmonary Disease

o Sputum Culture positive for H. capsulatum and CXR compatible Disseminated

o Blood Culture positive for H. capsulatum o Histoplasma Antigen in Blood or Urineo

Diagnosis: visualization of the organism within cells on a Wright’s stained smear of peripheral blood or a buffy coat

o Dx of organism in tissue or BAL Treatment

Treatment for all of the deep fungal diseases is with sequential amphotericin B & itraconazole or either voriconazole or fluconazole.

Treatment: Amphotericin B x 7-14 days Induction àitraconazole o Secondary Prophylaxis: 50-80% will relapse if lifelong therapy is not

maintained; amphotericin relapse rats of 3-19%, itraconazole prevents relapse in up to 95% of cases, fluconazole relapse rate of 12-18%

o Primary Prophylaxis: Itraconazole 200mg/day, effective in patients with CD4 count <100 cells/microL living in endemic areas

o C. inmitis General Range: Lower Sonoran Desert Infection is by inhalation of wind blown earth. Endemic to sothwestern US, northern mexico and parts of central and south-america Occurs in ~27% of HIV patients living in endemic areas Presentation

Primary Pulmonary Infection o Valley Fever: “Flu-Like” Symptoms to Severe Pneumonia (40%)

Begins 10-14 days after exposure with fever, cough, chest pain, malaise, erythema nodosum

Course: Spontaneous improvement and recovery in several weeks

No treatment in immune competent host

o No Symptoms in 60% Chronic Fibrocavitary Disease produced. Disseminated Disease can occur in compromised patients

o Immediate or by Reactivation if immunosuppression occurs Wide spectrem of presentation in HIV Non-immunocompromised: Focal pneumonia, skin involvement, and meningitis Extrathoracic manifestations, disseminated diseaes, and unusaul sites of

involvement Pulmonary Disease (85%): fever, cough, and dyspnea Xray: diffuse infiltrates are the MC radiographic findings (60%) Focal alveolar infiltrates 65%; nodules 25%; hilar adenopathy 20%; cavities

15%; pleural effusions 5% Diagnosis

Primary pulmonary disease or prior infection o Looks like TB but it isn’t and patient was exposed in the endemic area

and is skin test positive with Coccidioides antigen. (May have low level of antibody.)

Disseminated disease – o Complement fixation (CF) quantitative antibody determination shows

an increasing antibody titer. Paradox – antibody is not protective Diagnosis:

o Definitive diagnosis visualization of the fungus from a clinical specimen or recovery in culture

o Sputum culture yield 16%; BAL often requiredo Papanicolaou or Gomori methenamine silver stainso Cultures of BAL require 5 days to growo 80% positive tube precipitin or complement fixation serology

Treatment Diffuse pulmonary involvement have high mortality 70% w median survival of 1

montho Amphotericin B o Fluconazole and itraconazoleàcoccidioidal meningitis

Secondary prophylaxis: lifelong mainentance therapy is requierd.o Fluconazole is the preferred agent

Primary Prophylaxis: prior infection does not predict the development of active coccidiodomycosis in the hiv INFECTED POPULATION.

No DEFINITIVE RECOMMENDATIONS EXISTS Immunocompromised

o Amphotericin B if widely disseminated and acutely illo Replaced largely by Voriconazole as treatment of choiceo Also responds to azole drugs, fluconazole and itraconazole

PEARLS Histoplasma & Coccidioides mimic Mycobacterium tuberculosis clinically &

radiologically but not epidemiologically. Histoplasma & Coccidoioides mimic each other & Mycobacterium avium

complex (MAC) epidemiologically. Histoplasma, Coccidioides, & MAC are found in earth, are geographically

restricted, & are not transmissible person to person. Acute lung disease caused by H. capsulatum or C. inmitis does NOT need

treatment in the Immune Competent.

Overall, world wide, fungal lung disease is much less common than M. tuberculosis of the lung

o P. braziliensiso B. dermatiditis

Endemic area as for Histoplasmosis (Ohio & Mississippi Valleys) plus areas of Ontario & Manitoba.

The lung is the portal of entry. All who are infected need treatment.

Dimorphic fungus Endemic to the midwestern and south central US Inhalation of the organism into the lung Majority of immune competent patients will have dissemination to skin,

mucosa, bone, or genitourinary tract, weeks to years after infection. o Minority of immune competent patients with lung Blastomycosis will

have self limited disease. Those with self-limited lung disease cannot be distinguished from those whose disease

will disseminate. Symptoms of disseminated disease are fever, weight loss, lassitude. CXR lesions found in 2/3s of patients with dissemination. Uncommon, but serious complication of advanced HIV disease

o CD4 count <200 cells/microL o Course in HIV may be fulminant with a 40% early mortality in HIV

infected patients Clinical Presentation: pulmonary disease (80%); 42% disseminated disease to multiple

visceral organs including skin, liver, lymph nodes, and meninges as well as the lungs Fever, weight loss, and cough, pleuritic chest pain and significant dyspnea XRAY: 40% focal lobar infiltrates, 40% miliary or diffuse interstitial infiltrates

Diagnosis: cytologic or histologic stain or culture of variety of clinical specimens including

sputum, BAL , tissue biopsy, and CSF o Culture requires 2-4 weekso Serologic tests are frequently negative and unreliable

Treatment: Amphotericin B Itraconazole for focal, non-life threatening infections ***CHRONIC maintenance therapy is indicated. Itraconazole has become the

preferred agent Aspergillus pneumonia

o A. fumigatus common opportunistic agent producing infection in compromised hosto Creates cavitations with pneumonia and pulmonary infection and resembles T.B. on X-Rayo Common cause of sinusitiso Exacerbations common with drawl of steroidso Treatment is Voriconazole or Amphotericin B and Itraconazole

Candidiao More than 150 species of Candidia identified, only a few know to cause human infections

C. albicans, C. krusei, C. glabrata, C. tropicalis, etc.o Relatively rare to see pneumonia compared to other organ involvemento Spreads by hematogenous spread, in fact is 4th most common isolate from blood cultures and #1

noscomal infection.o Treatment is fluconazole, voriconazole and Amp. B . Responds to echinocandins as well.

Nonsocomial (redundant, but specific info) Definitions

o Hospital Acquired (HAP) à Ventilatory Associated (HAP) 85% of HAP VAP developed by 20% of intubated patients HAP: occurs 48 hours or more post admission, but was not incubating at the time of

admission VAP: occurs more than 72 hours after admission, following intubation HCAP: any patient hospitalized for 2+ days within 90 days of the infection onset

Nursing home or long-term care resident Received recent antibiotics Chemo Wound care within the past 30 days Attended a hospital or hemodialysis clinic

Riskso Mechanical ventilation and intubation increases the risk 6-21xo Age >70 yearso Chronic lung diseaseo Depressed consciousnesso Aspirationo Chest surgeryo The presence of an intracranial pressure monitor or nasogastric tubeo H-2 blocker or antacid therapyo Transport from the ICU for diagnostic or therapeutic procedureso Previous antibiotic exposure, particularly to third generation cephalosporins o Reintubation o Hospitalization during the fall or winter seasono Mechanical ventilation for acute respiratory distress syndrome (ARDS)o Frequent ventilator circuit changeso Nursing Home

Organismso Hospital Acquired Pneumonia (HAP)

Early onset S. pneumonia, Hib, MSSA

Late onset P. aeruginosa, MRSA, resistant GNB

Gram negative bacteria (other) > P. aeruginosa > S. aureus > Candida Purulent Bronchitis

Purulent sputum Normal CXR Typical in patients on ventilators

P. aeruginosa: High mortality (50%) Monotherapy is not adequate

o High failure rateso Relapseo Resistance

Empirical therapyo 2 active drugs

Beta lactam + aminoglycoside Beta lactam + fluuroquinolone

o VAP Resistance: P. aeruginosa, MRSA, A. baumannii, S. maltophilia Late onset

High mortality (39%)

65% died with high-risk pathogeno Found in resistance list

Acinetobacter spp Resistant to many antibiotics

o Most active agents Carbapenems

1st line A. baumannii Extended spectrum Beta lactamases

o Plasmids Resistant to ceftazidime,

cephalosporins, penicillins K. pneumonia Emerged in U.S. in the 1980s

Colistin Sulbactam

4-15% of VAP Found in ICU patients almost predominantly Risks

o Prior antibioticso Prolonged ICU stayo Mechanical ventilation

o HCAP:

MRSA

Pseudomonas aeruginosa

Acinetobacter spp.

MDR Enterobacteriaceae

Hospitalization > 48 hrs

X X X X

Hospitalization for 2 days in prior 90 days

X X X X

Nursing home or extended-care facility residence

X X X X

Antibiotic therapy in preceding 90 days

X X

Chronic Dialysis

X

Home Infusion Therapy

X

Home Wound Care

X

Family Member w MDR infection

X

HAP/VAP/HCAP suspected à onset > 5 days or risk factors for MDR pathogens à Yes à Broad spectrum therapy

à No à Limited spectrum therapy No Risk

HCAP: No Risk Factors for MDR Pathogen o Streptococcus pneumoniae o Haemophilus influenzae o Methicillin-sensitive Staphylococcus aureus o Antibiotic-sensitive enteric gram-negative bacilli

Escherichia coli Klebsiella pneumoniae Proteus species Serratia marcescens

Risk Streptococcus pneumoniae Haemophilus influenzae Methicillin-sensitive Staphylococcus aureus Antibiotic-sensitive enteric gram-negative bacilli

Escherichia coli Klebsiella pneumoniae Proteus species Serratia marcescens

MDR Pathogens o Pseudomonas aeruginosa o Klebsiella pneumoniae (ESBL)o Acinetobacter specieso MRSAo Legionella pneumophila o Drugs

Antipseudomonal cephalsporin (cefepime, ceftazidime) or

Antipseudomonal carbepenem (imipenem or meropenem) or

B-Lactam/B-lactamase inhibitor (piperacillin-tazobactam)PLUS

Antipseudomonal fluoroquinolone (ciprofloxacin or levofloxacin)

or Aminoglycoside (amikacin, gentamicin, or tobramycin)

PLUS Linezolid or vancomycin

o Nursing home pneumonia Etiology and Management is between community- and hospital-acquired pneumonia in

etiology and management S. pneumoniae and gram-negative bacilli

o H. influenzae and Moraxella catarrhalis are next most common. Epidemiology

o Leading cause of death among all nosocomial infections.o Second most common cause of nosocomial infections in the USA.o Associated morbidity of nosocomial pneumonia is so high that is estimated that 5 days are added

to the hospital length of stay (los).o Health care cost are astronomical

Treatmento Antibiotics are classified by mechanism of action

Cell wall Inhibition or Peptoglycan destruction Penicillins Cephalosporins Glycopeptides Monobactams Carbapenems Daptomycin

Membrane Permeability Disruption Polymycins Detergents

Antimetabolites/Folic Acid Sulfas Clotrimazole

Inhibition of DNA: Replication

o Fluroquinolones Repair

o Metronidazoleo Imidazoles

Transcriptiono Rifampino Rifamycin

Inhibition of Protein Synthesis:o Anti 30S

Tetracycline Glycylcyclines Aminoglycosides Oxazolidones

o Anti 50S Chloroamphenicol Macrolides Lincomycins Ketolides

o New Drugs Linezolid

Oxazolidinones Inhibits synthesis at 70S Gram positive Novel mode of action à lacks cross resistance problems MRSA is still resistant

o E. faecium too Ertapenem

Carbapenem Gram positive and negative Limited use with Enterococcus, P. aerugonisa

Resistance in some ESBLs Daptomycin

Cyclic lipopeptide Concentration dependent Gram positive No cross resistance Resistance with MRSA, S. aureus, E. faecalis POOR EFFICACY IN PULMONARY INFECTIONS

Tigecycline Glycylcyclines Bacteriostatic Inhibits translation at 30S Gram positive and negative Not very useful with Pseudomonas Biliary/fecal excretion P450 NOT AFFECTED Few drug interactions Standard dose

o Initial dose of 100 mg IVfollowed by 50 mg IV q12h

o Indicated in patients ≥18 years of age Renal impairment

o No dosage adjustment necessary o Not dialyzable

Hepatic impairmento No dosage adjustment necessary

in patients with mild to moderate impairment o In patients with severe hepatic impairment (Child Pugh C),

the initial dose is 100 mg IV followed by 25 mg IV q12h Flouroquinolones

Gemifloxocin- Factive Levofloxacin- Levaquin Gatifloxocin- Tequin Moxifloxacin- Avelox Mechanism of action is dual by inhibiting DNA Gyrase and Topoisomerase lV