Management of the patients with fever of unknown origin. Management of the patients with severe nosocomial and community-acquired pneumonias 

 

Classification of pneumonia:

community-acquired pneumonias;

Pneumonia in immunocompromised host

Nosocomial pneumonia

Pneumonia due to aspiration

Community-acquired pneumonia has become a major health problem throughout the world. Each year in the United States, an estimated 4 million cases occur. About 20% of these cases require hospitalization, the condition resulting in more than 65 million days of restricted activity overall. Mortality rates range from 1% to 5% in outpatients and from 15% to 30% in inpatients, making it the sixth leading cause of death. Many experts divide therapy for community-acquired pneumonia into two categories: inpatient and outpatient.

Problems in establishing a cause The etiology of community-acquired pneumonia is a long- and often-debated topic. Some researchers imply that outpatients contract different causative agents than do inpatients, while other investigators do not make major distinctions between the two categories. Other experts have attempted to elucidate the causes according to patient age. Even after examination of virtually every study completed on community-acquired pneumonia, it is extremely difficult to posit any useful probability of cause on the basis of age or outpatient versus inpatient setting.

The difficulty arises from a simple fact: in most patients with community-acquired pneumonia (about 98% of those treated as outpatients and 50% to 60% of those treated as inpatients), the causative organism is not known. Even in studies at academic centers where every effort is made to culture samples from all conceivable sites, the success rate in determining a cause is only about 50%. In most cases with an “established” cause, testing has been done on expectorated sputum, and this source of sample material always has the potential of contamination with upper-airway organisms. Correlation is not high between findings in expectorated sputum and findings in specimens from lower in the respiratory tract, obtained by bronchoscopy with a protected brush or by fine-needle or transtracheal aspiration.

A variety of organisms can cause community-acquired pneumonia. A review of studies during the past 20 years that included more than 100 subjects (total, >4,900 patients) reveals that the following are the most common pathogens(1): Streptococcus pneumoniae(9% to 75%; mean, 33%), Haemophilus influenzae (0 to 50%; mean, 10%), Legionella species (0 to 50%; mean, 7%), andChlamydia pneumoniae (0 to 20%; mean, 5%) (1,3,5,8). Other organisms reported, io particular order, were Mycoplasma pneumoniae, other gram-positive organisms, gram-negative organisms, anaerobes, mycobacteria, fungi, and viruses. The incidence of so-called “atypical” (legionellal, chlamydial, and mycoplasmal) pneumonias is particularly difficult to ascertain, because diagnosis of these infections is usually made by serologic testing. This method indicates only whether there has been exposure to these organisms and an immunologic response; it does not necessarily establish that they are causative agents of the pneumonia under scrutiny.

Despite all the contradictory statistics on etiology, most investigators agree that S pneumoniae is the leading cause of community-acquired pneumonia in both inpatients and outpatients.

 

Considerations in choosing outpatient therapy

Perhaps the greatest debate concerning community-acquired pneumonia has been over therapeutic options. Because outpatient therapy must be chiefly empirical, antibiotics should be chosen that provide adequate coverage against the putative treatable organisms known to cause community-acquired pneumonia. The Infectious Diseases Society of America recommends selecting from among the macrolides erythromycin, clarithromycin (Biaxin), and azithromycin (Zithromax); the fluoroquinolones levofloxacin (Levaquin), trovafloxacin mesylate (Trovan), grepafloxacin (Raxar), sparfloxacin (Zagam), and any other fluoroquinolone with enhanced activity against S pneumoniae; and (in patients between the ages of 17 and 40) doxycycline.

Duration of therapy     
The preferred duration of therapy for community-acquired pneumonia is an unresolved issue, and surprisingly, applicable prospective studies are not available. The Infectious Diseases Society of America recommends 7 to 10 days. However, one study found that clinical outcomes were as good with a 3- to 5-day course of azithromycin as with the usual 7- to 10-day course of comparable antibiotics. Outcome research is urgently needed, because both cost and resistance could be minimized by using shorter courses of antibiotic therapy.

Antibiotic resistance

Development of bacterial resistance has been a significant problem related to antibiotic use. The frequency of resistance among community-acquired pathogens is increasing and has been linked to inappropriate use of antibiotics, such as the following:

To treat viral infections

To treat resistant organisms

For longer periods than necessary

To treat a particular organism with a much-wider-spectrum agent thaeeded

Unnecessary use of antibiotics for viral illnesses is common and has led to increasing rates of antibiotic resistance among S pneumoniae and other community-acquired pathogens. In addition, boundaries between community and hospital environments are blurring, with potential negative consequences regarding resistance. Resistance genes occur in both pathogenic and commensal organisms to which people are exposed continually through food, the environment, and animals. The multitude of genetic mechanisms available for evolution and reassortment of antibiotic resistance genes virtually ensures that genes useful to survival of bacteria are rapidly disseminated.

On the bright side, resistance to newer fluoroquinolones (eg, trovafloxacin) may be slow to develop because bacteria might be required to mutate more than once to achieve a significant level of resistance. Encouragingly, one recent multicenter study found (theoretical considerations notwithstanding) that resistance to antibiotics did not parallel antibiotic use.

Table 1 compares the cost of outpatient treatment using these agents. Cost can vary by locale as well as over time. In general, the average retail price is 20% to 30% higher than the average wholesale price.

Table 1. Costs of oral antibiotic regimens for community-acquired pneumonia
Drug	Recommended regimen	Cost/day (AWP*)	Cost/day (ARP)
Erythromycin	500 mg q6h	$0.70-1.80	$0.88-2.25
Clarithromycin (Biaxin)	500 mg q12h	$5.50-7	$6.88-8.75
Azithromycin (Zithromax)	Day 1, 500 mg; then 250 mg qd	$6.30-7.50	$7.88-9.38
Levofloxacin (Levaquin)	500 mg qd	$7-8	$8.75-10
Sparfloxacin (Zagam)	Day 1, 400 mg; then 200 mg qd	$7-8	$8.75-10
Trovafloxacin mesylate (Trovan)	200 mg qd	$7-8	$8.75-10
Grepafloxacin (Raxar)	600 mg qd	$6-7	$7.50-8.75
Doxycycline	100 mg bid	$0.50-1	$0.63-1.25

 

Many experts believe that empirical outpatient treatment of community-acquired pneumonia must include coverage for the common causative organisms, which include such gram-positive bacteria as S pneumoniae and such atypical organisms as Legionella, Mycoplasma, and Chlamydia. Since S pneumoniae is conceded to be the most common causative agent in community-acquired pneumonia, the organism deserves particular attention in therapeutic considerations.

In general, choosing antibiotics to which organisms are highly resistant should be avoided. However, there is little clinical evidence demonstrating that using antibiotics to which recovered organisms have high or intermediate resistance results in more treatment failures than using antibiotics to which the organisms are sensitive. In one recent study, a few clinical failures occurred among patients who had highly penicillin-resistant S pneumoniae infection. It seems intuitively obvious that treating infections with antibiotics to which organisms are highly resistant will eventually result in significant numbers of treatment failures.

Differences by location 
Resistance to different antibiotics may vary by hospital and by locale, so the pattern of resistance in a geographic area of practice must be known to make a rational selection among antibiotics. Information on resistance patterns can be obtained from each hospital’s microbiology department and each state’s board of health.

Surveillance studies show almost exponential increases in penicillin-resistant S pneumoniae over the past 3 years in the United States. This trend is also true worldwide. If a location has considerable (eg, more than 5% to 10%) resistance to S pneumoniae, use of another antibiotic should be considered. High-level resistance to penicillin is associated with high-level resistance to macrolides, cephalosporins, and doxycycline as well. In contrast, to date, high-level resistance to the newer fluoroquinolones is less than 1%, and cross-resistance between these agents and penicillin has not, as yet, been recognized.

Minimizing resistance   
Theoretically, choosing doses of antibiotics on the basis of pharmacodynamics should increase eradication of bacteria and thus minimize development of resistance. Preventing antibiotic resistance through rapid DNA-based testing is an emerging and potentially promising biotechnologic tool. Additional new techniques under way to combat resistance include development of products that block bacterial adherence to tissues, design of drugs to fit model chemicals into the crystal structures of the catalytic sites of key enzymes from bacteria, and use of other highly sophisticated molecular biology tools.

More general solutions to the problem of increasing antibiotic resistance include intensive education of healthcare providers, enhanced education of patients, institution of mandatory surveillance programs, and funding of appropriate research.

Preventive measures

Virtually all experts on community-acquired pneumonia recommend use of polyvalent pneumococcal vaccine (Pneumovax 23, Pnu-Imune 23) in patients considered at increased risk. Some authors question the usefulness of pneumococcal vaccine, particularly in the elderly, but case-control and cohort studies have documented its efficacy. Prospective studies evaluating the impact of immunization on disease incidence, antibiotic resistance, and overall treatment cost are under way.

 

HYDROTHORAX

The term hydrothorax generally denotes the presence of a collection of serous fluid having a specific gravity of less than 1.015 or a protein content of less than 3 g/dL (transudate). The most common cause is congestive heart failure, but lymphatic obstruction and obstruction of the superior vena cava or vena azygos may also cause hydrothorax. The not unusual finding of hydrothorax in hepatic cirrhosis with ascites (6%) is explained by observations of ready transfer of radioiodine-labeled albumin from the peritoneal to the pleural spaces. The initial examination of the pleural fluid should be as described above.

 

The fluid should be removed by thoracentesis when it causes dyspnea.

 

The prognosis is that of the underlying disease.

 

HEMOTHORAX

 

Hemothorax (pooling of blood in a pleural space) is most commonly due to trauma but may also follow tumor, tuberculosis, and pulmonary infarction. The physical findings are the same as those of pleural effusion. Military experience has shown that early removal of all blood from the pleural space is desirable. If this cannot be accomplished by thoracentesis, an intercostal tube with water-seal drainage is indicated. If bleeding continues, thoracotomy is indicated. Great care must be taken during aspiration to avoid bacterial contamination of the pleural cavity. Surgical removal of residual blood clots may be necessary.

 

 

 

PLEURAL EMPYEMA (Nontuberculous)

 

Acute infection of the pleural space may result from (1) direct spread from adjacent bacterial pneumonia, (2) postsurgical infection, (3) post-traumatic (including thoracentesis)infection. Underlying chronic obstructive pulmonary disease or broncho-genie carcinoma is frequently present. The availability of early and specific therapy for these conditions has made empyema an uncommon disease. However, the mortality rate remains high (50% in some series). The incidence of anaerobic infection appears to be increasing. Hospital-acquired infections have a more serious prognosis.

 

The clinical findings are often obscured by the primary underlying disease. Pleural pain, fever, and ‘ ‘toxicity” after clinical improvement of the primary disease, in association with physical and x-ray signs of pleural fluid, are characteristic. Thoracentesis reveals a frankly purulent exudate from which the causative organism may be cultured. Empyema, like lung ab­scess, may become chronic, with a prolonged course and little tendency to spontaneous resorption (especially in bronchiectasis and tuberculosis).

 

The key to nonsurgical treatment of acute empyema is early diagnosis. Any collection of fluid occurring in the course of pulmonary inflammatory disease should be removed at once. If pus is present, a specimen should be obtained for Gram staining and cultures, including cultures for anaerobic organisms. Specimens for anaerobic culture must be collected without exposure to air and must be placed into suitable transport media immediately. (Coagulase-positive Staphylococcus aureus and gram-negative bacilli are the most common aerobic bacteria causing empyema; Bacteroides and peptostreptococci are the most frequently encountered anaerobic organisms.) The empyema should be aspirated as completely as possible. Some early localized empyemas can be treated by thoracentesis and antibiotic therapy alone. Any large or loculated empyema should be drained immediately via an intercostal tube. Open thoracotomy is sometimes required to ensure adequate drainage.

 

As soon as specimens have been obtained for culture, parenteral antibiotic treatment should be started with penicillin, 600,000 units intramuscularly every 6 hours, or, alternatively, cephalothin, 8 g intravenously daily. When the pus has a foul odor or the empyema is thought to be secondary to an intra-abdominal infection, chloramphenicol, 50 mg/kg daily orally, should be added to the initial treatment. The object is to obliterate the empyema space as soon as possible. Irrigations with saline through the catheter may be necessary. Chronic empyema usually results from inadequately treated acute empyema or from a bronchopleural fistula. Surgical drainage with or without decortication is usually necessary.

Summary

Most patients with community-acquired pneumonia are treated as outpatients, and choice of therapy is usually empirical because the etiologic agent is unknown. Therapy should include coverage for both typical and atypical organisms. In geographic areas with highly resistant S pneumoniae, one of the newer fluoroquinolones should be considered, since resistance to penicillin is associated with cross-resistance to macrolides and tetracyclines. Once-daily dosing should be given strong preference because more-frequent dosing results in poor compliance, which may lead to inadequate therapy and increased resistance. At present, the duration of therapy should probably be no less than 7 days.

Patients should be categorized for mortality risk with objective scoring methods, and the need for hospitalization should be decided accordingly. Greater use of observational and intermediate-care beds is encouraged, as is improved utilization of pneumococcal vaccine. The main types of pneumonia are presented.

 

PNEUMOCOCCAL PNEUMONIA

Essentials of Diagnosis

• Sudden onset of shaking chills, fever, chest pain, and cough with rust-colored sputum.

• X-rays show infiltration, often lobar in distribu- tion, but sometimes patchy.

• Pneumococci are present in the sputum and often in the blood.

• Leukocytosis.

General Considerations

Pneumonia is an inflammatory process in lung parenchyma most commonly caused by infection. The consolidation of pneumonia must be differentiated from pulmonary infarction, atelectasis with bronchial obstruction, and congestive heart failure, but it may coexist with any of these conditions. The pneumococcus accounts for 50-80% of community-acquired bacterial pneumonias; types1-9 and 12 are most commonly found in adults, whereas types 6, 14, 19, and 23 are most common in children. These bacteria frequently are in the normal flora of the respiratory tract. The development of pneumonia must therefore usually be attributed to an impairment of natural resis- tance. Conditions leading to aspiration of secretions include suppression of the cough or epiglottic reflex, impairment of upward migration of mucous sheets (propelled by cilia), and impairment of alveolar phagocyte function. Among conditions that predis- pose to pneumonia are viral respiratory diseases, mal- nutrition, exposure to cold, noxious gases, alcohol intoxication, depression of cerebral functions by drugs, and cardiac failure. Pulmonary consolidation may be in one or more lobes or may be patchy in distribution.

Clinical Findings

A. Symptoms and Signs: The onset is usually sudden, with shaking chills, “stabbing” chest pain (exaggerated by respiration but sometimes referred to the shoulder, abdomen, or flank), high fever, cough and “rusty” sputum, and occasionally vomiting. A history of recent upper respiratory illness can often be elicited.

The patient appears severely ill, with marked tachypnea (30-40/min) but no orthopnea. Respi- rations are grunting, nares flaring, and the patient often lies on the affected side in an attempt to splint the chest. Herpes simplex facial lesions are often present.

Initially, chest excursion is diminished on the involved side, breath sounds are suppressed, and fine inspiratory rales are heard. Later, the classic signs (absent breath sounds, dullness, etc) of consolidation appear. A pleural friction rub or abdominal distention may be present. During resolution of the pneumonia, the signs of consolidation are replaced by rales. Physical findings are often inconclusive, and repeated x-ray examination is helpful.

B. Laboratory Findings: Blood cultures are positive for pneumococci in 15-25% of cases early in the disease. In peripheral blood, leukocytosis (20-35 thousand/^L) is the rule, and a low white blood cell count carries a poorer prognosis.

Sputum must be examined by Gram’s stain and by culture. In the smears, the presence of many squamous epithelial cells suggests heavy contamination with saliva, and such specimens are of no value. Typical sputum from pneumococcal pneumonia contains many red and white cells (PMNs) and many pneumococci. If good sputum specimens are not obtainable, a trans- tracheal aspirate may reveal the causative agent, but this procedure is not without risk. A microscopic “quellung” reaction with pooled antiserum rapidly identifies pneumococci in fresh sputum.

C. X-Ray Findings (picture 1): Initially, there may be only a vague haziness across the involved part of the lung field. Later typical consolidation is well defined either in lobar or in patchy distribution. Fluid shadows in the costophrenic angles may appear before pleural exudate can be detected by physical examination. During reso lution of the consolidation, which may require 8-10 weeks, areas of radiolucency may appear, suggesting ‘ ‘pseudocavitation.”

 

Picture 1 This chest x-ray in a patient with a cough and fever showed a white area (yellow circle) in the right lower lung. This is pneumonia

 

Treatment

A blood culture and a good sputum specimen for smear and culture should always be obtained before treatment is started. The dosage and route of administration of antimicrobial drugs are influenced to some extent by the clinical severity of the disease, the pres- ence of unfavorable prognostic signs (see below), and the presence of complications.

Drug Category: Antibiotics

The initial antibiotic to treat low-risk patients is a macrolide. Macrolides are effective against most likely organisms in community-acquired bacterial pneumonia. Macrolides are used for gram-positive organisms, Legionella, and Mycoplasma. Azithromycin administered IV has the advantage of once-daily dosing over IV erythromycin.

Macrolides, as a class, have the potential to cause adverse GI effects. Newer agents are expensive, have fewer adverse GI effects, and fewer drug interactions compared to erythromycin. Macrolides are used for community-acquired pneumonia in patients younger than 60 years who are nonsmokers and have no comorbidity. Newer macrolides offer better compliance through reduced dosing frequency and improved activity against H influenzae and Mycoplasma.

Patients with community-acquired pneumonia who are older than 60 years or have comorbidity still are susceptible to S pneumoniae,but broader coverage is required to include Haemophilus, Moraxella, and other gram-negative organisms. Therefore, empiric therapy would include one of the macrolide agents outlined above plus one of the second-generation or third-generation cephalosporins, amoxicillin-clavulanate, or respiratory fluoroquinolone.

The choice of antimicrobial agent is based on the severity of patient illness, host factors (eg, comorbidity, age), and presumed causative agent (see Tables 1-3 in Medical Care). Outpatients are prescribed oral agents, and parenteral antibiotics are prescribed to patients admitted to the hospital.

Second-generation cephalosporins have added activity against P mirabilis, H influenzae, E coli, K pneumoniae, and M catarrhalisin addition to the gram-positive activity of first-generation cephalosporins.

Third-generation cephalosporins have wider activity against most gram-negative bacteria, such as Enterobacter, Citrobacter, Serratia, Neisseria, Providencia, and Haemophilus species, including beta-lactamase–producing strains.

Second-generation cephalosporins are not effective against Legionella or Mycoplasma. Generally, they are well tolerated but expensive. Oral second-generation and third-generation cephalosporins offer increased activity against gram-negative agents and may be effective against ampicillin-resistant S pneumoniae.

IV cephalosporins may be combined with a macrolide agent in patients with community-acquired pneumonia who are admitted to the hospital. They broaden the gram-negative coverage and, in the case of third-generation agents, may be effective against resistant S pneumoniae. Also, ceftazidime, a third-generation agent, is effective against Pseudomonas.

When a severely ill patient has features of sepsis, respiratory failure, or neutropenia, treatment with an IV macrolide is combined with an IV third-generation cephalosporin. An alternative regimen may include imipenem, meropenem, or piperacillin/tazobactam plus a macrolide plus vancomycin. A fulminant course should lead to consideration of Legionella, Mycoplasma, psittacosis, and Q fever as the cause of bacterial pneumonia.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. General Supportive Treatment:

1. Ventilation and oxygenation-An adequate airway must be maintained—if necessary, by tracheal suction, endotracheal tube, or tracheostomy. Oxygen must be supplied to any patient with severe pneumonia, cyanosis with Pao2 below 60, or marked dyspnea;

this will also help to prevent pulmonary edema. Oxygen may be supplied by nasal catheter, soft rubber mask, or oxygen tent. With masks, a 95% oxygen concentration can be maintained, whereas with nasal tubes or tents the concentration will reach only 40- 50%. However, masks are difficult to tolerate because of cough and expectoration. Oxygen must be humidified to prevent drying of secretions.

2. Management of shock and pulmonary edema-These are the most frequent causes of death in pneumonia. Oxygen administration tends to prevent pulmonary edema; impending right heart failure must be managed, and digitalization is urgent.

3. Management of toxic delirium-Toxic delirium occurs in any severe pneumonia and may be particularly difficult to manage in alcoholics. Delirium, anxiety, and restlessness during waking hours may be treated with diazepam, 5 mg, or chlordiazepoxide, 10 mg, or phenobarbital, 15-30 mg orally 4-6 times daily. Pentobarbital, 0.1 g, or flurazepam (Dalmane), 30 mg, at bedtime helps to ensure adequate rest. If sedatives or tranquilizers are given, it is helpful to check the patient’s sensorium frequently for any change suggestive of meningitis, which-requires a diagnostic lumbar puncture.

4. Fluids-Patients with pneumococcal pneumonia may perspire profusely and lose much fluid and salt. Sufficient fluid must be given to maintain a daily urinary output of at least 1500 mL. Electrolytes must be kept in balance.

5. Diet-Initially, the dyspneic patient is anorectic, and a liquid diet is preferred. With improvement, a normal diet will be tolerated. If complications suggest a long illness, a high-protein, high-calorie diet with vitamin supplementation is indicated.

6. Cough-If cough interferes with sleep and rest, it may be suppressed with codeine phosphate, 15-30 mg every 3-4 hours subcutaneously or orally;

or by elixir of terpin hydrate with codeine, 4 mL every 3—4 hours as necessary.

7. Pleuritic pain-For mild pain, spray ethyl chloride over the area of greatest pain for about 1 minute or inject a local anesthetic to anesthetize the involved dermatomes to provide temporary relief. Codeine phosphate, 15-30 mg, may be given as necessary for pain. For very severe pain, use meperidine, 50-100 mg subcutaneously, or morphine sulfate, 10-15 mg subcutaneously.

8. Abdominal distention-Abdominal disten- tion is usually due to air swallowing in severe dyspnea and is a frequent problem in patients with pneumonia. Neostigmine methylsulfate, 1:2000, 1 mL subcutane- ously, and insertion of a rectal tube will usually pro- duce rapid initial decompression. Gastric dilatation can be relieved by suction through a nasal tube passed into the stomach.

9. Congestive failure– (Distinguish from shock and pulmonary edema.) In elderly patients or patients with preexisting heart disease, congestive failure may be precipitated by pneumonia. Rapid digitalization is indicated.

10. Cardiac arrhythmias-Extrasy stoles usually require no treatment. If atrial fibrillation or flutter develops, rapid failure may be precipitated. Rapid digitalization is usually indicated in these cases.

Further Inpatient Care

• Hospitalization versus ambulatory care

·         

 

• The decision to hospitalize patients with community-acquired pneumonia is dictated by a series of well-recognized risk factors that increase either the risk of death or the risk of a complicated course for a patient with community-acquired pneumonia. Specific risk factors for mortality or a complicated course of pneumonia include the following:

o        

 

• Advanced age (>65 y)

• Comorbid illness or other findings – (1) COPD, including chronic suppurative diseases of the lung (eg, bronchiectasis, cystic fibrosis); (2) diabetes mellitus; (3) chronic renal failure; (4) congestive heart failure; (5) chronic liver disease of any etiology; (6) suspicion of aspiration; (7) postsplenectomy state; and (8) chronic alcohol abuse or malnutrition

• Certain physical findings may predict a poor outcome from community-acquired bacterial pneumonia. These physical findings include the following:

o        

 

• Respiratory rate in excess of 30 breaths per minute

• Diastolic blood pressure less than 60 mm Hg or systolic blood pressure less than 90 mm Hg

• Temperature higher than 38.3°C (101°F)

• Evidence of extrapulmonary sites of disease (eg, septic arthritis, meningitis)

• Confusion, decreased level of consciousness, or both

• The following series of laboratory findings predicts severe disease and, possibly, a complicated course of illness:

o        

 

• WBC count of fewer than 4000/μL or more than 30,000/μL, absolute neutrophil count of fewer than 1000/μL

• ABG determinations showing a PaO₂ of less than 60 mm Hg or PaCO₂ of greater than 50 mm Hg on room air

• Respiratory failure requiring mechanical ventilation

• Abnormal renal function as indicated by serum creatinine of greater than 1.2 mg/dL or blood nitrogen of greater than 20 mg/dL (>7 mmol/L)

• Chest radiographic findings for multilobar involvement, the presence of a cavity, rapid radiographic progression, and the presence of a pleural effusion

• Evidence of sepsis or organ dysfunction as manifested by a metabolic acidosis, an increased prothrombin time, increased partial thromboplastin time, or decreased platelets (a picture of disseminated intravascular coagulation).

• The decision to hospitalize also should take in to account social considerations, which include the absence of a responsible caregiver and or an unstable home situation.

• The Pneumonia Severity of Illness Scoring System (PSISS) was developed by Fine et al (Fine, 1997). This scoring system evaluates 20 different clinical and laboratory indices that are readily available. The PSISS is used to assist in deciding whether patients can be safely treated in an outpatient setting.

Table 8. Pneumonia-Specific Severity of Illness Scoring System for Patients With Community-Acquired Pneumonia

Patient Characteristics	Number of Points
Demographic factors
Age
Men	Age in years
Woman	Age in years minus 10
Nursing home resident	10
Coexisting Illnesses (definitions listed below)*
Neoplastic disease	30
Liver disease	20
Congestive heart failure	10
Cerebrovascular disease	10
Renal disease	10
Physical Examination Findings
Altered mental status	20
Respiratory rate >30 breaths per min	20
Systolic blood pressure <90 mm Hg	20
Temperature <35°C (95°F) or >40°C (104°F)	15
Pulse rate >125 breaths per min	10
Laboratory and Roentgenographic Findings
Arterial pH <7.35	30
Blood urea nitrogen >30 mg/dL (11 mmol/L)	20
Sodium <130 mmol/L	20
Glucose >250 mg/dL (14 mmol/L)	10
Hematocrit <30%	10
PaO2 <60 mm Hg	10
Pleural effusion	10

*Coexisting illnesses: The diagnosis of congestive heart failure is documented by history or by findings on physical examination, chest radiograph, echocardiogram, multiple-gated acquisition scan, or left ventriculogram. The clinical diagnosis of stroke or transient ischemic attack is documented by magnetic resonance imaging or CT scan findings. A history of chronic renal disease or abnormal blood urea nitrogen and creatinine concentrations should be documented in the medical record. Altered mental status is defined as disorientation to person, place, or time that is not known to be chronic or as stupor or coma.

• Hospitalization versus ambulatory care is determined by the total points calculated from the PSISS. Patients are categorized in to 5 risk classes, as follows:

o        

 

• Risk class I – Older than 50 years, no preexisting illness or vital sign abnormality

• Risk class II – Fewer than 70 points

• Risk class III – 71-90 points

• Risk class IV – 91-130 points

• Risk class V – More than 131 points

• Although further epidemiologic studies are required to make definite recommendations for hospital versus home care for patients with community-acquired pneumonia, preliminary data (Fine, 1997) indicate that patients in risk classes I and II can be treated at home with planned outpatient follow-up evaluations. Patients in risk class III should be observed in the emergency department before their disposition is decided. Patients in risk classes IV and V are ill and usually require admission to the hospital.

• Response to therapy

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• Having initiated a course of therapy based on empiric guidelines, carefully evaluating the patient’s response to therapy is essential. With appropriate antibiotic therapy, improvement in the clinical manifestations of pneumonia should be observed in 48-72 hours. Because of the time required for antibiotics to act, antibiotics should not be changed within the first 72 hours unless marked clinical deterioration occurs.

• With pneumococcal pneumonia, the cough usually resolves within 8 days and crackles heard on auscultation clear within 3 weeks. The timing of radiologic resolution of the pneumonia varies with patient age and the presence or absence of an underlying lung disease. The chest radiograph usually clears within 4 weeks in patients younger than 50 years without underlying pulmonary disease. In contrast, resolution may be delayed for 12 weeks or longer in older individuals and those with underlying lung disease.

• Patients who do not respond to treatment

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• A common concern is patients who do not improve despite antibiotic treatment. If patients do not improve within 72 hours, consider an organism that is not covered by the initial empiric antibiotic regimen. Lack of response also could be secondary to drug resistance, nonbacterial infection, unusual pathogens (eg, P carinii, M tuberculosis), drug fever, or a complication such as empyema or abscess formation. One must broaden the differential diagnosis to include noninfectious etiologies such as malignancies, inflammatory conditions, or congestive heart failure.

• When reevaluating a patient who is not responding, a careful history of travel and animal exposure should be obtained to rule out unusual pathogens. If this is unrevealing, then further diagnostic procedures may be required. Bronchoscopy helps evaluate the airway for obstruction due to a foreign body or malignancy. Infection with previously unsuspected pathogens such as P carinii or M tuberculosis often is diagnosed using bronchoscopy. During bronchoscopy, protected brushing and bronchioalveolar lavage specimens may be obtained for microbiologic examination and quantitative cultures. Transbronchial biopsy also may be helpful in some cases. Routine bacterial cultures have limited utility when obtained from bronchoscopy after antibiotics have already been administered.

• A retrospective study evaluated the use of fiberoptic bronchoscopy ionresolving pneumonia. A specific diagnosis that could account for the prolonged course was found in 12 of 14 patients. The etiologies included Pneumocystis,mycobacteria, cytomegalovirus, and actinomycosis and noninfectious entities such as bronchioalveolar carcinoma, adenocarcinoma, and eosinophilic pneumonia. A second prospective study found the diagnostic sensitivity of video bronchoscopy after the initiation of antibiotics to be 41%.

• In addition to bronchoscopy, further imaging studies, such as CT scan of the thorax, may be helpful. Finally, open or thoracoscopic lung biopsy may need to be performed if all other procedures do not aid in diagnosis and the patient continues to be ill. Thoracoscopic lung biopsy is associated with less morbidity compared to the open lung biopsy.

• Other inpatient care

·         

 

• Antibiotic therapy should be reevaluated based on laboratory data and clinical response.

• Adequate respiratory support (eg, low-flow oxygen, assisted ventilation) is provided as dictated by the patient’s clinical situation.

• Bronchial hygiene includes suctioning of secretions, chest physiotherapy, and positioning to encourage dependent drainage. These are used to optimize the elimination of purulent sputum and to avoid atelectasis.

• General supportive measures include proper hydration, nutrition, and patient ambulation.

Further Outpatient Care

• When treated in an outpatient setting, arranging adequate follow-up evaluations for the patient is mandatory. Patients also should be instructed to return if their condition deteriorates.

• Patients should have a follow-up chest radiograph in approximately 6 weeks to ensure resolution of consolidation.

• Chest radiograph findings indicating nonresolution of symptoms should raise the consideration of an endobronchial obstruction as a cause of postobstructive pneumonia. A CT scan may be of benefit in these cases.

Deterrence/Prevention

• Prevention of community-acquired pneumonia

·         

 

• Influenza vaccination for elderly individuals results in a reduction of the rate of hospitalization for pneumonia and influenza by 48-57%.

• S pneumoniae is the most common cause of pneumonia overall and fatal pneumonia. The incidence of pneumococcal disease is the highest in children younger than 2 years and in adults older than 65 years. Other important risk factors are chronic heart disease, chronic lung disease, cigarette smoking, and asplenia. A 23-valent capsular polysaccharide vaccine and a heptavalent protein-polysaccharide conjugate vaccine are currently available. Both vaccines are efficacious in prevention of invasive pneumococcal disease. The role of the pneumococcal vaccine has not been defined as clearly as that of the influenza vaccine in adults. However, the advisory committee on immunization practice recommends pneumococcal vaccination for persons older than 65 years and for younger patients with chronic illnesses.

• Prevention of nosocomial pneumonia

·         

 

• A number of preventative strategies have been applied. Some of these probably are effective or promising, and some are currently being evaluated.

• The efficacious regimens are hand washing and isolation of patients with multiple resistant respiratory tract pathogens. Hand washing between patient contacts is a basic and often neglected behavior by medical personnel.

• Interventions that should be considered or undertaken include nutritional support, attention to the size and nature of the GI reservoir of microorganisms, careful handling of ventilator tubing and associated equipment, subglottic secretion drainage, and lateral-rotation bed therapy.

• The regimens of unproven value in preventing nosocomial pneumonia, although used on limited investigational bases, are selective digestive decontamination with a regimen of topical and systemic antibiotic prophylaxis. Selective digestive contamination has been studied for many years with a goal of eliminating all potential pathogens from the GI tract. Incidence of nosocomial pneumonia is not always reduced; therefore, efficacy of these regimens has been questioned. Also, mortality reduction often is not observed.

• Some experimental regimens are undergoing clinical evaluation. These are monoclonal antibodies to specific bacterial antigens and reduction of endogenous sources of bacterial infection by mechanical means. The development of new biomaterials for endotracheal tubes is one such therapy, leading to the eradication of a reservoir of a large number of bacteria in the airway.

• Smoking cessation

Complications

• Destruction of lung tissue from infection (leading to bronchiectasis)

• Necrotizing pneumonia

• Empyema

• Pulmonary abscess

• Respiratory failure

• Acute respiratory distress syndrome

• Ventilator dependence

• Superinfection with gram-negative organisms

• Death

Prognosis

• Generally, prognosis is good in otherwise healthy patients with uncomplicated pneumonia.

• Advanced age, aggressive organisms (eg, Klebsiella, Legionella, resistant S pneumoniae), comorbidity, respiratory failure, neutropenia, and features of sepsis, alone or in combination, increase morbidity and mortality.

Patient Education

• For excellent patient education resources, visit eMedicine’s Pneumonia Center and Procedures Center. Also, see eMedicine’s patient education articles Bacterial Pneumonia and Bronchoscopy.

 

Medical/Legal Pitfalls

• The guidelines for empiric management of community-acquired bacterial pneumonia are formed with the intent of following evidence-based recommendations, but the recommendations of these guidelines are not based on a firm scientific foundation. Future studies should focus on the following issues:

·         

 

• Duration of therapy

• Duration of therapy related to severity of initial illness

• Appropriate time to switch hospitalized patients from parenteral therapy to oral therapy

• Pathogens responsible for pneumonia wheo organism is identified with extensive diagnostic testing

• In the future, a number of unresolved questions about nosocomial pneumonia need to be examined. These should focus on the diagnosis of nosocomial pneumonia, determinants of specific pathogens, duration of therapy, and timing of switch to oral therapy. Ultimately, prevention of nosocomial pneumonia is the most effective way to avoid disease associated with mortality.

• In patients who are elderly or debilitated, if bacteremia is present with pneumococcus, the mortality rate remains approximately 40% even if treated.

• Empiric therapy for hospitalized patients initially should be broad and cover the likely causative organisms.

• Always consider the possibility of Legionella when evaluating community-acquired pneumonia because delayed treatment increases mortality significantly.

• Remember that the most prevalent causative organism is pneumococcus, regardless of the host; empiric therapy must be selected with this consideration in mind.

Special Concerns

• Relative adrenal insufficiency occurs in a high proportion of patients with severe CAP. Median cortisol levels were 15.5 mcg/dL; 65% met the criteria for adrenal insufficiency, 75% had cortisol levels below 25 mcg/dL and 47.5% had cortisol levels below 15 mcg/dL. These finding highlight the importance of measuring cortisol levels and may help explain the potential benefits of hydrocortisone infusion in these patients.

 

OTHER BACTERIAL PNEUMONIAS

Primary bacterial pneumonias caused by single bacterial species other than the pneumococcus may account for up to 25% of community-acquired and 80% of hospital-acquired pneumonias. All of these pneumonias may have somewhat similar physical find- ings and x-ray evidence of pulmonary infiltration or •consolidation. For proper treatment, it is crucial to identify the causative agent by blood culture and by sputum examination with stained smear and culture. Transtracheal aspiration, fiberoptic bronchoscopy, or even lung biopsy may be needed for specific diagnosis and treatment.

Streptococcal Pneumonia

Pneumonia due to hemolytic streptococci occurs usually as a sequela to viral infection of the respiratory tract, especially influenza or measles, or in persons with underlying pulmonary disease. The patients are usually in a severely toxic condition and cyanotic. Pleural effusion develops frequently and early and progresses to empyema in one-third of untreated pa- tients. The diagnosis rests on finding large numbers of streptococci in smears of sputum and culturing hemolytic streptococci from blood and sputum.

The treatment of choice is with penicillin G in a dosage similar to that for pneumococcal pneumonia (see above). If treatment is started early, the prognosis is good.

Staphylococcal Pneumonia (picture 2)

Pneumonia caused by Staphylococcus aureus occurs as a sequela to viral infections of the respiratory tract (eg, influenza) and in debilitated (eg, postsurgical) patients or hospitalized infants, especially after antimicrobial drug administration. There is often a history of a mild illness with headache, cough, and generalized aches that abruptly changes to a very se- vere illness with high fever, chills, and exaggerated cough with purulent or blood-streaked sputum and deep cyanosis. There may be early signs of pleural effusion, empyema, or tension pneumothorax. X-ray examination reveals lung consolidation, pneumatoceles, abscesses, empyema, and pneumothorax. The demonstration of pyopneumothorax and of cavities with air-fluid levels by x-ray is highly suggestive of Staphylococcal pneumonia. The diagnosis must be confirmed by stained smear of sputum (masses of white cells and gram-positive cocci, many intra- cellular) and culture (predominantly S aureus), and

also by means of cultures of pleural fluid and blood. The white count is usually more than 20,000//zL.

Initial therapy (based on sputum smear) consists of nafcillin, 6-12 g/d, or vancomycin, 2 g/d, given intravenously in divided doses as a bolus. If the staphylococcus proves to be penicillin-sensitive by laboratory test, penicillin G, 20-60 million units/d intravenously, is the antibiotic of choice. Drugs should be continued for several weeks. If empyema develops, drainage must be established. The prognosis varies with the underlying condition of the patient and the drug susceptibility of the organism.

 

 

Picture 2. The patchy infiltrates bilaterally with the right greater than the left containing air bronchograms are characteristic of a bilateral pneumonic process which extends into the alveolar spaces.

 

Legionella Pneumonia

The eponym legionnaires’ disease has been given to a serious pneumonia that afflicted people attending the American Legion Convention in Philadelphia in 1976. Other outbreaks have been diagnosed ret- rospectively at least since 1965, and sporadic infec- tions have occurred at least since 1947 in many places.

Legionella pneumophila is a poorly staining gram-negative bacterium that grows slowly on special media (eg, charcoal-yeast extract) at 35 °C. There are at least 8 species of Legionella, some with multiple serotypes. These organisms can be recovered in human disease from sputum, bronchial washings, pleural fluid, lung biopsies, or blood. Legionella species occur in the environment and are acquired by humans from aerosols, dust from air-conditioning systems, water, or soil. The infection is not usually communi- cable from patient to contacts. Asymptomatic infec- tion is common at all ages, whereas symptomatic infection is most often an opportunistic pneumonia in immunocompromised individuals.

Asymptomatic infection is evident only by a rise in specific antibodies. Symptomatic infection is ob- served mainly in elderly persons, smokers, and pa- tients undergoing hemodialysis or renal transplant.

The incubation period is estimated to be 2-10 days. Initial symptoms are malaise, diffuse myalgias, and headache, followed in 12-48hours by high, non- remittent fever and chills. Nausea, vomiting, and diarrhea are frequent early in the illness. On the third day a dry cough begins that is nonproductive or produces scanty mucoid, sometimes blood-streaked sputum. Dyspnea and hypoxia become marked as signs of consolidation develop. Pleuritic chest pain occurs in one-third of patients. Severe confusion or delirium may occur.

There is leukocytosis with a shift to the left, hyponatremia, abnormal liver function tests, and, occasionally, microscopic hematuria. Chest x-rays reveal patchy, often multilobar pulmonary con- solidation, and, occasionally, small pleural effusions. The illness usually worsens for 4-7 days before im- provement begins in those who recover. During severe outbreaks, the mortality rate has been 10% in those with manifest disease. Death is attributed to respi- ratory or renal failure or shock, with disseminated intravascular coagulation.

The diagnosis is based on a clinical picture com- patible with the specific features of the disease and on negative results of bacteriologic laboratory tests for other pneumonias. The organism can be identified by immunofluorescence in cultures, lung biopsy, and, rarely, sputum specimens. A retrospective diagnosis is based on a significant rise in specific serum antibodies detected by immunofluorescence.

The treatment of choice is erythromycin, 0.5-1 g every 6 hours intravenously or orally for 2-3 weeks. This usually results in improvement in 2-3 days. Rifampin, 10-20 mg/kg/d, has been suggested for patients who fail to respond to erythromycin. Assisted ventilation and management of shock are essential.

 

Pneumocystis carinii Pneumonia

This parasitic infection occurs in debilitated children or immunodeficient adults. It has been a prominent opportunistic infection in AIDS patients. The diagnosis is made by lung biopsy and the demonstration of typical cysts of P carinii in impression smears of lung tissue stained with methena- mine-silver. Early treatment with sulfamethoxazole- trimethoprim can cure the pneumonia. The same drug has been effective in prophylaxis during immunosuppression. An alternative, more toxic drug is pentamidine isethionate (available through the Centers for Disease Control, Atlanta, GA 30333).

 

“MIXED” BACTERIAL PNEUMONIAS (Hypostatic Pneumonia, “Terminal” Pneumonia, Bronchopneumonia)

Essentials of Diagnosis

• Variable onset of fever, cough, dyspnea, expectoration.

• Symptoms and signs often masked by primary (debilitating) disease.

• Greenish-yellow sputum (purulent) with mixed flora.

• Leukocytosis (often absent in aged and debilitated patients).

• Patchy infiltration on chest x-ray.

General Considerations

Mixed bacterial pneumonias include those in which culture and smear reveal several organisms, not one of which can clearly be identified as the causative agent. These pneumonias usually appear as complica- tions of anesthesia, surgery, aspiration, trauma, or various chronic illnesses (cardiac failure, advanced carcinoma, uremia). They are common complications of chronic pulmonary diseases such as bronchiectasis and emphysema. Old people are most commonly affected (“terminal” pneumonia). Patients treated with intermittent positive pressure breathing apparatus or immunosuppressive drugs may develop pneumonia caused by gram-negative rods.

The following findings in a debilitated, chroni- cally ill, or aged person suggest a complicating pneumonia: (1) worsening of cough, dyspnea, cyanosis; (2) low-grade, irregular fever; (3) purulent sputum; and (4) patchy basal densities on a chest film (in addition to previously noted densities caused by a primary underlying disease, if any), sometimes with local necrosis and cavitation.

Clinical Findings

A. Symptoms and Signs: The onset is usually insidious, with low-grade fever, cough, expectoration, and dyspnea that may become marked and lead to cyanosis. Physical findings are extremely variable and may not be impressive against a background of cardiac or pulmonary disease. The signs listed under Other Bacterial Pneumonias may also be present.

B. Laboratory Findings: The appearance of a greenish or yellowish (purulent) sputum should suggest a complicating pneumonia. Smears and cul- tures reveal a mixed flora, often including anaerobes. Predominant types should be noted. Leukocytosis is often absent in the aged and debilitated patient present- ing with a mixed infection.

C. X-Ray Findings: X-ray (Picture 3) shows patchy, irregular infiltrations, most commonly posterior and basal (in bedridden patients). Abscess formation may be observed. Careful interpretation will avoid confusion with shadows due to preexisting heart or lung disease.

 

Picture 3. Hypostatic pneumonia

 

Differential Diagnosis

Mixed bacterial pneumonias must be differ- entiated from tuberculosis, carcinoma, and other spe- cific mycotic, bacterial, and viral pulmonary infec- tions (to which they may be secondary).

Treatment

Clear the airway and correct hypoxia. Unless a probably significant etiologic agent can be identified, give one of the new cephalosporins (eg, cefotaxime, 12 g/d intravenously) as initial therapy. This will be modified according to clinical and laboratory results.

Prognosis

The prognosis depends upon the nature and sever- ity of the underlying pulmonary disease and varies with the predominating organism.

 

ASPIRATION PNEUMONIA

Aspiration pneumonia is an especially severe type of pneumonia, often with a high mortality rate. It results from the aspiration of gastric contents in addition to aspiration of upper respiratory flora in secretions. Important predisposing factors include impairment of the swallowing mechanism (eg, esopha- geal disease), inadequate cough reflex (eg, anesthesia, postoperative state, central nervous system disease, drug abuse), and impaired gastric emptying (eg, pyloric obstruction). Pulmonary injury is due in large part to the low pH (< 2.5) of gastric secretions.

Scattered areas of pulmonary edema and bron- chospasm occur, and the x-ray appearance (pictures 4-5) may be confused with that of pulmonary emboli, atelectasis, bronchopneumonia, and congestive heart failure.

 

Removal of aspirated material by catheter suction or bronchoscopy may be attempted, but this usually fails to remove all aspirate completely. Corticosteroids (eg, prednisone, 100 mg orally on the first or second day) may reduce the intensity of the inflammatory reaction to acidic gastric secretion, but the value of corticosteroids in the treatment of aspiration pneumo- nia is not proved, and they increase the risk of superinfection. Some aspiration pneumonias have no bacterial component, but in many others a mixed bacterial flora is involved. Antimicrobial drugs directed against the latter (eg, penicillin G plus an aminoglycoside or the best available cephalosporin) are sometimes adminis- tered without waiting for evidence of progressive pul- monary infection. In doing so, however, there is a risk of favoring the development of resistant mi- croorganisms. Therefore, administration of antimi- crobials should not continue without laboratory and clinical evidence of microbial infection. Assisted ventilation and supplementary oxygen are beneficial.

Picture 4. Abscess is forming after aspiration

 

 

Picture 5. Right sided aspiration pneumonia

 

Infection in the immunocompromised host

Viral Pneumonias

Viruses are a common cause of serious infections of the lower respiratory tract among immunocompromised patients. Pathogens most commonly implicated are the herpesviruses–herpes simplex, varicella-zoster, and cytomegalovirus. These viruses belong to the family Herpesviridae, which consists of large, enveloped, double-stranded DNA viruses.

Herpesviruses vary widely in their ability to infect different types of cells. Further, they share the common ability to establish lifelong latent infection. This latter aspect is of particular concern for seropositive immunosuppressed persons, whose immune systems may be unable to contain the virus in its latent form.

Other viruses that cause significant lower respiratory tract disease in immunocompromised patients include adenoviruses and measles virus.

Epidemiologic, etiologic, and clinical characteristics   
Immunocompromised patients are at particular risk for virus pneumonia. These include patients who are receiving cancer chemotherapy, those who are neutropenic, those infected with HIV, burn victims, those with congenital cell-mediated immunodeficiency, and those who are severely debilitated or malnourished as a result of prolonged hospitalization. Although the lung is often involved in disseminated HSV infection, disseminated disease seldom occurs among those with mucocutaneous HSV infections. Visceral dissemination develops in fewer than 10% of virus -seropositive transplant recipients with infection.

HSV pneumonia develops by two principal mechanisms. First, the presence of focal or multifocal infiltrates correlates with antecedent upper airway infection with virus. This pattern is most likely due to direct extension of viral infection from the upper to the lower respiratory tract, aspiration of infectious secretions, or reactivation of dormant HSV in vagal ganglia. Tracheitis or esophagitis and oral mucocutaneous lesions often precede development of pulmonary disease. Second, diffuse interstitial infiltrates may develop following viremia secondary to dissemination of HSV from genital or oral lesions or transfusion of HSV-infected blood. Early dissemination also may be reflected by other organ dysfunction, such as elevated liver enzyme levels.

The spectrum of respiratory diseases due to HSV infection ranges from oropharyngitis to membranous tracheobronchitis and diffuse or localized pneumonia. Usually the trachea and large bronchi are involved in creating a thick inflammatory membrane that can ultimately cause significant resistance to ventilation. Community-acquired pneumonia caused by HSV is uncommon, occurring usually only after a prolonged and complicated hospital stay.

Dyspnea and cough are the most common symptoms of HSV pneumonia. Fever, tachypnea, intractable wheezing, chest pain, and hemoptysis also occur. Cutaneous, genital, or oral lesions may herald pulmonary or disseminated disease.

Focal lesions on chest film begin as small nodules that are best seen in the periphery, away from normal vascular markings. As the disease progresses, the nodules may coalesce to form extensive infiltrates. HSV pneumonia may initially present as a focal or segmental pneumonia that has spread from upper airway lesions. However, it can ultimately extend to other areas of the lung, producing diffuse infiltrates similar to the pattern seen with viremic HSV infection.

Diagnosis
The diagnosis of virus pneumonia should be based on clinical suspicion, radiographic findings (picture 6), isolation of HSV from the lungs, and histologic findings of a necrotizing or hemorrhagic pneumonia. Since virus can be isolated from oropharyngeal secretions in 2% to 25% of normal hosts, positive sputum cultures are often difficult to interpret. The use of tracheal aspirates to bypass the upper respiratory tract can yield samples with significantly improved specificity. Bronchoscopy is especially useful for direct sampling of bronchial mucosal lesions and for obtaining bronchial brushings, washings, and biopsy specimens for histologic and cytologic examination. Scrapings from the base of ulcerated lesions can be examined with Wright or Giemsa stain for multinucleated giant cells and intranuclear inclusions. Specimens also can be examined by immunofluorescent staining with polyclonal- or monoclonal-specific antibodies or by electron microscopy. Appropriate viral cultures of mucosal lesions, blood, and respiratory secretions should always be obtained in cases of suspected herpetic pneumonia. Serologic assays are of little diagnostic use.

Picture 6 A-normal chest X –ray; B-right sided viral pneumonia

Treatment
Acyclovir (Zovirax), after it is metabolized to acyclovir triphosphate, inhibits viral DNA synthesis by competitively binding to viral DNA polymerase. Since oral acyclovir is poorly absorbed, intravenous acyclovir at a dosage of 250 mg/m² every 8 hours is currently the treatment of choice for HSV pneumonia (table 2). Adverse reactions are infrequent, but patients should be well hydrated to prevent renal impairment secondary to precipitation of acyclovir in the tubules, which occurs in 5% to 10% of patients. The dosage of acyclovir must be decreased in patients with underlying renal insufficiency.

Table 2. Treatment of severe viral infections of the lower respiratory tract
Virus	Therapy
Herpes simplex	Acyclovir (Zovirax)
Varicella-zoster	Acyclovir, VZIG
Cytomegalovirus	Ganciclovir (Cytovene), IVIG, foscarnet sodium (Foscavir)
Adenovirus	Supportive care, ribavirin (Virazole)*
Measles	Supportive care, IVIG, ribavirin*
IVIG, intravenous immunoglobulin; VZIG, varicella-zoster immune globulin. *Currently not considered standard care or still under investigation.

More than half of all cases of viral pneumonia are complicated by other infections. Empirical broad-spectrum antibiotic therapy that includes an antistaphylococcal drug should be instituted in patients with progressive virus pneumonia that does not respond to antiviral therapy. If deterioration continues despite the addition of antibiotics, a definitive diagnostic procedure such as bronchoscopy or open lung biopsy should be pursued to search for other opportunistic organisms, such as Aspergillus, Candida,and Pneumocystis carinii.

The role of adjunctive corticosteroids is still controversial. These agents should not be considered as standard care, especially in an already immunocompromised host. Ventilatory support is often required for severe hypoxemia. Fluid management is of special concern because fulminant pneumonia is often associated with pulmonary edema and alveolar hemorrhage.

Preventive efforts should be directed toward chemoprophylaxis of high-risk seropositive patients during induction of immunosuppression for transplantation. Passive or active immunization has not been proved to be helpful.

Summary

Three herpesviruses (herpes simplex, varicella-zoster, and cytomegalovirus) commonly cause respiratory tract infections in immunocompromised patients. Adenoviruses and measles virus are also significant causes of respiratory disease in this population.

Diagnosis of herpesvirus infections is difficult because these viruses can establish latency and are often shed intermittently in the absence of invasive disease. A positive respiratory tract culture of herpesviruses alone is not diagnostic of active invasive disease. Preventive measures should focus on limiting the patient’s exposure to active infection, broad use of available vaccines in children and susceptible adults, and use of hyperimmune globulin and chemoprophylaxis in high-risk patients.

Adenovirus pneumonia is diagnosed by viral culture and rapid antigen detection assays, whereas measles pneumonia is often identifiable by the characteristic rash. Treatment of either adenovirus or measles pneumonia is primarily supportive.

 

SYSTEMIC FUNGAL DISEASES

(Systemic Mycoses)

General Diagnostic Principles

Several considerations are important in the diagnosis of the deep mycoses.

1. Many of the causative fungi are “opportunists,” not usually pathogenic un­less they enter a compromised host. Opportunistic fungus infec­tions are particularly apt to occur and should be anticipated in patients after ionizing (x-) irradiation and during therapy with corticosteroids, immunosuppressives, or antimetabolites; they also tend to occur in patients with azotemia, diabe­tes mellitus, bronchiectasis, emphysema, TB, Hodgkin’s disease or other lymphoma, leukemia, or burns. Candidosis, aspergillosis, phycomycosis, nocardiosis, and cryptococcosis are typical opportunistic infections.

2. Fungal diseases occurring as primary infections may have a typical geo­graphic distribution. For example, in the USA, cocddioidomycosis is virtually confined to the southwest, while histoplasmosis occurs in the East and Midwest. especially in the Ohio and Mississippi River valleys. Blastomycosis is restricted to North America and Africa; paracoccidioidomycosis, often called South American blastomycosis, is confined to that continent. However, travelers can develop a symptomatic infection some time after returning from such endemic areas.

3. The major clinical characteristic of virtually every deep mycosis is its chronic course. Septicemia or an acute pneumonia is rare. Lung lesions develop slowly. Months or years may elapse before medical attention is sought or a diagnosis is

made.

4. Symptoms are rarely intense; fever, chills, night sweats, anorexia, weight loss, malaise, and depression may all be present.

5. When a fungus disseminates from a primary focus in the lung, the manifes­tations may be characteristic. Thus, cryptococcosis usually appears as meningitis, progressive disseminated histoplasmosis as hepatic disease, and blastomycosis as a skin lesion.

6. Delayed cutaneous hypersensitivity tests and serologic tests are available for only 3 or 4 of the infections discussed in this chapter. Even in these, the tests become positive either so late (e.g., cocddioidomycosis) or so infrequently (e.g., blastomycosis) that they are of no diagnostic value for the acutely ill patient.

7. The diagnosis is usually confirmed by isolation of the causative fungus from sputum, bone marrow, urine, blood, or CSF, or from lymph node, liver, or lung biopsy. When the fungus is a commensal of man or is prevalent in his environment (e.g., Candida, Aspergjilus), it is difficult to interpret its isolation from such specimens as sputum, and confirmatory evidence of tissue invasion is necessary to attribute an etiologic role to it

8. In contrast to viral and bacterial diseases, fungal infections can be diagnosed histopathologically with a high degree of reliability. It is the distinctive fungal morphology, not the tissue reaction to the fungus, that permits specific etiologic

identification.

9. Even when the microorganism has been demonstrated histopathologically m tissues, the activity of the disease must be established before treatment is begun. Culture of the causative microorganism or such clinical and laboratory findings as fever, leukocytosis, elevated ESR, abnormal liver function, worsening of chest film findings, or elevated serum globulins are helpful as indications for therapy.

General Therapeutic Principles

General medical care, surgery, and chemotherapy constitute modes of treat­ment for systemic fungus infections. Ketoconazole, a new antifungal imidazole derivative, appears to have major advantages: oral dosage, broad antifungal ac­tivity, and minimal adverse effects; but testosterone synthesis may be blocked, usually transiently, and serious idiosyncratic hepatotoxidty may occur. Current usage is 200 to 400 mg orally once a day with a meal. It may be given for pro­longed periods to establish and maintain clinical remission or to prevent reinfection. Because amphotericin B is used in many systemic mycoses. it is covered in detail here. Indications and directions for other therapeutic measures are given below in the discussions of specific mycoses.

Amphoteridn B, a fungicidal and fungistatic antibiotic, has reversed the progno­sis of many fungal infections. An initial IV dose of 0.1 mg/kg/day is increased by 0.05 to 0.10 mg/kg every day until 1.0 mg/kg (but not exceeding 50 mg/dose) is given daily or every other day. The antibiotic is dissolved in 5% D/W (optimal concentration, 0.1 mg/ml). (CAUTION: Saline solution precipitates the drug and should not be used. Follow the manufacturer’s instructions in preparing and storing solutions.)

The drug should be given over a 2- to 6-h period. Reactions are usually mild, but some patients may experience chills, fever, headache, anorexia, nausea, and, occasionally, vomiting, particularly with the initial injections. The severity of re­actions may be reduced by giving aspirin or an antihistamine (e.g., diphenhydramine 50 mg) before, after 3 h, and at the end of treatment. If this therapy is ineffective, hydrocortisone 25 to 50 mg IV may be given at the beginning of the amphotericin B infusion.

Chemical thrombophlebitis may occur; adding heparin to the infusion (or into the tubing just prior to starting the injection) may lessen the incidence.

The BUN or serum creatinine should be determined before and periodically during treatment. A slight increase can be ignored. A moderate rise may be re­versed by giving the drug on alternate days, but if not, treatment should be dis­continued until the levels approach normal. If this requires only a few days, treatment can be resumed with the previous dose, but if a longer period is neces­sary, therapy should be restarted with a smaller dose. Serum potassium should be determined regularly, since hypokalemia is common and occasionally is dramatic and dangerous. Oral liquid supplements are usually sufficient; rarely, potassium IV (not added to the amphotericin B infusion) may be necessary Intrathecal injection may be indicated in meningitis, but great care must be taken to ensure proper dose and volume: 50 mg of amphotericin B should be painstaikingly dissolved in 10 ml of sterile water. The total volume should then be diluted in a 250-ml bottle of 5% D/W from which 10 ml has been removed. From 0.5 ml (0.1 mg) to 5.0 ml (1.0 mg) should then be drawn into a 10-ml syringe, further diluted to 10 ml with CSF, and injected slowly (over at least 2 min). A lumbar, cisternal, or ventricular site may be used.

HISTOPLASMOSIS

An infectious disease caused by Histoplasma capsulatum, characterized by a pri­mary pulmonary lesion and occasional hematogenous dissemination, with ulcerations of the oropharynx and GI tract, hepatomegaly, splenomegaly, lymphadenopalhy, and adrenal necrosis.

Etiology and Incidence

H. capsulatum in tissue is an oval budding cell 1 to 5 ft in diameter. Infection follows inhalation of dust that contains the spores. Severe disease is more fre­quent in men.

Chest x-ray (picture 7-8) surveys in certain geographic areas have demonstrated many resi­dents with symptomless, nontuberculous, occasionally calcified pulmonary le­sions; delayed cutaneous hypersensitivity reactions to histoplasmin suggest widespread but subclinical infection. The highest incidence of such hypersensitiv­ity is in the Ohio and Mississippi River valleys.

Symptoms and Signs

There are 3 recognized forms of the disease. The primary acute form causes symptoms (fever, cough, malaise) indistinguishable in endemic areas (except by culture) from otherwise undifferentiated URI or grippe-like disease. The progres­sive disseminated form follows hematogenous spread from the lungs and is charac­terized by hepatomegaly, lymphadenopathy, splenomegaly, and, less frequently, oral or GI ulceration. Addison’s disease is an uncommon but serious manifestation. The lesions in the liver are granulomatous, show the intracellular fungus, and may lead to hepatic calcification. Addison’s disease of other etiology, lymphoma, Hodgkin’s disease, leukemia, and sarcoidosis must be differentiated. The chronic cavitary form produces pulmonary lesions indistinguishable, except by cul­ture, from cavitary TB. The principal manifestations are cough, increasing dyspnea, and eventually disabling respiratory embarrassment. That histoplasmosis is a cause of uveitis has been postulated but not proved.

 

Picture 7  Histoplasmosis of the lungs. Both sides’ infiltrations.

Picture 8 CT scan of histoplasmosis of the lungs

Diagnosis

Demonstration of H. capsulatum by culture is diagnostic. Specimens for culture may be obtained from sputum, lymph nodes, bone marrow, liver biopsy, blood, urine, or oral ulcerations. Tissues may also be examined microscopically after staining (Goroori’s methenamine silver, periodic add-Schiff, or Gridley) picturtes 9-10, Delayed cutaneous hypersensitivity and CF tests are of no diagnostic value, since they are usually negative early in the disease.

Picture 9 This is a bone marrow smear from a patient with disseminated histoplasmosis showing intracellular organisms in bone marrow macrophages

Picture 10 (Oil immersion) Intracellular pseudo-encapsulated pathogen

 

Prognosis and Treatment

The acute primary form is usually benign; it is fatal only in those rare cases with massive infection. The progressive disseminated form has a high mortality. In the chronic cavitary form, death results from severe respiratory insufficiency.

Primary acute disease rarely requires chemotherapy (see amphotericin B and also ketoconazole in General Therapeutic Principles, above). The disseminated form responds to amphotericin B; in the chronic cavitary form, the fungi disap­pear with therapy, but fibrotic lesions show little change.

 

COCCIDIOIDOMYCOSIS

(San Joaquin or Valley Fever)

An infectious disease caused by the fungus Coccidioides immitis, occurring in a primary form as an acute, benign, self-limiting respiratory disease, or in a progressive form as a chronic, often fatal, infection of the skin, lymph glands, spleen, liver, bones. kidneys, meninges, and brain.

Etiology, Incidence, and Pathology

The disease is endemic in the southwestern USA and occurs most frequently in men aged 25 to 55. Infection is acquired by inhalation of spore-laden dust. Indi­viduals contracting the disease while traveling through endemic areas may not develop manifestations until later, after leaving the area.

The basic pathologic change is an acute, subacute, or chronic granulomatous process with varying degrees of fibrosis. Lesions may show central necrosis; the organisms are surrounded by lymphoctyes and by plasma, epithelioid, and giant cells. Cavitation or granuloma (“coin lesion”) formation may occur in chronic lung infection.

Symptoms and Signs

Primary pulmonary coccidioidomycosis, the more common form, may occur asymptomaucally, as a mild URI, as acute bronchitis, occasionally with pleural effusion, or as pneumonia. Symptoms, in descending order of frequency, include fever, cough, chest pain, chills, sputum production, sore throat, and hemoptysis. Physical signs may be absent, or occasional scattered rales and areas of dullness to percussion may be present. Leukocytosis is present and the eosinophil count may be high. Some patients develop “desert rheumatism,” a more recognizable form with conjunctivitis, arthritis, and erythema nodosum.

Progressive coccidioidomycosis develops from the primary form; evidence of dissemination may appear a few weeks, months, or, occasionally, years after pri­mary infection or long residence in an endemic area. Symptoms include continuous low-grade fever, severe anorexia, and loss of weight and strength. Progressive cyanosis, dyspnea, and mucopurulent or bloody sputum are present in the pulmo­nary type. The bones, joints, skin, viscera, brain, and meninges may be involved as the disease spreads.

Diagnosis

Coccidioidomycosis should be suspected in a patient with an obscure illness who has been or is in an endemic area. Diagnosis is established by finding the characteristic spherules of C. immitis in sputum, gastric washings, pleural fluid, CSF, pus from abscesses, biopsy specimens, or exudate from skin lesions by direct examination or culture. In the tissues, the fungus appears as thick-walled, non-budding spherules 20 to 80 fi in diameter.

A delayed cutaneous hypersensitivity reaction to coccidioidin or spherulin usu­ally appears 10 to 21 days after infection, but is characteristically absent in pro­gressive disease. Precipitating and CF antibodies are present regularly and persistently in the progressive form but only transiently in acute primary cases. X ray findings are on figures 1-2.

Prognosis and Treatment

For primary pulmonary Coccidioidomycosis, treatment is not needed and the outlook is excellent. The progressive type, however, is fatal in 55 to 60% of cases. Amphotericin B (see amphotericin B and also ketoconazole in General Therapeu­tic Principles, above) is indicated in all patients with the progressive form. Results are less satisfactory than in blastomycosis or histoplasmosis. Meningitis requires prolonged intrathecal administration, usually for years. Untreated meningitis is fatal.

 

SYSTEMIC CANDIDOSIS

(Candidiasis; Moniliasis)

 

Etiology and Incidence

The infections are usually caused by C. albicans. Superficial candidosis is uni­versal, but patients with leukemia, or with organ transplants, or receiving immunosuppressive or antibacterial therapy are especially prone to C. spp. septicemia. C. spp. (frequently C. parapsilosis) endocarditis is related to intravascular trauma such as cardiac catheterization, surgery, or indwelling venous catheters.

Symptoms and Signs

C. spp. endocarditis resembles bacterial disease, with fever, heart murmur, splenomegaly, and anemia; large vegetations and emboli to major vessels are fre­quently present and are differential features. Renal involvement is usually found on laboratory and autopsy examination. C. spp. septicemia usually resembles gram-negative bacterial sepsis in frequency of fever, shock, azotemia, oliguria, renal shutdown, and fulminant course. C. spp. meningitis is chronic, like crypto-coccal meningitis, but lacks the latter” s usually fatal outcome when untreated. C. spp. pyelonephritis and pulmonary disease are less well characterized. Osteomyelitis is rarely encountered; it resembles that due to other microorganisms.

Diagnosis

Because C. spp. are commensals of man, their culture from sputum, mouth, vagina, urine, stool, or skin must be interpreted cautiously. To confirm the diag­nosis, the culture must be complemented by a characteristic clinical lesion, exclu­sion of other etiology, and histologic evidence of tissue invasion. Isolation from blood or CSF, however, establishes the presence of C. spp. infection and supports the appropriate clinical impression: septicemia, endocarditis, or meningitis.

Treatment

Such predisposing conditions as diabetic acidosis must first be controlled. In systemic candidosis, amphoteridn B IV is preferable therapy. As an alternative, flucytosine may be given as for cryptococcosis (see above) if the isolate is sensitive to it. Ketoconazole appears promising in investigational studies in this disorder.

 

ASPERGILLOSIS

Etiology, Symptoms, and Signs

The fungus, an “opportunist,” appears after antibacterial or antifungal therapy (to which it is usually resistant) in bronchi damaged by bronchitis, bronchiectasis, or tuberculosis. The “fungus ball” (aspergilloma), a characteristic form of the disease, appears on the chest film as a dense round ball, capped by a slim menis­cus of air, in a cavity; it is composed of a tangled mass of fibrin, exudate, and a few inflammatory cells. Aspergillomas usually occur in old cavitary disease (e.g., tuberculosis) or, rarely, in patients with rheumatoid spondylitis. Symptoms (cough, productive sputum, dyspnea) and findings on physical examination or chest film are usually those of the underlying disease. However, hemoptysis has been a disturbing and even occasionally fatal complication. In the presence of leukemia, organ transplantation, or corticosteroid or immunosuppressive therapy, dissemination to the brain and kidneys may occur. The clinical picture in this form is a typical septicemia: fever, chills, hypotension, prostration, and delirium.

 

Picture 11. Patient is a 11 year old male presents with 4 months history of asthmatic symptoms. The usual asthmatic treatment brought no relief. Low dose steroids brought some improvement, but patient’s symptoms returned when the steroids were withdrawn.

   Examination of the chest films (picture 11) reveals bilateral perihilar opacities centrally extending out into the mid-lung fields bilaterally. There is a pattern resembling “hotdogs” or “V shaped clusters of grapes” radiating from the hilus. This pattern is due to impaction of the bronchus by viscid secretions containing aspergillus hyphae. Dilation occurs distal to the bronchial plugs creating bronchiectasis which can be demonstrated by bronchography. Clinically, two primary presentations of allergic aspergillosis may be encountered. The disease may be superimposed upon life-long asthma, or may be an etiologic factor in the development of asthma in patients late in life. In addition to the presence of asthma and asthmatic attacks, the patients almost invariable have peripheral blood eosinophilia, fever, and a rather characteristic chest roentgenogram.

   This condition responds dramatically to steroid therapy as steroids act to decrease host overresponsiveness, allowing bronchial edema to resolve.

 

Diagnosis and Treatment

Because it is a commensal of man, culture of A. spp. from sputum, mouth, or bowel must not be considered diagnostic unless a clinically compatible illness is present, other causes have been eliminated, and tissue invasion has been demon­strated. In disseminated and pulmonary disease, amphotericin B should be given IV although tolerated doses are usu­ally ineffective, since most strains are resistant.

ACTINOMYCOSIS

(Lumpy Jaw)

A chronic infectious disease characterized by multiple draining sinuses and caused by the anaerobic gram-positive microorganism Actinomyces israelii, often present as a commensal on the gums, tonsils, and teeth.

Incidence and Pathology

The disease is seen most often in adult males. In the cervicofacial form, the rnost common portal of entry is decayed teeth; pulmonary disease results from aspiration of oral secretions; abdominal disease, from a break in the mucosa of a diverticulum or the appendix.

The characteristic lesion is an indurated area of multiple, small, communicating abscesses surrounded by granulation tissue. Disease spreads to contiguous tissue and, rarely, hematogenously. Other anaerobic bacteria are usually also present.

Symptoms and Signs

There are 4 clinical forms of actinomycosis. (1) The abdominal form affects the intestines (usually the cecum and appendix) and the peritoneum. Pain, fever, vomiting, diarrhea or constipation, and emaciation are characteristically present. An abdominal mass with signs of partial intestinal obstruction appears, and draining sinuses and fistulas may develop in the abdominal wall. (2) The cervicofacial form usually begins as a small, flat, hard swelling, with or without pain, under the oral mucosa or the skin on the neck, or as a subperiosteal swelling of the jaw. Subsequently, areas of softening appear and develop into sinuses and fistulas with a discharge that contains the characteristic “sutfur granules” (rounded or spherical, usually yellowish, granules up to 1 mm in diameter). The cheek, tongue, pharynx, salivary glands, cranial bones, meninges, or brain may be affected, usually by direct extension. (3) In the thoracic form, involvement of the lungs resembles TB. Extensive invasion may occur before chest pain, fever, and productive cough appear. Perforation of the chest wall, with chronic draining sinuses, may result. (4) In the generalized form, hematogenous spread occurs to the skin, vertebral bodies, brain, liver, kidney, ureter, and (in women) the pelvic organs.

 

 

Diagnosis

This is based on clinical symptoms, x-ray findings (picture 12), and demonstration of A. israelii in sputum, pus, or biopsy specimen. In pus or tissue, the microorganism appears as tangled masses of branched and un-branched wavy filaments, or as the distinctive “sulfur granules.” These consist of a central mass of tangled filaments, pus cells, and debris, with a midzone of interlacing filaments surrounded by an outer zone of radiating, club-shaped, hya­line and refractive filaments that take the eosin stain in tissue.

Lung lesions must be distinguished from those of TB and neoplasms. Lesions in the abdomen occur most frequently in the ileocecal region and are difficult to diagnose, except at laparotomy or when draining sinuses appear in the abdominal wall. Aspiration liver biopsy should be avoided because of me danger of inducing a persistent sinus. A tender, palpable mass suggests appendiceal abscess or re­gional enteritis. Nodules in any location may simulate malignant growths.

 

Picture 12 Lung Actinomicosis

Clinical presentation:   
53 year old man with left side pain and a lump in the left axilla, dullness to percussion in the left lower chest. Had been treated for an infection 3 and 25 years before. Works as a fitter, cutting insulation by hand. Smokes 10 cigarettes a day.

The view is taken central. The size of the left lobe is reduced and the margins of left hemidiaphragm, the lower left heart margin and the costophrenic recess are obscured by a density that has a clear central margin as it extends into the left axilla, implying a pleural density. There is shadowing at the apex of both lungs. This is well-defined and irregular with calcifications. The right hilar vessels are vertical and sparse in both upper zones with elevation of the hilar point on both sides, implying loss of upper lobe volume. There is coarse linear calcification immediately above the diaphragm, well shown on the right and a little obscured on the left. In this particular view, no rib erosion is identified.

 

Prognosis and Treatment

The disease is slowly progressive. Prognosis relates directly to early diagnosis, is most favorable in the cervicofacial form, and is progressively worse in the pulmo­nary, abdominal, and generalized forms.

Most cases will respond to medical treatment but, owing to the extensive indu­ration and relatively avascular fibrosis, response is slow and treatment must be continued for at least 8 wk and occasionally for > 1 yr. Extensive and repeated surgical procedures may be required. Aspiration is indicated for small abscesses and drainage for large ones. Penicillin G, at least 12 million u./day IV, should be given initially; penicillin V 1 gm orally q.i.d. may be substituted after about 2 wk. Tetracycline 500 mg orally q 6 h may be given instead of penicillin. Treatment must be continued for several weeks after apparent clinical cure.

 

Medical treatment

 

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