10: Cough, Fever, and Respiratory Infections

The causes of cough and congestion vary from trivial self-limited upper respiratory viral infections to serious, imminently life-threatening forms of pneumonia. The approach to such patients focuses on 2 pivotal questions. First, does the patient have symptoms, signs, or risk factors for pneumonia that warrant a chest radiograph or other evaluation? Second, in patients with pneumonia, is it simply a community-acquired pneumonia (CAP) or another type of pneumonia that requires alternative/additional treatment (such as Pneumocystis jirovecii pneumonia [PCP] or tuberculosis [TB])?

A variety of symptoms suggest pneumonia because they are unusual in upper respiratory tract infections or bronchitis. These include dyspnea, high fever (with the exception of influenza [see below]), altered mental status, hypoxia, hypotension, dullness to percussion, crackles, decreased breath sounds, bronchophony, or egophony. Any patient with such symptoms or signs requires a minimum evaluation with a chest radiograph to rule out pneumonia. A chest radiograph should also be strongly considered in patients at increased risk for poor outcomes, including immunocompromised patients; elderly patients; and those with heart failure (HF), chronic kidney disease, or chronic obstructive pulmonary disease (COPD) (in whom abnormal lung findings are also more difficult to appreciate). Figure 10-1 shows a diagnostic algorithm illustrating the initial approach to patients with cough and congestion.

In patients with pneumonia, the next pivotal step is to determine the likely etiologic pathogen(s), which will ensure patients receive appropriate therapy. Even in patients coming from the community, it is not safe to assume that all have the typical CAP pathogens. In many such patients, other types of pneumonia that require different/additional antimicrobial therapy will ultimately be diagnosed. A careful review of both the patient’s risk factors and chest radiograph often provide critical clues that suggest additional microorganisms needing antibiotic coverage. Figure 10-2 illustrates the approach to patients with pneumonia. Pneumonia in patients with known immunocompromise will not be covered in this chapter (known HIV, transplant recipients, and patients with granulocytopenia).

Differential Diagnosis of Acute Cough and Congestion

1. Common cold

2. Sinusitis

3. Bronchitis

4. Influenza

5. Pneumonia

   1. CAP

   2. Aspiration pneumonia

   3. TB

   4. Opportunistic (eg, PCP)

The differential diagnosis for Ms. L includes acute bronchitis, influenza, aspiration pneumonia, and CAP. Ms. L’s high fever is a pivotal feature of this case. Acute bronchitis is not usually associated with significant fever (unless caused by influenza). Influenza can cause high fevers and chest symptoms but almost always occurs between December and May. Therefore, despite Ms. L’s normal lung exam, the high fever raises the possibility of CAP and makes this the leading diagnosis. Table 10-1 lists the differential diagnosis.

A high fever (temperature > 38°C) should raise the suspicion of pneumonia.

Influenza occurs from December to May in the northern hemisphere; it is highly unlikely at other times.

Leading Hypothesis: CAP

Textbook Presentation

Productive cough and fever are usually the presenting symptoms in patients with pneumonia. Symptoms may worsen over days or develop abruptly. Pleuritic chest pain, shortness of breath, chills, and rigors may also develop.

Disease Highlights

1. Most common cause of infectious death in the United States

2. Streptococcus pneumoniae is the most commonly identified pathogen in patients hospitalized for pneumonia whereas Mycoplasma pneumoniae is the most commonly identified pathogen in outpatients.

3. Other common pathogens include Chlamydia, Haemophilus influenzae, Legionella, and respiratory viruses (influenza, parainfluenza, respiratory syncytial virus, and adenovirus).

4. 3.4% of pneumonias are associated with underlying malignancy (postobstructive pneumonias)

5. Complications

   1. Respiratory failure

   2. Death

   3. Empyema (See Chapter 9, Chest Pain)

6. Prognosis is good overall.

   1. 8% hospitalization rate

   2. 95% radiographic cure in 1 month

   3. Mortality 1.2%

Evidence-Based Diagnosis

1. Diagnosis of pneumonia

   1. Diagnosis is usually clinical, based on constellation of cough, fever, and infiltrate on chest film.

   2. Prevalence of symptoms in patients with pneumonia

      1. Cough, 96%

      2. Fever, 81% but 53% in the elderly

         Elderly patients with pneumonia often do not have a fever. Clinicians should have a low threshold for obtaining a chest radiograph in elderly patients or in patients with COPD with cough or with mental status changes.

      3. Dyspnea, 46–66%

      4. Pleuritic chest pain, 37–50%

      5. Chills, 59%

      6. Headache, 58%

   3. Physical exam

      1. No single finding is very sensitive. Therefore, the absence of any single finding does not rule out pneumonia (Table 10-2).

         • (1) Neither a normal lung exam nor the absence of fever rule out pneumonia (LR–, 0.6 and 0.8, respectively).

         • A normal lung exam does not rule out pneumonia.

         • (2) Normal vital signs make pneumonia less likely (LR 0.18).

         • (3) The combination of normal vital signs and normal chest exam make pneumonia highly unlikely (95% sensitive, LR 0.09).

      2. Egophony is fairly specific and significantly increases the likelihood of pneumonia when present (LR+ 8.6).

   4. The history and physical cannot reliably distinguish typical from atypical pneumonias.

   5. WBC > 10,400 cells/mcL: LR+, 3.7; LR–, 0.6

   6. Chest film

      1. The chest film is imperfect.

         • (1) Sensitivity 67–75%, specificity 85% when compared with chest CT scan or discharge diagnosis.

           A normal chest radiograph does not rule out pneumonia when the pretest probability is high (ie, a patient with cough, fever, and crackles). Such patients should still receive antibiotics.

         • (2) Sensitivity may be lower in dehydrated patients.

         • (3) A single anterior-posterior chest film view has a lower sensitivity than posteroanterior and lateral (59% vs 90%) views.

           Posteroanterior and lateral chest film views are superior to single anterior-posterior views and should be obtained when possible.

      2. 94% of infiltrates are in the lower and middle regions.

         CAP rarely affects the upper lobes; consider TB or aspiration pneumonia when upper lobe involvement is seen.

      3. The chest radiograph cannot distinguish typical from atypical pneumonias.

Treatment

1. Prevention

   1. Two vaccines are currently available to prevent invasive pneumococcal disease:

      1. An older 23-valent pneumococcal polysaccharide vaccine (PPSV 23) and a newer 13-valent pneumococcal conjugate vaccine (PCV 13)

      2. PCV 13 vaccine has fewer serotypes but generates an equivalent or larger immune response.

   2. Vaccine recommendations (Advisory Committee on Immunization Practices [ACIP])

      1. All adults aged ≥ 65 years: A single dose of PPSV 23 regardless of previous history of pneumococcal vaccination

      2. Any adult who received PPSV prior to age 65 should receive a second dose at 65 or later once at least 5 years have passed since the first vaccination.

      3. The recommendations for immunocompromised adults and those with high risk conditions¹ are complex. Certain patients require PPSV 23 alone, some PCV 13 and PPSV 23, and others revaccination. Details can be found at the CDC Web site http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6140a4.htm

2. Evaluation

   1. Chest film is recommended in the evaluation of all patients with CAP.

   2. Evaluate oxygenation in all patients (arterial blood gas [ABG] or SaO₂)

   3. An ABG is required in patients with respiratory distress, particularly those with preexistent COPD.

      A normal SaO₂ on pulse oximetry does not exclude hypercarbia and respiratory failure. A blood gas to check PaCO₂ is required for patients with respiratory distress.

   4. Determining the causative agent

      1. CAP is the most common pneumonia among outpatients with an infiltrate and fever.

      2. Nonetheless, clinicians should always consider other less common pneumonias including aspiration, TB, pneumocystis and HCAP (see Figure 10-2), which may warrant additional testing or therapy (see below for details).

         • (1) A history of neurologic impairment or drug abuse increases the likelihood of aspiration pneumonia.

         • (2) Chronic symptoms, upper lobe disease, or cavitary lesions increase the likelihood of TB.

         • (3) HIV risk factors or bilateral fluffy infiltrates increase the likelihood of PCP.

         • (4) Recent nursing home or institutional living or hospitalization warrants coverage for HCAP or hospital-acquired pneumonia.

      3. In the absence of clinical or radiographic clues that suggest other types of pneumonia, most patients are treated empirically, to cover the most common organisms responsible for CAP.

      4. However, a variety of tests, including sputum culture, sputum Gram stain, blood culture, and urinary antigen tests for pneumococcus and Legionella, can help determine the pathogen in CAP.

         • (1) The yield of these tests in outpatients with CAP is low and routine testing is optional in outpatients.

         • (2) Sputum cultures are often unreliable due to contamination by oral flora.

           • (a) Normal flora should not be misinterpreted to mean no infection.

           • (b) When positive, sputum cultures can help determine the resistance pattern.

         • (3) Sputum Gram stains are also often unreliable due to poor quality, preparation, and interpretation.

           • (a) Overall, only 14% of hospitalized patients had an adequate specimen with a dominant organism.

           • (b) In patients with pneumococcal bacteremia, the Gram stain was positive in 63–80%.

         • (4) Blood cultures are positive in 5–14% of patients.

         • (5) Pneumococcal urinary antigen is 50–80% sensitive and 90% specific (false-positives may occur secondary to colonization).

         • (6) Legionella urinary antigen is 70–90% sensitive and 99% specific.

         • (7) The Infectious Diseases Society of America (IDSA) has published guidelines for more extensive testing on select inpatients (Table 10-3).

      5. Patients with severe pneumonia should have blood and sputum cultures, sputum Gram stain, and urinary tests for pneumococcal and Legionella antigen.

   5. Patients with pleural effusions require diagnostic thoracentesis to rule out empyema or complicated parapneumonic effusions, which require chest tube drainage in addition to antibiotics (see Chapter 9, Chest Pain).

   6. HIV testing is recommended for all adults aged 15–65 years who have CAP.

3. Determine the need for hospitalization

   1. Indications for admission

      1. Hypoxia

      2. Shock

      3. Pleural effusion

      4. Multilobar infiltrates on chest film

      5. Failure of prior outpatient therapy

      6. Confusion

      7. Unable to tolerate oral intake

      8. Unreliable social situation

      9. Certain underlying diseases (sickle cell disease, immunocompromise, severe COPD or HF)

   2. Prospective validated clinical tools can help determine the need for admission. The CURB-65 score is the most widely used, validated model that predicts mortality.

      1. Criteria are confusion (to person, place, or time), uremia (BUN > 20 mg/dL), RR ≥ 30 breaths per minute, systolic BP < 90 mm Hg or diastolic BP ≤ 60 mm Hg, age ≥ 65.

      2. Scores of > 1 are associated with an increased mortality and the need for hospital admission.

4. Determine the need for ICU admission: The IDSA and ATS have published guidelines on ICU admissions for patients with severe pneumonia. ICU admission is recommended for septic shock requiring vasopressors and those on mechanical ventilation as well as patients with ≥ 3 minor criteria (RR > 30 breaths per minute, PaO₂/FiO₂ ratio ≤ 250, multilobar infiltrates, confusion, BUN ≥ 20 mg/dL, WBC < 4000 cells/mL, platelet count < 100,000 cells/mL, temperature < 36°C, or hypotension requiring aggressive fluid resuscitation).

5. Antibiotics

   1. Treatment must cover pyogenic (S pneumoniae) and atypical (Mycoplasma and Chlamydia) organisms.

   2. Penicillin-resistant S pneumoniae (PRSP)

      1. Increasing resistance in United States

      2. Marked geographic variability in frequency of resistance but up to 65% in some areas

      3. PRSP often resistant to cephalosporins and macrolides but not quinolones with extended activity against S pneumoniae.

   3. Empiric therapy (recommendations from the IDSA 2007)

      1. Outpatients

         • (1) Previously healthy outpatients are usually treated with an advanced macrolide (azithromycin or clarithromycin) or doxycycline. (Macrolides are preferred.)

         • (2) Certain patients require alternative therapy with either a respiratory quinolone (moxifloxacin, levofloxacin, or gemifloxacin) or combination therapy of a beta-lactam (amoxicillin or amoxicillin-clavulanate or cefpodoxime) and macrolide. This includes patients with any of the following:

           • (a) Comorbidities (heart, lung, liver, or kidney disease; diabetes mellitus; alcoholism; cancer; asplenia; immunosuppression)

           • (b) Antibiotic use within the last 3 months

           • (c) Exposure to children in day care centers (increasing the risk for S pneumoniae resistance)

           • (d) Evidence of pneumococcal pneumonia (diplococci on Gram stain, positive pneumococcal urine antigen, positive sputum culture for pneumococcus, or sudden onset of high fever and rigors)

           • (e) Areas with a rate of macrolide resistance > 25%

      2. Inpatients should be treated with respiratory fluoroquinolone (levofloxacin or moxifloxacin) or advanced macrolide with a beta-lactam (ceftriaxone, cefotaxime or ampicillin-sulbactam).

6. Consultation is recommended for patients admitted to the ICU for antibiotic choice and consideration of other interventions including drotrecogin alpha (activated protein C) and screening for adrenal insufficiency.

7. Follow-up chest film

   1. 3.4% of pneumonias are associated with an underlying tumor (postobstructive pneumonia) that may be obscured by the infiltrate

   2. Follow-up radiography can ensure pneumonia resolution and discover an underlying mass.

   3. Particularly important in patients at increased risk for pneumonia, including patients over 50 or who are smokers.

   4. Chest film resolution lags behind clinical resolution.

      1. By day 10, most patients have clinical resolution but only 31% had a normal chest radiograph and 68% of patients had a normal chest radiograph by day 28.

      2. Follow-up chest film should be performed promptly in any patient with clinical deterioration and after day 28 in patients at risk for malignancy.

Ms. L does not have risk factors for aspiration pneumonia. Influenza is highly unlikely in August. The differential diagnosis is narrowed to CAP and acute bronchitis.

Alternative Diagnosis: Acute Bronchitis

Textbook Presentation

Acute bronchitis presents in the healthy adult primarily as a cough of 1–3 weeks duration. Myalgias and low-grade fevers may be seen. This is distinct from an acute exacerbation of COPD (see Chapter 33, Wheezing & Stridor).

Disease Highlights

1. Etiology

   1. Viruses

      1. Influenza

      2. Parainfluenza

      3. Respiratory syncytial virus

      4. Adenovirus

      5. Rhinovirus

      6. Coronavirus

   2. Bacterial

      1. Bacteria cause < 10% of cases

      2. Organisms include Bordetella pertussis, Mycoplasma, and Chlamydia.

   3. Noninfectious

      1. Asthma

      2. Pollution

      3. Tobacco

      4. Cannabis

2. Symptoms

   1. Initial phase: Cough and systemic symptoms secondary to infection are seen.

   2. Fever absent or low grade. Consider pneumonia in patients whose fever is high-grade (> 38°C) or persistent.

   3. Protracted phase

      1. 40–65% of patients without prior pulmonary disease show evidence of reactive airway disease during acute bronchitis.

      2. In 26% of patients, cough persists secondary to bronchial hyperresponsiveness and lasts ≥ 2–4 weeks.

Evidence-Based Diagnosis

1. Sputum may be clear or discolored. Discoloration arises from tracheobronchial epithelium cells and WBCs and is not diagnostic of bacterial infection.

   Purulent sputum is not an indication for antibiotic therapy in patients with acute bronchitis.

2. Chest film is not routine but should be obtained when pneumonia is being considered (see Figure 10-1); indications include

   1. Patients at risk for pneumonia: elderly patients and those with heart, lung, kidney disease or are immunocompromised

   2. Symptoms of dyspnea, high fever, rigors, pleuritic chest pain, or altered mental status

   3. Abnormal vital signs including high fever (temperature > 38°C), tachypnea (RR > 24 breaths per minute), tachycardia (HR > 100 bpm)

   4. Focal findings on lung exam or hypoxemia

3. Testing for influenza can be considered in febrile patients who present during influenza season within 48 hours of symptoms onset in whom antiviral therapy is being considered (see below).

Treatment

1. Antibiotics

   1. Antibiotics do not provide major clinical benefit and are not recommended for most patients with acute bronchitis. Antibiotics can be considered in high-risk patients (those with underlying heart, lung, kidney disease or immunosuppression) or when the clinical index of suspicion for CAP is high despite a normal chest film.

   2. Influenza treatment shortens the course of illness in patients with influenza treated within 48 hours of symptoms (see below) and can be considered in patients with bronchitis due to this pathogen.

2. Bronchodilators significantly reduce cough in patients with bronchial hyperreactivity, wheezing, or airflow obstruction at baseline.

3. Antitussives are useful symptomatic measures.

At this point, obtaining a chest radiograph is critical. A CBC, sputum and blood cultures can be obtained but are not sensitive enough to rule out pneumonia.

25–50% of patients with pneumonia do not have crackles on auscultation. Chest film is required when pneumonia is suspected.

A follow-up chest radiograph is indicated in patients with pneumonia to exclude an underlying obstructing mass.

The clinical findings of cough, shortness of breath, crackles on pulmonary exam, and infiltrates on chest film all suggest pneumonia. One pivotal feature of this case is the long duration of symptoms. CAP is possible but less likely with such protracted symptoms. More chronic processes such as aspiration pneumonia or TB should be considered. Another pivotal feature of Mr. P’s case is his alcoholism. Alcoholism, substance abuse, and neurologic disorders are leading risk factors for aspiration, and his alcoholism makes aspiration pneumonia the leading diagnosis. The duration of his complaints and temporal wasting also raise the possibility of more chronic pneumonias caused by TB, fungi, or PCP. TB is more common in alcoholic patients and malnourished patients. Given the public health risks, TB is a must not miss possibility. A third pivotal feature in this patient is his high-risk sexual behavior increasing his risk for HIV infection and PCP. PCP primarily affects HIV-infected patients. It is important to consider PCP even in patients without a history of known HIV infection because PCP can be the first sign of HIV infection. The sexual history makes PCP (or another HIV-related pneumonia) an active alternative diagnosis. Finally, uncomplicated influenza does not persist for 4 weeks, although a postinfluenza pneumonia could be considered in the proper season. Table 10-4 lists the differential diagnosis.

Leading Hypothesis: Aspiration Pneumonia

Textbook Presentation

Aspiration pneumonia typically develops in patients with impaired mentation (ie, the demented elderly patient or alcoholic). Classic symptoms include fever, cough, chest pain, and putrid sputum. The syndrome most commonly evolves over days to weeks rather than acutely.

Disease Highlights

1. There are 2 types of aspiration: Small volume aspiration, typically of oropharyngeal secretions, and large volume aspiration, typically of gastric contents.

   1. Aspiration of colonized oropharyngeal secretions is common but may be complicated by pneumonia when the combination of a large bacterial load (due to poor dentition) and virulence overcome host defenses (particularly cough).

   2. Gastric acid aspiration may result in chemical damage (aspiration pneumonitis), which may be accompanied by subsequent infection (aspiration pneumonia).

2. Risk factors for aspiration

   1. Neurologic disease (dementia, cerebrovascular accident, seizures)

   2. Sedation (illicit drug or alcohol overdose, general anesthesia)

   3. Dysphagia (status post head and neck surgery)

   4. Gastroesophageal reflux disease, vomiting

   5. Endoscopy, tracheostomy, bronchoscopy, nasogastric feeding

3. Aspiration pneumonitis

   1. Aspirated contents with lower pHs and larger volumes lead to more damage

   2. Clinical syndrome

      1. Usually follows large volume aspiration (ie, during anesthesia)

      2. Cyanosis, shortness of breath, and pulmonary infiltrates develop within 2 hours.

      3. Fever is usually low grade.

      4. Sputum may be putrid.

      5. Outcome varies

         • (1) Rapid recovery within 24–36 hours (62%), bacterial superinfection (26%), acute respiratory distress syndrome (12%)

         • (2) Bacterial superinfection may lead to pneumonia, lung abscess, or empyema.

4. Aspiration pneumonia refers to infection due to aspirated organisms.

   1. Accounts for 5–15% of pneumonias

   2. Poor dentition increases the risk of aspiration pneumonia.

   3. Aspiration is usually not witnessed.

   4. Clinical features include cough, fever, sputum production, and shortness of breath, which may progress over days to weeks.

   5. Organisms

      1. Community-acquired aspiration pneumonia may be caused by anaerobes, aerobic streptococci, S pneumoniae, Staphylococcus aureus, and H influenzae.

      2. Hospital-acquired aspiration pneumonias may be caused by anaerobes, gram-negative organisms (including Pseudomonas), or S aureus.

Evidence-Based Diagnosis

1. Often presumptive based on aspiration risk factors, putrid sputum, and typical chest film. Many patients have periodontal disease.

2. Oropharyngeal motility studies can identify certain patients at risk, particularly those with neurologic impairment.

3. Rigors and acute onset suggest more virulent organisms (ie, S pneumoniae and S aureus).

4. Chest film

   1. Aspiration pneumonia classically involves the basal segment of lower lobes but can involve the posterior segments of the upper lobes if aspiration occurred while the patient was recumbent.

   2. Cavitation is more common in aspiration pneumonia than in CAP.

Treatment

1. Prevention

   1. Soft diets and feeding strategies can reduce subsequent aspiration.

   2. Tube feedings decrease the incidence of aspiration pneumonia in patients with dysphagia (54% vs 13% with oral feeding). However, despite tube feedings, patients can still aspirate from gastroesophageal reflux, vomiting, and aspiration of oropharyngeal contents.

   3. Several studies suggest that angiotensin-converting enzyme (ACE) inhibitors increase the cough reflex and decrease the rate of pneumonia in persons at-risk (NNT 9–19).

   4. Amantadine promotes dopamine release (which facilitates cough and decreases dysphagia). It also has been shown to decrease the rate of pneumonia in elderly patients with prior stroke (NNT 4.3).

   5. Oral hygiene decreases colonization and subsequent pneumonia.

   6. Postprandial semirecumbent positions decrease the rate of aspiration pneumonia compared with supine positions.

2. Supportive treatment

   1. Suction any material in airway.

   2. Intubation if necessary for ventilation, oxygenation, or to protect airway in patients with altered level of consciousness.

3. Aspiration pneumonitis

   1. Antibiotics

      1. Often used initially due to the high frequency of subsequent superinfection.

      2. Can be discontinued if no infiltrates develop within 48–72 hours.

      3. Pneumonia is more likely in patients with gastric colonization (resulting from a H₂-blocker, proton pump inhibitor, or from bowel obstruction).

   2. Corticosteroids are controversial.

4. Aspiration pneumonia: antibiotics are indicated.

   1. Community-acquired aspiration: First-line options include clindamycin or amoxicillin/clavulanate or amoxicillin with metronidazole.

   2. Hospital-acquired aspiration:

      1. Coverage requires addition of an antibiotic that is effective against gram-negative organisms and S aureus.

      2. Options include carbapenem or piperacillin-tazobactam.

At this point, it is appropriate to order blood cultures, sputum cultures, and Gram stain. The patient’s chest radiograph does not have any features that suggest TB (see below), which makes TB less likely. Nonetheless, purified protein derivative (PPD) placement or QuantiFERON testing and obtaining sputum for acid-fast bacillus (AFB) stain and culture would be reasonable. Finally, given the diffuse symmetric infiltrate on chest radiograph and his sexual history, PCP must be considered and testing for HIV is mandatory. Although the patient’s CURB-65 score is 0, his hypoxia and lack of a reliable social structure make admission mandatory. Antibiotics that cover both CAP and aspiration pneumonia should be started.

Alternative Diagnosis: PCP

Textbook Presentation

Patients with PCP may have diagnosed or undiagnosed advanced HIV disease. Patients commonly complain of progressive shortness of breath and dry cough of 1–3 weeks duration.

PCP is often the presenting manifestation of AIDS. Suspect PCP in patients with diffuse bilateral pneumonia, particularly of subacute onset.

Disease Highlights

1. PCP is caused by the fungal organism P jirovecii and typically presents as a diffuse bilateral pneumonia.

2. PCP occurs most commonly in patients with HIV disease and CD4 counts < 200 cells/mcL.

3. PCP is the most common cause of acute diffuse lung disease in immunocompromised patients and is the leading cause of AIDS-related death in HIV-infected patients.

4. PCP may also develop in patients undergoing organ transplantation or chemotherapy and in patients with idiopathic CD4 lymphocytopenia.

Evidence-Based Diagnosis

1. History

   1. Patients may or may not already carry diagnosis of HIV or AIDS.

   2. Fever is present in 79–100% of cases.

   3. Cough is present in 95% of cases. It is usually (but not always) nonproductive.

   4. Progressive dyspnea is present in 95% of cases.

2. Physical exam

   1. Fever is present in 84%.

   2. Tachypnea is present in 62%.

   3. Chest auscultation is normal in 50% of cases.

3. Chest film

   1. Usually shows diffuse symmetric bilateral alveolar or interstitial infiltrates (81–93% of cases)

   2. In HIV-infected patients, interstitial infiltrates are present in 69% of patients and increase the likelihood of PCP (versus TB or bacterial pneumonia) (LR+ 4.25).

   3. Isolated upper lobe disease may be seen in patients taking inhaled pentamidine as PCP prophylaxis.

   4. Occasionally shows pneumothorax

   5. Normal in 10–25% of cases

      PCP should be considered in dyspneic patients with HIV and CD4 counts < 200 cells/mcL even when the chest exam and chest radiograph are normal.

4. Specific diagnostic tests

   1. Although the chest radiograph and lactate dehydrogenase (see below) can suggest PCP or make the diagnosis less likely, patients require specific tests to confirm or exclude PCP.

   2. Clinical diagnosis (without confirmational staining of sputum or bronchoalveolar lavage [BAL]) is incorrect in 43% of patients.

   3. Induced sputums are typically the first test used to diagnose PCP.

      1. 55–92% sensitive, 100% specific

      2. The addition of immunofluorescent monoclonal staining increases sensitivity.

   4. BAL is used to diagnose PCP when sputum stains are negative.

      1. Diagnosis is based on staining the fluid obtained during BAL.

      2. Silver, Giemsa or immunofluorescent staining using monoclonal antibodies have been used.

      3. Sensitivity is 86–97%.

      4. Sensitivity of BAL is lower (62%) after inhaled pentamidine prophylaxis. Transbronchial biopsy improves the diagnostic yield in these patients.

   5. The most common diagnostic strategy is sputum analysis with silver stain and immunofluorescence. Positive results confirm PCP. Negative results should prompt BAL.

   6. Other diagnostic tools being investigated include the study of sputum, blood, and nasal pharyngeal specimens with polymerase chain reaction (PCR) and a serum measurement of 1,3-beta-D-glucan (See below).

5. Nonspecific diagnostic tests

   1. 1,3-beta-D-glucan

      1. A cell wall component of pneumocystis and other fungi (Candida, Aspergillus, but not Cryptococcus)

      2. Sensitivity 96%, specificity 84%, LR+ 6.0, LR– 0.05

      3. May prove to be a useful serum tool to rule out PCP if negative, but given the low specificity other tests would be needed to confirm PCP if positive.

      4. Also can be elevated in invasive candidiasis and aspergillosis

   2. High-resolution chest CT scan

      1. Patchy or nodular ground-glass appearance; ground glass most marked in perihilar regions. Cystic lesions may be seen.

      2. 100% sensitive, 83–89% specific

      3. LR+, 5.9; LR–, 0

   3. Pulmonary function tests

      1. Carbon monoxide diffusing capacity of the lungs (DLCO) is usually low in PCP and highly sensitive.

      2. Likelihood of PCP is < 2% if DLCO is > 75% predicted.

Treatment

1. Antimicrobial therapy

   1. Trimethoprim-sulfamethoxazole (TMP-SMX) is initial treatment of choice.

   2. Side effects are common including rash, fever, GI symptoms, hepatitis, neutropenia and hyperkalemia. CBC, liver function tests (LFTs), and K+ should be monitored.

   3. Antibiotic therapy may markedly worsen preexisting hypoxia. Many patients require concomitant corticosteroids to prevent acute respiratory distress syndrome (see below).

   4. Alternatives are available for patients intolerant to TMP-SMX but some allergic patients may be desensitized.

   5. Occasional resistance to TMP-SMX has been reported.

   6. Other options reserved for patients with mild to moderate PCP infections include clindamycin plus primaquine, dapsone plus TMP or atovaquone.

2. Corticosteroids

   1. Reduce mortality and respiratory failure in patients with severe PCP treated with TMP-SMX (relative risk for mortality 0.56)

   2. Initiate at time of PCP therapy if room air PaO₂ < 70 mm Hg or the A-a gradient ≥ 35 mm Hg.

   3. Should be added to patients who do not initially qualify for corticosteroid treatment but deteriorate while taking TMP/SMX.

   4. Prednisone 40 mg twice daily for 5 days, then 40 mg daily for 5 days, then 20 mg daily for 11 days.

      Concomitant corticosteroid therapy is lifesaving in patients with PCP whose PaO₂ < 70 mm Hg.

3. Highly active antiretroviral therapy (HAART) should also be initiated within 2 weeks of treatment for PCP in HIV-infected patients (not already receiving HAART).

4. Prophylaxis

   1. Indications (any of the following)

      1. Prior PCP

      2. CD4 counts < 200 cells/mcL

      3. HIV-infected patients with unexplained persistent fevers or oral candidiasis for more than 2 weeks

   2. TMP-SMX is superior to pentamidine and the drug of choice. In addition, it is effective prophylaxis against toxoplasmosis and some bacterial infections.

   3. Significant adverse reactions are common with TMP-SMX. Rash, fever, neutropenia, and hypotension may necessitate discontinuation of TMP-SMX. Consultation with an infectious disease specialist is recommended.

   4. Dapsone, pentamidine, and atovaquone are alternative therapies in patients intolerant of TMP-SMX. Some authorities recommend screening patients for glucose 6-phosphate dehydrogenase (G6PD) deficiency prior to instituting dapsone.

   5. HAART can restore the CD4 count and allow for discontinuation of prophylaxis when CD4 count > 200 cells/mcL for approximately 3 months (unless PCP developed in patients with CD4 counts above 200 cells/mcL).

Alternative Diagnosis: TB

Textbook Presentation

TB pneumonia usually develops due to reactivation of latent mycobacteria residing in the upper lobes. Symptoms are chronic and include cough, fever, weight loss, and night sweats. By the time patients seek medical attention, they have often had these symptoms for weeks or months. The weight loss and duration of symptoms often suggest cancer.

Disease Highlights

1. Obligate aerobe has predilection for lung apices.

2. The organism is slow growing; the generation time is 20–24 hours, resulting in slow progression.

3. Common and serious

   1. Infects 33% of the world’s population

   2. 8.7 million new cases per year (2011 data) and 1.4 million deaths (worldwide)

   3. 95% of cases occur in developing countries.

4. Epidemiology

   1. 7% of US population is PPD positive.

   2. Foreign-born persons have the highest rate of TB (9.7 times higher than US-born persons) and account for 85% of multidrug resistant TB (MDR-TB) in the United States.

   3. Asians, blacks, and Hispanics have higher rates of TB than whites (22.9, 8.3 and 7.4 times, respectively). Foreign-born persons account for a majority of TB cases in Asians and Hispanics but not blacks.

   4. 67% of cases occur in the nonwhite population.

   5. In the nonwhite population, the median age is 39. In whites, the median age is 62.

   6. Reactivation TB accounts for 90% of TB in older patients and 67% of TB in younger patients.

   7. High risk groups

      1. HIV

         • (1) HIV-infected patients are at highest risk for TB (200 times increased incidence).

         • (2) In 2011, HIV-infected persons accounted for 1.1 million TB cases worldwide (13% of the total).

         • (3) TB may be the first manifestation of HIV.

           Patients with active or latent TB should be tested for HIV.

         • (4) Extrapulmonary TB without pulmonary disease is more common in patients with AIDS (30%) than in those without AIDS (15%).

         • (5) In early HIV infection, TB is fairly typical. However, in advanced HIV infection, pulmonary TB is much more often atypical.

      2. Alcoholics

      3. Other high-risk groups

         • (1) Foreign-born persons

         • (2) Immunosuppressed patients (including patients taking corticosteroids)

         • (3) Patients with cancer, diabetes mellitus, end-stage renal disease, transplants, or malnutrition

         • (4) PPD-positive patients

         • (5) Patients with evidence of prior TB on chest film

         • (6) Economically disadvantaged, inner city residents

         • (7) Nursing home residents

         • (8) Hispanics and African Americans

         • (9) Drug-dependent persons, homeless persons, prison inmates

5. Pathophysiology

   1. Inhaled organism lands in the middle and lower lobes (due to increased ventilation).

   2. Multiplies over next 3 weeks, spreads to hilar nodes and often bloodstream.

   3. Organism reproduces preferentially in areas of high PaO₂ (lung apices, renal cortex, vertebrae).

   4. In 90% of patients, the immune system then contains the organism resulting in typical scarring (Ghon complex). However, the chest film can be normal.

   5. Above sequence usually asymptomatic.

   6. In some patients a few viable organisms remain. This is referred to as latent TB infection (LTBI). Latent TB can reactivate later (reactivation TB).

   7. The PPD is positive 6–8 weeks after the initial infection. These patients are resistant to subsequent exogenous infection (but not reactivation).

   8. Primary TB

      1. In approximately 10% of patients (higher in immunocompromised patients and children), the initial infection is not controlled and causes primary TB.

      2. Primary TB accounts for 23–34% of adult cases.

      3. Fever is the most common symptom (70%) and usually occurs in isolation.

      4. Chest radiograph usually shows consolidation (50%).

         • (1) Disease is usually unifocal (75%) but may be multifocal.

         • (2) Usually involves lower and middle lobes (63% of cases).

         • (3) Lymphadenopathy is seen in 10–67% of adults and is rarely the sole radiologic manifestation.

         • (4) Pleural effusions, usually unilateral, develop in 24% and may occur with or without infiltrates.

         • (5) Normal in 15% of patients with primary pulmonary TB

         • (6) Other findings include miliary pattern 6%, cavitation 15%.

      5. Often occurs in those unable to mount a sensitized macrophage response.

      6. PPD may be negative in these patients.

      7. Most cases of primary TB resolve spontaneously without treatment.

      8. Pneumonia progresses without treatment in 10–15% of patients.

   9. Reactivation TB

      1. 3–5% of patients with LTBI experience reactivation due to declining immune function.

      2. Reactivation TB results in 90% of adult non–AIDS-related TB.

      3. 71% of cases occur in foreign-born patients.

      4. Symptoms are usually insidious and include chronic cough, weight loss, night sweats, anorexia, and low- or high-grade fevers.

      5. Reactivation TB progresses unless patient is treated.

   10. Pleural TB takes 2 forms: tuberculous empyema and tuberculous pleural effusions.

       1. Tuberculous empyema

          • (1) Secondary to direct infection of pleural space (often from rupture of neighboring tuberculous cavity)

          • (2) Rare

          • (3) Pleural fluid characterized by pus and numerous TB organisms

       2. Tuberculous effusions

          • (1) Tuberculous effusions result from a delayed hypersensitivity reaction to mycobacterial antigens in the pleural space.

          • (2) Usually due to reactivation in adults (75%)

          • (3) Typical features include acute high fever, cough (94%), and pleuritic chest pain (78%).

          • (4) Chest radiograph shows unilateral effusion in 95% of cases. Parenchymal infiltrate is seen in 50% of cases.

          • (5) Effusion is usually exudative (see below).

          • (6) PPD is usually positive (69–93%).

   11. Extrapulmonary TB may involve the spine, kidney, pericardium, and central nervous system.

Evidence-Based Diagnosis

1. A variety of risk factors, symptoms, and radiographic findings can suggest TB (Table 10-5). Sensitivity is likely to be overestimated because TB was not systematically evaluated in all patients.

   1. Risk factors: The most important risk factors are immigrant from TB endemic areas (LR+ 4.1), history of positive PPD test (LR+ 3.8), or history of TB (LR+ 3.6)

   2. Symptoms

      1. No symptom is terribly sensitive for TB. Weight loss and cough for > 2 weeks increase the likelihood of TB more significantly than night sweats or hemoptysis.

      2. Hemoptysis was neither sensitive nor specific for TB.

      3. Fever is present in only 55%.

      4. Other clues may include lack of systemic toxicity or failure to respond to antibacterial therapy.

         Patients with TB may complain primarily of weight loss or night sweats and have a normal lung exam. Fever and hemoptysis may be absent. Pulmonary TB still needs to be considered in such patients.

      5. Symptoms and risk factors for disease tend to vary between older patients who often have reactivation TB and younger patients in whom primary TB is more common. Compared with older patients, younger patients have a higher incidence of alcoholism (66% vs 37%). In addition, younger patients more frequently have fever (62% vs 31%), night sweats (48% vs 6%), and hemoptysis (40% vs 17%).

   3. Radiography

      1. A normal chest film is very unlikely in patients with pulmonary TB (97% sensitive).

      2. Cavitary disease and apical disease markedly increase the likelihood of TB (LR+ 8.3 and 4.8, respectively).

      3. Most patients with TB have one of three radiographic patterns: apical, cavitary, or reticulonodular disease (LR+, 5.0; LR–, 0.16).

         TB should be considered in patients with apical, cavitary, or reticulonodular patterns on chest radiograph. TB is unlikely if none of these features are present.

      4. Calcification can be seen in active lesions. Demonstrating stability requires comparison of prior films.

      5. The chest radiograph in HIV-positive patients is often atypical (see Chapter 5, AIDS/HIV).

2. Clinical decision rules:

   1. A variety of clinical decision rules can help determine the likelihood of TB in patients with pneumonia and the need for isolation on admission.

   2. None have ideal sensitivity and specificity.

   3. High sensitivity is preferred to ensure patients with TB are isolated and reduce the risk of nosocomial transmission of TB.

   4. The clinical decision rules with the highest sensitivity (96–98% sensitive, 20–48% specific) categorized patients at high risk if they had any of the following risk factors:

      1. Immigrants from TB prevalent areas

      2. Positive TB history or history of positive PPD

      3. Homelessness, incarceration

      4. Weight loss

      5. Chest film with apical or cavitary infiltrates

3. PPD

   1. Immune response to 0.1 mL intradermal PPD

   2. Turns positive 4–7 weeks after primary infection

   3. Test results are determined by measuring the maximal diameter of induration (not redness).

   4. Maximal induration occurs 48–72 hours after injection.

   5. The criteria for a positive reaction depend on the clinical situation.

      1. An induration of ≥ 5 mm is considered positive in HIV-infected persons, organ-transplant recipients, patients on immunosuppressive agents (including > 15 mgper day of prednisone or TNF-alpha antagonists), those with recent contact with active TB, or persons with radiographic findings consistent with prior TB.

      2. An induration of ≥ 10 mm is considered positive in recent immigrants (< 5 years) from high prevalence areas, injection drug users, persons with clinical conditions that place them at high risk (including end-stage renal disease, malnutrition; diabetes mellitus; lymphoma; leukemia; carcinoma of the lung, head, or neck; silicosis, gastrectomy; or jejunoileal bypass), residents and employees of nursing homes, prisons, or homeless shelters.

      3. An induration of ≥ 15 mm is considered positive in any person.

   6. Significant reaction suggests prior infection, not necessarily active disease. Patients with positive tests who do not have active TB are classified as having LTBI.

   7. Sensitivity (for active TB) 70–80%

      1. Primary TB: PPD is often negative.

      2. Reactivation TB: PPD is positive in 80% of cases.

      3. Tuberculous pleurisy: PPD is usually positive.

      4. AIDS patients with TB: PPD is positive in 50% of cases.

         A negative PPD does not rule out active TB.

   8. Specificity is 98–99% but is lower in patients who received bacillus Calmette-Guérin (BCG) vaccination after infancy.

      1. BCG is a TB vaccine used in some countries to prevent TB.

      2. BCG has some similarities to PPD and may cause false-positive PPD reactions.

         • (1) False-positive PPD reactions (≥ 10 mm) are rare in adults who received BCG in infancy (≈1%).

         • (2) However, false-positives are more common in BCG recipients who were vaccinated ≥ 2 years of age (40%). False-positive PPDs remained common in this group even more than 10 years later (20%).

         • (3) Interferon gamma assays are more accurate in patients previously vaccinated with BCG (see below).

   9. Indications for single PPD test

      1. Clinical suspicion of active TB

      2. Immigrants from high-incidence areas (eg, Africa, Asia, Latin America)

      3. Status post exposure to TB

      4. Fibrotic lung lesion

   10. Annual PPD

       1. Useful to determine whether patient has recently converted

       2. Recent converters are at higher risk for developing active TB.

       3. Conversion defined as increase in induration of ≥ 10 mm

       4. Therapy is indicated for patients who have recently converted due to high risk of developing active TB.

       5. Indications for annual PPD

          • (1) HIV infection

          • (2) Health care workers

          • (3) Correctional facility workers

          • (4) Residents in long-term–care facilities

          • (5) Medical conditions that carry an increased risk of active TB (see above)

          • (6) Homeless persons

   11. Booster phenomenon

       1. In patients with latent TB, the PPD may revert to negative many years after infection.

       2. In such patients, the initial PPD may be negative but stimulate immune memory cells such that subsequent PPD tests may be positive.

       3. Subsequent positive tests may be misinterpreted as recent conversion.

       4. Misinterpretation can be avoided by performing the 2-step skin tests in patients scheduled for annual PPD.

       5. Patients with initial negative PPD are retested 1 week later.

          • (1) Patient in whom the second PPD test is positive should be treated as though the first test was positive.

          • (2) Patients in whom the second PPD test is negative are truly negative. Any future positive reactions in these patients should be considered recent conversions.

4. Interferon gamma assays

   1. Lymphocytes from patients with LTBI or active TB produce interferon gamma when exposed to TB antigens.

   2. Blood tests have been recently developed that expose the patient’s lymphocytes to highly specific TB antigens (not shared with BCG or most nontuberculous mycobacteria) and measure the production of interferon gamma by the patient’s lymphocytes.

   3. These tests are highly specific for active or latent TB infection.

      1. Prior BCG vaccination and infection with nontuberculous mycobacteria may cause false-positive PPD reactions but do not cause false-positive reactions with interferon gamma assays. A positive interferon gamma assay is much more accurate than a positive PPD in such patients (LR+ > 10 vs 1.9, respectively).

      2. A CDC report summarized the accuracy of these tests in patients who have not previously received BCG Table 10-6.

   4. Positive results confirm either active or latent TB.

   5. Positive results do not distinguish active TB from LTBI. In patients with pneumonia, a positive result could be due to active TB or latent TB in a patient with some other form of pneumonia (ie, streptococcal).

   6. Negative tests decrease the likelihood of TB infection but are not sufficiently sensitive to rule out active TB when the clinical suspicion is high (LR−, 0.13–0.25).

   7. In addition to the higher specificity and sensitivity of these assays over PPD, they have the added advantage of not requiring a return visit by the patient to have the PPD read, and do not require the expertise of an intradermal injection or reading.

   8. The CDC has recommended that interferon assays be used in prior recipients of BCG and in patients at low likelihood of returning for a second visit to have their PPD interpreted (eg, homeless persons).

5. Diagnosis of active TB

   1. AFB stain and culture

      1. Culture is the gold standard and is specific.

      2. Sensitivity depends on the number of specimens (Table 10-7).

      3. Microscopy

         • (1) Patients with positive smears are more infectious than patients who are culture positive but have negative smears; 35% of family members of persons with positive smears are PPD positive compared with 9% of family members when patients are smear negative.

         • (2) Sputum or other specimens may be stained with Ziehl-Neelsen or a fluorochrome dye.

         • (3) Fluorochrome dyes are more sensitive

         • (4) Ziehl-Neelsen and fluorochrome dyes are nonspecific staining both TB and atypical mycobacteria.

   2. Specific nucleic acid amplification tests of sputum for TB RNA or DNA are specific for TB and can help distinguish TB from other mycobacteria.

      1. Unlike culture, rapidly available within 1–2 days

      2. More specific than AFB smears and helps distinguish TB from Mycobacterium avium complex (MAC) or commensual organisms that are also acid-fast positive.

      3. The CDC recommends nucleic acid amplification testing for all patients being evaluated for TB.

      4. Useful when AFB stains positive

         • (1) Positive rapid tests help confirm TB, negative tests make TB less likely.

         • (2) 95% sensitive and specific in this situation.

      5. Also useful if suspicion of TB is high and smear is negative

         • (1) Rapid tests reported to be 50–80% sensitive, 93% specific.

         • (2) Positive tests suggest TB.

         • (3) Cultures are still required to test for drug susceptibility.

      6. Inhibitors of nucleic acid amplification present in 3–7% of sputum samples. Tests can detect inhibitors when suspected.

   3. A diagnostic algorithm that incorporates sputum smear, nucleic acid amplification and culture for the diagnosis of TB is shown in Figure 10-3.

   4. Bronchoalveolar lavage (BAL)

      1. Bronchoscopy with BAL can be used to diagnose TB and other conditions.

      2. Useful when clinical suspicion of TB is high, sputum AFB smears are negative, and patients are unable to produce sputum

      3. The diagnostic yield of BAL can be augmented by testing BAL specimens with nucleic acid amplification and having patients submit post bronchoscopy sputums for AFB (which are occasionally diagnostic in patients with both negative pre-endoscopy specimens and negative BAL specimens).

   5. Tuberculous pleurisy with effusion

      1. Typical pleural fluid findings

         • (1) Exudative effusion

         • (2) Pleural fluid glucose variable

         • (3) Pleural fluid pH always < 7.4

         • (4) WBC 1000–6000 cells/mcL with neutrophilic predominance early and lymphocytic predominance later

         • (5) Pleural fluid eosinophils > 10% suggests alternative diagnosis (unless prior thoracentesis).

      2. Sensitivity of tests for diagnosis of tuberculous pleurisy

         • (1) Pleural fluid culture, < 30%

         • (2) Pleural biopsy culture, 40–80%

         • (3) Pleural biopsy histology (caseating granulomas), 50–97%

         • (4) Histology and pleural tissue culture > 60–95%

         • (5) Sputum culture, 20–50%

      3. Adenosine deaminase: Utility unclear due to different cut points and different isoenzymes.

      4. Pleural fluid interferon gamma 89% sensitive, 97% specific

Treatment

1. Isolation: see above

2. Principles of therapy

   1. Multidrug resistance TB (MDR-TB) is a significant problem.

   2. Precise drug recommendations evolve due to resistance.

   3. Susceptibility testing is critical to ensure an appropriate regimen is used.

   4. Direct observed therapy (DOT)

      1. Premature discontinuation and nonadherence promotes drug resistance and must be avoided.

      2. DOT refers to treatment protocols where public health officials directly observe patients swallow each dose of medication (administered 2–3 times/week).

      3. DOT is strongly recommended.

   5. Due to the public health risks of MDR-TB, the responsibility for prescribing appropriate therapy and ensuring adherence rests on the public health program and clinician.

   6. Effective regimens require at least 2 drugs to which the organism is susceptible.

   7. Effective therapy takes many months.

   8. To determine the duration of therapy, all patients should have monthly sputum smears analyzed for AFB stain and culture until 2 consecutive sputum cultures are negative.

   9. All patients should be seen monthly to assess symptoms, side effects, and adherence to therapy.

   10. Infectious disease consultation is advised.

   11. TB therapy in HIV-infected patients is complex due to innumerable drug interactions with HAART and the need for differing regimens depending on the degree of immunosuppression. Consultation is advised

3. Multidrug resistant TB (MDR-TB)

   1. Defined as organisms that are resistant to isoniazid and rifampin

   2. Accounts for 3.7% of new cases and 20% of previously treated cases worldwide.

      1. 60% of cases of MDR-TB worldwide were in India, China, and Russia.

      2. In some countries, the rate of MDR-TB among new cases is 9–32% and > 50% in those previously treated.

   3. Suspect MDR-TB in patients previously treated for TB, in patients who are HIV positive, in close contacts of patients with MDR-TB, and in patients who have not responded to therapy.

   4. 9% of MDR-TB cases are extensively drug resistant (XDR-TB).

   5. DOT should be used for patients with MDR-TB.

   6. Surgery is occasionally used for patients with localized disease and persistently positive sputums. Antituberculous therapy is continued.

   7. Expert consultation is mandatory.

4. Treatment in patients at low risk for MDR-TB

   1. Obtain baseline LFTs, CBC, basic metabolic panel, and uric acid. HIV testing is recommended. Tests for hepatitis B and C should be obtained in high-risk groups or patients with abnormal baseline LFTs. Ophthalmology evaluation is recommended for patients receiving ethambutol.

   2. Obtain follow-up LFTs in symptomatic patients and those at high risk for isoniazid hepatotoxicity, including patients with risk factors for hepatitis (eg, alcohol consumption, pregnancy and postpartum, HIV-infection, chronic liver disease, or other hepatotoxic medication) and patients receiving pyrazinamide after the first 2 months.

   3. Initiate therapy with isoniazid, rifampin, pyrazinamide, and ethambutol.

   4. After 2 months, the regimen is simplified to isoniazid and rifampin, if the organism is fully susceptible, for an additional 4 months.

   5. Patients with cavitary TB who have positive sputum culture at 2 months should receive isoniazid and rifampin for an additional 3 months (9 months of therapy altogether).

   6. The median duration of fever after the institution of antituberculous drugs was 10 days but ranged from 1 to 109 days. For patients with tuberculous effusion, resorption can take 4 months.

5. Pleural fluid drainage does not improve outcome in patients with tuberculous effusions (nonempyema).

6. Latent TB

   1. Definition of positive PPD test depends on the population.

   2. The patients with the highest priority for treatment of latent TB include recent contacts of infectious TB, patients with HIV infection, and recent immigrants from areas with high prevalence of TB.

   3. Prior to treatment for LTBI, active infection must be ruled out with a careful history, physical exam, and chest radiograph.

   4. Expert consultation is recommended if exposure to drug-resistant TB is likely.

   5. Isoniazid is most commonly used treatment option; other options exist for patients with isoniazid-resistant TB and in those intolerant of isoniazid.

   6. Isoniazid

      1. Dose is 300 mg/day for 9 months or 900 mg twice a week with DOT.

      2. Side effects

         • (1) Hepatitis

           • (a) Reported incidence is 0.1–2.3%; may be higher in older patients.

           • (b) Alcohol consumption is the most important risk factor for isoniazid hepatitis. Patients who are taking isoniazid should avoid drinking alcohol.

           • (c) Monitor monthly for clinical symptoms of hepatitis.

           • (d) Obtain baseline and monthly LFTs in patients with risk factors for hepatitis (alcohol consumption, pregnant and postpartum patients, HIV-infected patients, patients with chronic liver disease or other hepatotoxic medications). Baseline LFTs are optional for patients without these risk factors.

           • (e) Obtain LFTs in symptomatic patients (right upper quadrant pain, anorexia, or nausea).

           • (f) Discontinue isoniazid in symptomatic patients with transaminase elevations > 3 times the upper limit of normal or in asymptomatic patients with elevations > 5 times the upper limit of normal.

         • (2) Peripheral neuropathy

           • (a) Develops in 2% of patients taking isoniazid

           • (b) Can be prevented with pyridoxine (25–50 mg/day); this is also advised for pregnant women and breastfeeding women taking isoniazid.

Patients with a history of alcohol abuse must be monitored for withdrawal during any hospitalization.

Influenza

Textbook Presentation

Although there is a wide range of severity of influenza symptoms, patients typically complain of a severe, febrile, respiratory illness that began abruptly. Complaints include an abrupt onset ("like being hit by a train”), severe myalgias (even their eyes hurt when they look around), diffuse pain (they may complain that their hair or skin hurts), respiratory symptoms (cough, rhinitis, pharyngitis), and fever that is often pronounced and peaks within 12 hours (occasionally as high as 40–41°C). Patients may have rigors (frankly shaking chills) and headache (Figure 10-4).

Disease Highlights

1. Pathogenesis

   1. Influenza virus A or B infects respiratory epithelium.

   2. Antigenic change in the virus surface glycoprotein (hemagglutinin or neuraminidase) renders populations susceptible to the virus. Antigenic shifts are most common with influenza virus A and are associated with epidemics.

   3. Adults are infectious from the day prior to the onset of symptoms until about 5 days later (10 days in children).

   4. The incubation period is 1–4 days.

2. Epidemiology

   1. Results in 200,000 hospitalizations per year in United States and 3000–49,000 deaths

   2. Influenza typically occurs during the winter months in the Northern and Southern hemispheres (between December and May in the Northern Hemisphere).

   3. Influenza occurs throughout the year in the tropics.

      Influenza is an unlikely diagnosis in the late spring, summer, or early fall.

   4. Current prevalence of influenza helps determine likelihood and is updated (along with susceptibility patterns); see http://www.cdc.gov/flu/weekly/fluactivity.htm.

   5. Spread is primarily airborne (inhalation of virus-containing large droplets aerosolized during coughing and sneezing).

3. Manifestations

   1. History

      1. Onset is sudden in 75% of cases.

      2. Fever

         • (1) Present in 51% of cases

         • (2) Peaks within 12–24 hours of onset of illness

         • (3) Typically 38.0–40.0°C, occasionally 41.0°C

         • (4) Typical duration is 3 days but may last 1–5 days

           High fever within 12–24 hours of symptom onset is typical of influenza but not other viral respiratory pathogens. Fever that increases over several days is not typical of influenza. When accompanied by cough, such a fever suggests bacterial pneumonia.

      3. Prevalence of other symptoms in influenza

         • (1) Headache, 58–81%

         • (2) Cough, 48–94%

         • (3) Sore throat, 46–70%

         • (4) GI symptoms are not characteristic of influenza.

           Patients with significant diarrhea or vomiting should be evaluated for an alternative diagnosis.

      4. Symptoms help distinguish influenza from acute bronchitis or pneumonia (Table 10-8).

      5. Influenza may also present as a COPD or HF exacerbation (with or without fever) and severe febrile illnesses.

   2. Crackles are seen in < 25% of patients.

4. Complications

   1. Pneumonia

      1. High-risk groups for pneumonia and death include

         • (1) Elderly. Influenza mortality rates are 200 times greater in patients over age 65 than in patients aged 0–49 years.

         • (2) HIV-infected patients also suffer a 100 times increase in mortality.

         • (3) Other high-risk groups include patients with heart disease, lung disease, renal disease, diabetes mellitus, hemoglobinopathies, cancer, immunocompromised states, impaired handling of respiratory secretions, morbid obesity, and pregnancy (pre and postpartum) as well as Native Americans and residents of nursing homes facilities.

      2. 2 types of pneumonia are seen in influenza patients: influenza pneumonia as a direct result of influenza infection and postinfluenza bacterial pneumonia.

      3. Influenza pneumonia

         • (1) Often develops within 1 day of onset of influenza

         • (2) Most frequent in patients with underlying cardiopulmonary disease, diabetes mellitus, immunodeficiency states, and pregnancy.

         • (3) Patients with influenza pneumonia complain of shortness of breath more often than patients with uncomplicated influenza (82% vs 17%).

           Obtain a chest film in patients with influenza and shortness of breath to rule out pneumonia.

         • (4) Associated with tachycardia, tachypnea, cyanosis, and crackles on pulmonary exam

         • (5) Hypoxemia and leukocytosis may be seen

         • (6) Chest film shows bilateral or lobar pulmonary infiltrates.

         • (7) 29% mortality

      4. Postinfluenza (secondary) bacterial pneumonia

         • (1) Suspect when initial improvement is followed by relapse with worsening cough, purulent sputum, and increasing fever.

         • (2) Among patients hospitalized for influenza pneumonia, 30% have concomitant bacterial pneumonia caused by S pneumoniae, S aureus (commonly MRSA), or group A streptococci.

         • (3) Chest film may show either bilateral or lobar infiltrates.

         • (4) S pneumoniae is most common (29–48%).

         • (5) S aureus is next most common (7–40%), is highly destructive, and associated with significant incidence of empyema and death.

         • (6) Haemophilus and Moraxella may also cause secondary pneumonia.

   2. Exacerbation of asthma or COPD

   3. Less common complications include HF, myositis, myocarditis, myocardial infarction, pericarditis, meningoencephalitis, Guillain-Barré syndrome

Evidence-Based Diagnosis

1. History, physical exam, and vaccination status. The summary of findings and likelihood ratios is presented in Table 10-9.

   1. The negative LRs are modest, suggesting it is difficult to rule out influenza clinically. The absence of fever and cough helps decrease the likelihood of flu in patients of all ages, but less so in patients aged 60 years or older.

   2. Fever and cough, particularly in older patients, increases the likelihood of influenza.

   3. A clinical prediction rule helps rule in influenza (fever ≥ 37.8°C with at least 2 of the following: headache, myalgia, cough, or sore throat and symptom onset within 48 hours. In addition, the rule requires at least 2 cases of confirmed influenza in the community).

2. Laboratory results

   1. Confirmation is usually not required for affected outpatients but is recommended for all hospitalized patients with suspected influenza.

   2. During influenza outbreaks, empiric therapy (see below) without laboratory confirmation is appropriate in patients with typical symptoms, clear lung fields, and no history of vaccination who present within 48 hours of symptom onset.

   3. Testing is most appropriate in noninfluenza periods and may be particularly useful in identifying outbreaks to implement control measures.

      1. Various methods are available including reverse transcriptase PCR (RT-PCR), culture, immunofluorescence staining, and rapid influenza diagnostic tests (RIDT)

      2. RT-PCR is considered the gold standard and preferred when available. However, it is not widely available and results may be delayed.

      3. RIDT can provide results at the point of care often within 15 minutes.

         • (1) Specificity

           • (a) In general, the RIDTs are highly specific 98.2% (LR+ 34.5).

           • (b) Positive tests help rule in influenza

           • (c) Live attenuated influenza vaccine within the last 7 days can cause false-positive RIDTs.

         • (2) Sensitivity

           • (a) The tests are not terribly sensitive (62.3%) and cannot rule out influenza (LR– 0.38).

           • (b) Test sensitivity is lower in adults than children (53.9% vs 66.6%), and lower in influenza B than influenza A (52.2% vs 64.6%)

           • (c) The tests are most sensitive on days 2 and 3 compared with days 1 or 4 (≈ 75% vs 55%)

         • (3) The source of the sample (throat vs nasopharyngeal swabs) does not affect sensitivity and specificity.

         • (4) Antiviral therapy should not be withheld from patients with a negative RIDT result when the clinical suspicion is high (typical symptoms during influenza season).

      4. The CDC recommends testing hospitalized patients with immunofluorescence, RT-PCR or viral culture.

   4. Institutionalized patients are at higher risk for respiratory syncytial virus, which can mimic influenza. Testing may be useful in such patients.

   5. The IDSA recommends testing in patients in whom it will influence management, especially immunocompromised patients, immunocompetent patients at risk for severe illness, hospitalized patients with pneumonia during influenza season, elderly patients with fever of unknown origin, health care personnel, residents of or visitors to an institution.

Treatment

1. Prevention

   1. The 2013 ACIP recommends annual influenza vaccination for all persons ≥ 6 months ideally by October of each year (in the Northern Hemisphere)

      1. A variety of vaccines are available, including

         • (1) Inactivated influenza vaccine, which may be trivalent or quadrivalent,

         • (2) Recombinant influenza vaccine, trivalent

         • (3) Live attenuated intranasal influenza vaccine, quadrivalent

      2. Inactivated influenza vaccine

         • (1) Uses inactivated (killed) viruses that are currently prevalent.

         • (2) Updated and administered annually.

         • (3) Vaccination results in 50% fewer cases of influenza, associated pneumonia, and hospitalizations.

         • (4) 68% decrease in all cause mortality

         • (5) Contraindications

           • (a) Egg allergy: A subset of inactivated influenza vaccines can be used in patients with egg allergy (eg, Flucelvax)

           • (b) Significant febrile illness at time of vaccination (Patients may be vaccinated during mild nonfebrile upper respiratory tract infections.)

           • (c) History of Guillain-Barré syndrome following prior vaccination

         • (6) Adverse effects

           • (a) Soreness at injection site occurs in 10–64% of patients.

           • (b) No increase in systemic symptoms (compared with placebo)

           • (c) Guillain-Barré may increase by 1 case per million recipients.

           • (d) Upper respiratory tract infection symptoms are not more common than placebo.

           • (e) Inactivated influenza vaccine cannot cause influenza.

      3. Live attenuated intranasal vaccine

         • (1) Uses live-attenuated strains administered intranasally that replicate poorly in the warmer lower respiratory tract.

         • (2) Increases upper respiratory symptoms due to intranasal viral replication. Compared with placebo, live attenuated intranasal vaccine increases nasal congestion (45% vs 27%) and sore throat (28% vs 17%).

         • (3) Persons vaccinated with live attenuated intranasal influenza vaccine can transmit the attenuated infection to other persons.

         • (4) Should not be given to contacts of severely immunosuppressed individuals (ie, hematopoietic stem cell recipients).

         • (5) Approved for healthy nonpregnant persons 2–49 years

         • (6) Updated and administered annually

         • (7) Should not be given to patients with significant nasal congestion that may impair delivery

         • (8) Still under study in older adults

         • (9) Contraindications include egg allergy, pregnancy, a prior history of Guillain-Barré syndrome, or underlying medical conditions that serve as an indication for inactivated influenza vaccination (heart or lung disease [including asthma but excluding hypertension]; immunocompromise; renal, hepatic, or hematologic disease [including sickle cell disease]; neurologic or neuromuscular disease; pregnancy; immunosuppression; morbid obesity; and nursing home residents).

   2. Chemoprophylaxis

      1. Significantly more costly than vaccination

      2. Oseltamivir and zanamivir are neuraminidase inhibitors active against influenza viruses A and B and are usually highly effective as chemoprophylaxis.

      3. Amantadine and rimantadine are not effective against influenza B (and often not against influenza A) and should not be used for chemoprophylaxis or treatment.

      4. Indications for chemoprophylaxis

         • (1) Persons at high risk (or those who come in contact with such persons) who were vaccinated after exposure to influenza (continue treatment until 7 days after last exposure or 2 weeks after vaccination). Additionally, such patients should receive chemoprophylaxis if there was a poor match between the vaccine and circulating virus strain.

         • (2) Persons with immune deficiencies who are unlikely to mount a response to vaccination (ie, those with advanced HIV disease) could also receive prophylaxis.

         • (3) Persons with contraindications to vaccination.

         • (4) Persons living in institutions during outbreaks (ie, nursing homes) regardless of vaccination status.

2. Treatment of influenza

   1. Zanamivir and oseltamivir

      1. When given within 48 hours of symptom onset, they reduce the symptom severity and the duration of symptoms approximately 1–2 days. Oseltamivir has also been demonstrated to reduce the incidence of pneumonia.

      2. A benefit may be present when started within 96 hours of symptoms in hospitalized patients.

      3. Safety during pregnancy is unknown.

      4. Studies suggest that empiric therapy is cost effective for several groups.

      5. RIDT is recommended if prevalence of influenza is low.

   2. Oseltamivir

      1. Route of administration is oral. Taking the drug with food decreases nausea and vomiting, which occurs in 10% of patients.

      2. Transient neuropsychiatric events have been recorded.

      3. Reduce the dose by 50% if creatinine clearance < 30 mL/min.

      4. Drug resistance

         • (1) A strain of influenza A (H1N1) was discovered to be resistant to oseltamivir in the 2008–2009 season (99% of isolates).

         • (2) The CDC has recommended combining oseltamivir with rimantadine or using zanamivir alone for this strain or if the influenza strain is unknown.

         • (3) Oseltamivir alone is recommended for other strains of influenza (influenza B or influneza A, H3N2).

   3. Zanamivir

      1. Route of administration is inhalation; can cause bronchospasm. Other adverse side effects include diarrhea and nausea.

      2. Not recommended in patients with asthma or COPD.

   4. Indications for treatment in patients with suspected influenza

      1. All hospitalized patients, patients with severe influenza (pneumonia), and patients at high risk for complications including pregnant patients (see above Complications)

      2. Therapy should be started within 48 hours when possible but may still provide a benefit in severely sick patients when started within 5 days of symptom onset.

      3. In addition to antiviral therapy, patients with influenza pneumonia and postinfluenza pneumonia should receive anti-bacterial coverage that includes coverage for methicillin-resistant S aureus (MRSA).

      4. Consider for patients without risk factors for complications who present within 48 hours of symptom onset and wish to shorten the duration of illness.

Healthcare-Associated Pneumonia (HCAP)/Hospital-Acquired Pneumonia (HAP) and Ventilator-Associated Pneumonia (VAP)

Textbook Presentation

Patients with HCAP present similarly to patients with CAP although they are often sicker due to a combination of greater comorbidities and an increased likelihood of colonization and infection with virulent pathogens. Those with HAP may be recovering from surgery when fever or delirium heralds the development of HAP.

Disease Highlights

1. A variety of clinical situations increase the likelihood that patients are colonized with multidrug resistant bacteria.

2. Pneumonia in such patients is often secondary to these multidrug resistant organisms and requires different antimicrobial coverage than patients with CAP.

3. Mortality in patients with HCAP is greater than for patients with CAP (19.8–24.6% vs 9.1–10%).

4. Risk factors include recent or current hospitalization, mechanical ventilation, nursing home and assisted-living residence, hemodialysis, infusion therapy or immunosuppression.

5. Classification

   1. HCAP: Pneumonia that develops in any of the following:

      1. A nonhospitalized patient within 90 days of a prior hospitalization

      2. Nursing home or long-term–care facility resident

      3. Patients receiving antibiotics or chemotherapy

      4. Patients who have received wound care within last 30 days

      5. Patients undergoing hemodialysis or home infusion

   2. HAP: Pneumonia that develops more than 48 hours after hospitalization.

   3. VAP: Pneumonia that was not present on admission and develops more than 48–72 hours after endotracheal intubation.

6. Patients with HCAP, HAP, or VAP are at markedly increased risk for infection with multidrug resistant organisms, including MRSA, gram-negative bacilli including Pseudomonas aeruginosa and Acinobacter baumanii. They may also be infected with organisms that commonly cause CAP (S pneumoniae and H influenzae).

Evidence-Based Diagnosis

1. The diagnosis of pneumonia is typically made clinically by the presence of a new lung infiltrate and ≥ 2 of the following: fever > 38°C, leukocytosis or leukopenia, and purulent secretions.

2. The American Thoracic Society Guidelines recommend obtaining a lower respiratory tract culture in these patients. Samples may include endotracheal aspirate, or samples from bronchoscopy (BAL or protected brush specimen.)

3. Blood cultures are recommended for patients with VAP.

Treatment

1. Antimicrobial spectrum should be broadened to cover afore mentioned bacteria taking into account local resistance patterns and available culture data

2. Recent recipients of antibiotics should include antibiotics from a different class

3. Typically coverage includes antibiotics active against both MRSA and Pseudomonas. Infectious disease consultation is recommended.

Pertussis

Textbook Presentation

The typical adult with pertussis presents with “viral type” upper respiratory infection symptoms of nonproductive cough, rhinorrhea, sore throat, and sneezing. However, instead of resolving over 3–7 days the cough persists and is paroxysmal, often severe and occasionally even terminates in posttussive emesis. Whooping, a deep inspiration at the end of a cough, is unusual in adults.

Disease Highlights

1. The average incubation period is 7–10 days but may be 28 days or longer.

2. Half of pertussis cases occur in adolescents and adults.

3. Develops in about one-third of household contacts.

4. Typically occurs in 3 stages: catarrhal, paroxysmal, and chronic.

   1. Catarrhal stage lasts 1–2 weeks.

      1. Typical symptoms include rhinitis, lacrimation, sore throat, coughing, and sneezing.

      2. The cough is usually mild.

      3. Fever is absent or low grade.

   2. Paroxysmal phase begins in the second week with fits of 5–10 or more forceful coughs (paroxysms) in an otherwise well appearing patient.

      1. A deep inspiration may occur at the end of coughing (the “whoop").

      2. Emesis may occur at the end of coughing.

      3. Can last 2–3 months (the chronic phase).

      4. The cough may be severe and prevent sleeping.

      5. Unusual complications from coughing in adults include hernia, pneumothorax, rib fracture, and weight loss.

Evidence-Based Diagnosis

1. Among patients with cough of > 6–7 days the prevalence of pertussis is 3–20% but the likelihood increases in adult patients with acute cough > 3weeks 12–32%.

2. The median duration of cough is 42 days (27–66).

3. Clinical symptoms

   1. Absence of paroxysms or posttussive gagging makes pertussis unlikely.

      1. Paroxysmal cough: 100% sensitivity, 12% specificity, LR+ 1.1, LR– 0

      2. Posttussive gagging: 100% sensitive, 28.7% specific, LR+ 1.4, LR– 0

   2. No symptom is terribly specific or diagnostic.

      1. Whooping sensitivity 26%, specificity 85.4%, LR+ 1.8, LR– 0.9

      2. Posttussive emesis sensitivity 56%, specificity 68%, LR+ 1.7, LR– 0.65

   3. Productive cough makes pertussis unlikely (occurs in 3% of patients with pertussis)

      Pertussis is unlikely in patients with productive coughs.

   4. Other common causes of persistent cough include other infections, therapy with an ACE inhibitor, gastroesophageal reflux disease, asthma, and allergic cough.

   5. Testing options include culture, PCR, and serology.

      1. Culture is 30–60% sensitive, 100% specific, and takes 7–10 days.

      2. For patient with symptoms of 2–4 weeks, culture and PCR are recommended.

      3. For patients with symptoms > 4 weeks, serology is recommended (diagnosis is confirmed with a 4-fold change in titer or an IgG anti-PT level ≥ 100–125 EU/mL).

Treatment

1. Vaccination

   1. Childhood vaccination diminishes over 5–10 years and is rarely effective for more than 12 years.

   2. ACIP recommends a single Tdap vaccination for all adults.

2. Treatment

   1. Treatment usually started during the paroxysmal phase.

      1. Probably does not affect the course of illness

      2. Decreases spread to others. Without postexposure prophylaxis (see below) the secondary attack rate is > 80% among susceptible persons.

      3. Infected patients should avoid contact with young children and infants and working in healthcare facilities for at least 5 days after starting antibiotics.

   2. Azithromycin and clarithromycin are drugs of choice.

   3. Postexposure prophylaxis recommended for people in close contacts with pertussis regardless of the immunization status.