acute respiratory complaints of cough and congestion

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acute respiratory complaints of cough and congestion

Scott D. C. Stern, MD

CHIEF COMPLAINT

PATIENT

Ms. L is a 22-year-old woman who comes to your office in November complaining of cough and fever.

What is the differential diagnosis of acute cough and congestion? How would you frame the differential?

CONSTRUCTING A DIFFERENTIAL DIAGNOSIS

The differential diagnosis of acute cough and congestion ranges from trivial self-limited upper respiratory viral infections to serious, imminently life-threatening pneumonia. Importantly, there are many causes of pneumonia that need to be identified in order to make an accurate diagnosis and provide appropriate treatment.

Differential Diagnosis of Acute Cough and Congestion

A.  Common cold

B.  Sinusitis

C.  Bronchitis

D.  Influenza

E.  Pertussis

F.  Pneumonia

1.  Community-acquired pneumonia (CAP)

2.  Hospital-acquired pneumonia

3.  Aspiration pneumonia

4.  Tuberculosis (TB)

5.  Opportunistic (eg, Pneumocystis jirovecii pneumonia [PJP])

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 a CAP vs. another type of pneumonia (such as PJP, aspiration pneumonia, TB, etc.) that requires additional diagnostic evaluation and/or treatment?

PATIENT

Ms. L reports that she was in her usual state of health until 5 days ago when a cough developed. There was no associated sore throat, rhinitis, myalgias or headache. Two days ago, a low-grade fever (37.8°C) developed, which increased last night to 38.8°C. She reports that her sputum is yellow and that she has no chest pain or shortness of breath.

How reliable is the history and physical exam for detecting pneumonia?

A.  The diagnosis of pneumonia is usually based on clinical findings (cough, fever, crackles), accompanied by infiltrate on chest film. Microbiologic confirmation is usually unnecessary.

B.  When evaluating a patient who has acute respiratory symptoms it is imperative to determine who is likely to have pneumonia and therefore needs a radiograph to evaluate their symptoms.

C.  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 with a cough.

3.  Dyspnea, 46–66%

4.  Pleuritic chest pain, 37–50%

5.  Chills, 59%

6.  Headache, 58%

D.  Physical exam

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

Table 10-1. Likelihood ratios for physical findings in pneumonia.

a.  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.

b.  Normal vital signs make pneumonia less likely (LR–, 0.18).

c.  The combination of normal vital signs and normal chest exam make pneumonia highly unlikely (sensitivity, 95%; LR–, 0.09).

Normal vital signs and a normal lung exam make pneumonia unlikely.

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

In summary, there are signs and symptoms that 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, and abnormal findings on chest examination (dullness to percussion, crackles, decreased breath sounds, bronchophony, or egophony). Any patient with such symptoms or signs requires 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, patients with heart failure, chronic kidney disease, or chronic obstructive pulmonary disease (COPD) (in whom abnormal lung findings are also more difficult to appreciate). On the other hand, patients with normal vital signs, a normal lung exam and who are not at risk for poor outcomes do not normally need a chest radiograph. Figure 10-1 shows a diagnostic algorithm illustrating the initial approach to patients with cough and congestion.

Figure 10-1. Initial approach to patients with cough and congestion.

In patients discovered to have pneumonia, the next pivotal step is to determine the likely etiologic pathogen(s) to ensure patients receive appropriate therapy. While most patients seen in the community with pneumonia have community-acquired pneumonia (due to Streptococcus pneumoniae, Mycoplasma pneumoniae, Legionella, and others), it is important to realize that many patients from the community have other types of pneumonia (ie, aspiration pneumonia, influenza pneumonia, TB pneumonia, etc.) caused by other pathogens that require different/additional antimicrobial therapy. A careful review of both the patient’s risk factors and chest radiograph often provide critical clues that suggest additional microorganisms needing evaluation and antibiotic coverage (Figure 10-2).

Figure 10-2. Diagnostic approach to pneumonia.

Pneumonia in patients with known immunocompromise will not be covered in this chapter (known HIV, transplant recipients, and patients with granulocytopenia).

On physical exam, Ms. L is in no acute distress. Vital signs are RR, 18 breaths per minute; BP, 110/72 mm Hg; pulse, 92 bpm; temperature, 38.8°C. Pharynx is unremarkable; lung exam reveals normal breath sounds without crackles, dullness, bronchophony, or egophony.

At this point, what is the leading hypothesis, what are the active alternatives, and is there a must not miss diagnosis? Given this differential diagnosis, what tests should be ordered?

RANKING THE DIFFERENTIAL DIAGNOSIS

As noted above, the initial differential diagnosis of acute cough and fever includes acute bronchitis, influenza, and pneumonia. Like many real-life patients, this patient’s clinical picture is not typical for any of these conditions. Acute bronchitis may cause a cough and low-grade fever but 38.8°C is unusual. Pneumonia could clearly cause a cough and fever but is often associated with an abnormal lung exam. Influenza often causes cough and fever, (and a normal lung exam) but the subacute onset of fever and lack of other upper respiratory symptoms is unusual. It is also early in the season for influenza. Nonetheless, you decide that influenza is the leading hypothesis with acute bronchitis and pneumonia being active alternatives. Given the clinical uncertainty, a chest film and nasopharyngeal swab for influenza are ordered. Table 10-2 lists the differential diagnosis.

Table 10-2. Diagnostic hypotheses for Ms. L.

Leading Hypothesis: Influenza

Textbook Presentation

Although there is a wide range of severity of influenza symptoms, patients typically complain of a severe, febrile, respiratory illness that begins abruptly. The onset is often abrupt (“like being hit by a train”), associated with 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 high fever (occasionally as high as 40–41°C) that peaks within 12 hours. Patients may have rigors (frankly shaking chills) and headache (Figure 10-3).

Figure 10-3. Timetable of symptoms and signs of influenza. (Reproduced with permission from Montalto NJ: An office-based approach to influenza: Clinical diagnoses and laboratory testing, Am Fam Physician. 2003 Jan 1;67(1):111–118.)

Disease Highlights

A.  Pathogenesis

1.  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.

2.  Influenza infects respiratory epithelium.

3.  Adults are infectious from the day prior to the onset of symptoms until about 5–7 days later (10 days in children).

4.  The incubation period is 1–4 days.

B.  Epidemiology

1.  Results in 55,000–431,000 hospitalizations per year in the United States and 17,000–51,000 deaths

2.  Influenza typically occurs during the winter months (between December and March in the Northern Hemisphere versus April and September in the Southern 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 frequently by the CDC: https://www.cdc.gov/flu/weekly/fluactivitysurv.htm.

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

C.  Manifestations

1.  History

a.  Onset is sudden in 75% of cases.

b.  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.

c.  Prevalence of other symptoms in influenza

(1)  Headache, 58–81%

(2)  Cough, 48–94%

(3)  Sore throat, 46–70%

(4)  Gastrointestinal symptoms are not characteristic of influenza.

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

d.  Symptoms help distinguish influenza from acute bronchitis or pneumonia (Table 10-3).

Table 10-3. Comparison of features in influenza, community-acquired pneumonia, and acute bronchitis.

e.  Influenza may also present as a COPD or heart failure exacerbation (with or without fever) and severe febrile illnesses.

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

D.  Complications

1.  Pneumonia

a.  Influenza may cause pneumonia. This should be suspected in patients with dyspnea, tachypnea, hypoxia, abnormal lung findings or sepsis and is confirmed radiographically. Dyspnea is seen in 82% of influenza patients with pneumonia vs 17% without.

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

b.  Groups at high risk 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 have a 100-fold increase in mortality compared to immunocompetent patients < 49 years.

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

c.  Influenza pneumonia

(1)  Influenza may cause pneumonia but is often associated with bacterial coinfection.

(a)  Bacterial coinfection is present in at least 18–34% of cases managed in the ICU and up to 55% of fatal cases.

(b)  Common pathogens include S pneumoniae, Staphylococcus aureus (commonly methicillin-resistant S aureus), and group A streptococci.

(c)  Clinical features do not distinguish patients with or without coinfection.

(d)  Although bacterial infection has often been taught to occur after influenza, it often develops during periods of high viral shedding, and develops concurrent with or shortly after influenza infection.

(e)  Additionally, symptoms and radiographs are similar between patients with influenza pneumonia with or without coinfection. While some radiographic findings can suggest necrotizing pneumonia due to S aureus (cavitary disease, pleural effusions), they are not sufficiently sensitive to rule it out. Chest film shows bilateral or lobar pulmonary infiltrates.

Suspect and treat bacterial superinfection in patients with influenza and pneumonia.

2.  Exacerbation of asthma or COPD

3.  Less common complications include heart failure, myositis, myocarditis, myocardial infarction, pericarditis, meningoencephalitis, Guillain-Barré syndrome, septic shock, and multiorgan failure.

Evidence-Based Diagnosis

A.  The history, physical exam, and vaccination status affect the likelihood of disease. The summary of findings and likelihood ratios are presented in Table 10-4.

Table 10-4. Likelihood ratios for signs and symptoms in influenza.

1.  The negative LRs are modest, suggesting it is difficult to rule out influenza clinically.

a.  The absence of fever and cough helps decrease the likelihood of flu but does not rule it out (LR–, 0.4–0.42). They are even less useful in ruling it out in patients aged 60 years or older (LR–, 0.72, 0.57).

Influenza should be considered in febrile elderly patients during influenza season, even in those without cough.

b.  An emergency department study confirmed the poor sensitivity of a clinical diagnosis of influenza (sensitivity, 36%; specificity, 78%; LR+, 1.6; LR–, 0.82)

c.  Another emergency department study documented that < 50% of patients with influenza of < 48 hours and a CDC indication for influenza treatment received antiviral therapy.

d.  The CDC definition of an “influenza-like illness” (temperature > 37.8°C with either cough or sore throat) is also insensitive (sensitivity, 31%; specificity, 88%; LR+, 2.6; LR–, 0.78).

2.  Fever with cough, particularly in older patients, increases the likelihood of influenza (LR+, 5.0).

Fever > 37.8°C with cough should suggest influenza (as well as various types of pneumonia), particularly in patients ≥ 60 years old.

3.  A clinical prediction rule helps rule in influenza:

a.  Fever ≥ 37.8°C with at least 2 of the following: headache, myalgia, cough, or sore throat and symptom onset within 48 hours.

b.  In addition, the rule requires at least 2 cases of confirmed influenza in the community (LR+, 6.5).

B.  Laboratory results

1.  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.

2.  The Infectious Diseases Society of America (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 institutionalized persons.

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

a.  Various methods are available including reverse transcriptase polymerase chain reaction (RT-PCR), culture, immunofluorescence staining, and rapid influenza diagnostic tests

(1)  RT-PCR

(a)  The gold standard for the diagnosis of influenza

(b)  Virtually 100% sensitive and specific

(c)  However, sensitivity of RT-PCR of nasopharyngeal samples is only 50% in patients with severe influenza pneumonia.

(d)  Takes 1–8 hours to perform and is done in the laboratory (and not on site in the clinics).

(2)  A large variety of more rapid tests, which include rapid influenza diagnostic tests that detect influenza antigens, digital immune assays, and nucleic acid amplification tests (NAAT), have been developed to diagnose influenza and many can be done on site.

(a)  The sensitivity of these tests is suboptimal (33–87%) and negative tests do not rule out influenza (LR–, 0.13–0.67), especially in patients with severe disease or in patients in whom influenza is strongly suspected. Empiric therapy or PCR testing is appropriate in some patients.

(b)  The specificity is high (97%) and positive tests confirm the diagnosis of influenza. (LR+, 23–100). However, positive test results do not rule out concomitant bacterial infection, which should still be considered in patients with influenza and pneumonia.

4.  Figure 10-4 illustrates the CDC recommendation for influenza testing.

Figure 10-4. Centers for Disease Control and Prevention recommendation for influenza testing. (Reproduced with permission from Centers for Disease Control and Prevention, National Center for Immunization and Respiratory Diseases (NCIRD). Guide for considering influenza testing when influenza viruses are circulating in the community. Last reviewed March 4, 2019.)

5.  In hospitalized patients with severe lower tract infection, lower respiratory tract specimens (ie, sputum, endotracheal aspirate, or bronchoalveolar lavage [BAL]) should also be collected and tested with RT-PCR as they may be positive despite negative results from nasopharyngeal swabs.

6.  Patients with pneumonia should have additional testing for coinfection including a sputum Gram stain, sputum and blood cultures, and urine for Streptococcal and Legionella antigen.

Treatment

A.  Prevention

1.  Vaccination

a.  Vaccination results in 50% fewer cases of influenza, associated pneumonia, and hospitalizations.

b.  68% decrease in all cause mortality

c.  Due to the high rate of influenza virus mutation, the vaccine is modified annually to match the current strains of circulating virus. It is administered annually from late October until the end of influenza season, typically May.

d.  The 2018–2019 Advisory Committee on Immunization Practices (ACIP) recommends annual influenza vaccination for all persons ≥ 6 months who do not have contraindications.

e.  Persons at increased risk for complications from influenza (see above) should be especially targeted for vaccination. Other targeted populations include caregivers for the aforementioned patients and health care personnel.

f.  A variety of influenza vaccines are available including inactivated virus vaccines, recombinant vaccines, and live-attenuated virus vaccines. Preparations may be trivalent (targeting 3 currently active influenza viruses) or quadrivalent (targeting 4 viruses), standard dose or high dose or adjuvanted. The optimal choice varies annually. The ACIP annual recommendations can be found at https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/flu.html.

g.  Live-attenuated intranasal vaccine uses live-attenuated strains administered intranasally that replicate poorly in the warmer lower respiratory tract. Upper respiratory infection side effects are common. Compared with placebo, they increase upper nasal congestion (45% vs 27%) and sore throat (28% vs 17%). Additionally, persons vaccinated with live-attenuated intranasal influenza vaccine can transmit the attenuated infection to other persons.

h.  Contraindications (for any of the influenza vaccines)

(1)  Any prior allergic reaction to the influenza vaccine

(2)  History of Guillain-Barré syndrome following influenza vaccination.

(3)  Moderate to severe current illness with or without a fever.

(4)  Egg allergy is not a contraindication to influenza vaccination.

(5)  Additional contraindications/precautions exist for the live-attenuated vaccine. Its use should be limited to patients ≤ 49 and it should not be given to patients with asthma or any of the high-risk conditions listed above. It should not be administered to persons who are caregivers to patients with either asthma or are immunocompromised. Additionally, antiviral medications in the 48 hours prior to vaccination or the week following vaccination may interfere with its effectiveness.

2.  Chemoprophylaxis

a.  Significantly more costly than vaccination

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

c.  Indications for chemoprophylaxis

(1)  Persons at high risk (or those who come in contact with such persons) who were vaccinated after exposure to influenza. 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, transplant recipients) could also receive prophylaxis.

(3)  Persons with contraindications to vaccination.

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

B.  Treatment of influenza

1.  Zanamivir and oseltamivir

a.  When given within 48 hours of symptom onset, to patients with documented influenza, they reduce the symptom severity and the duration of symptoms approximately 1 day. Oseltamivir has also been demonstrated to reduce the incidence of lower respiratory tract infections requiring antibiotics (NNT 22), pneumonia (ARR 1.1% NNT 90) and all-cause hospitalizations (NNT 91).

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

c.  Safety during pregnancy is unknown.

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

e.  Influenza testing (see above) is recommended if prevalence of influenza is low.

2.  Oseltamivir

a.  Route of administration is oral. Side effects include nausea (NNH 27) and vomiting (NNH 21).

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

c.  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 influenza A, H3N2).

3.  Zanamivir

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

b.  Not recommended in patients with asthma or COPD.

4.  Peramivir 600 mg IV × 1 dose, is an alternative for patients with uncomplicated influenza with symptoms of less than 2 days in duration.

5.  Indications for treatment in patients with suspected influenza

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

b.  Therapy should be started within 48 hours when possible but may still provide a benefit when started within 5 days of symptom onset in severely sick patients and those at risk for complications.

c.  When indicated, treatment should be initiated as soon as possible and not delayed while awaiting test results.

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

e.  In addition to antiviral therapy, patients with influenza and pneumonia should receive antibacterial coverage that includes coverage for S pneumoniae and S aureus (commonly MRSA).

Ms. L’s RT-PCR is negative for influenza.

Is the clinical information sufficient to make a diagnosis? If not, what other information do you need?

Given the high sensitivity of the RT-PCR, a negative result essentially rules out influenza, (even more so given the modest pretest probability of influenza in November).

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

You wonder about acute bronchitis and pneumonia and wait for the results of the chest radiograph.

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 and Stridor).

Disease Highlights

A.  Etiology

1.  Viruses (including influenza, parainfluenza, respiratory syncytial virus, adenovirus, rhinovirus and coronavirus)

2.  Bacterial

a.  Bacteria cause < 10% of cases

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

3.  Noninfectious

a.  Asthma

b.  Pollution

c.  Tobacco

d.  Cannabis

B.  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

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

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

Evidence-Based Diagnosis

A.  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.

B.  Chest film is not routine but should be obtained when pneumonia is being considered (see Figure 10-1); indications include any of the following:

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

C.  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 above).

Treatment

A.  Antibiotics

1.  Antibiotics do not provide major clinical benefit and are not recommended for most patients with acute bronchitis.

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

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

C.  Antitussives and expectorants are useful symptomatic measures.

A chest film reveals a left lower-lobe infiltrate, confirming the diagnosis of pneumonia.

Is the clinical information sufficient to make a diagnosis of community-acquired pneumonia? If not, what other information do you need?

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 occur.

Disease Highlights

A.  CAP typically refers to patients with signs, symptoms, and radiographic evidence of pneumonia without known immunocompromise, and that was not hospital acquired (developing more than 48 hours after admission).

B.  Most common cause of infectious death and hospitalization in the United States

C.  Epidemiology

1.  Epidemiology varies with location, time period and diagnostic tool utilized. The local epidemiology and time period are important considerations (ie, influenza season).

2.  S pneumoniae is usually the most common pathogen. Other bacterial pathogens include M pneumoniae, S aureus, Legionella, and others

3.  Viral infection is common. A meta-analysis revealed a viral pathogen in 44.2% of patients (in studies that sampled lower respiratory tract with BAL and sputum). Common viruses include human rhinovirus, influenza A and B, human metapneumovirus, respiratory syncytial virus, parainfluenza virus, coronavirus, and others.

4.  Viral-bacterial coinfection is surprisingly common in patients with CAP.

a.  Concomitant viral and bacterial infections occurred in 19–39% of all patients, 44% of patients with S pneumoniae.

b.  In one study of severe CAP, 79% of patients with a positive viral PCR also had bacterial infection.

c.  Furthermore, the odds ratio of death was higher in patients with concomitant infection 2.1 (1.3–3.3)

A positive viral PCR does not exclude concomitant bacterial CAP.

D.  3.4% of pneumonia are associated with underlying malignancy (postobstructive pneumonia)

E.  Complications

1.  Respiratory failure

2.  Sepsis

3.  Death

4.  Empyema (See Chapter 9, Chest Pain)

F.  Prognosis is good overall.

1.  8% hospitalization rate

2.  95% radiographic cure in 1 month

3.  Mortality 1.2%

Evidence-Based Diagnosis

A.  The diagnosis of CAP is classically made in patients with a combination of infectious symptoms (fever, chills, or rigors), respiratory symptoms (dyspnea) and signs (cough, chest pain, and crackles), and infiltrate on chest film.

B.  However, patients often lack 1 or more of these elements.

C.  As noted in Table 10-1 neither the absence of fever nor a normal lung exam individually rules out pneumonia (LR–, 0.6–0.8), so clinicians must maintain a high level of vigilance. However, the absence of both fever and abnormal lung findings makes the diagnosis unlikely (LR–, 0.08).

D.  Imaging

1.  Chest radiograph

a.  Most commonly used test to diagnose or exclude pneumonia but imperfect

b.  Sensitivity 71–78%, specificity 59–91% when compared with chest CT scan or discharge diagnosis (LR+, 1.9–8.1; LR–, 0.3–0.4). Additionally, a single anterior-posterior chest film has a lower sensitivity than posteroanterior and lateral views (59% vs 90%).

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

c.  False-negative chest films were more common in patients with crackles on exam or a high C-reactive protein.

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.

d.  Sensitivity may be lower in dehydrated patients.

e.  In CAP, 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.

2.  Chest CT

a.  Imaging more detailed than chest radiograph with results that are often different and change management

(1)  In 1 emergency department study, one-third of patients with a normal chest film had infiltrates on CT scan (suggesting that these patients had pneumonia).

(2)  30% of patients with an apparent infiltrate on chest film did not have an infiltrate on CT scan.

(3)  25% of patients had their antibiotic plan revised based on CT findings.

(4)  14% of patients had their site of care plan changed based on CT findings.

b.  CT scanning should be considered in the evaluation of patients with CAP especially those with clinical or laboratory evidence that favors CAP but have a normal chest film.

3.  Ultrasound

a.  Ultrasound has not typically been used to diagnose patients with CAP.

b.  Meta-analysis reported a wide range in sensitivity 57–99%, specificity 54–99%, LR+, 1.8–95, and LR–, 0–0.54; 95% confidence interval sensitivity 80–90%, specificity 70–90%.

c.  The appropriate role of ultrasonography in CAP is unclear.

E.  An elevated WBC is neither sensitive nor specific. WBC > 10,400 cells/mcL: LR+, 3.7; LR–, 0.6

F.  Procalcitonin

1.  A biomarker expressed in bacterial infections that has been evaluated both as a diagnostic tool for CAP and a tool to identify which patients with CAP would benefit from antibacterial therapy

2.  Several studies suggest that procalcitonin does not adequately identify pneumonia with considerable overlap between patients with and without CAP

G.  Legionella urinary antigen is 70–90% sensitive and 99% specific.

H.  PCR

1.  Nucleic acid detection with PCR can identify adenovirus, coronavirus, human metapneumovirus, rhinovirus, influenza A and B, parainfluenza, respiratory syncytial virus, pertussis, Chlamydophila, and Mycoplasma.

2.  Role in the evaluation of patients with CAP is limited.

a.  Nasopharyngeal PCR does not identify common bacterial pathogens (eg, S pneumoniae, Legionella).

b.  Given the high frequency of bacterial and viral coinfection, documentation of viral infection does not exclude bacterial infection nor the need for antimicrobial therapy.

c.  Limited sensitivity and specificity.

(1)  Specificity < 85%. 15% of asymptomatic outpatients have positive nasopharyngeal PCR tests.

(2)  Unlike the excellent sensitivity of nasopharyngeal PCR in most patients with influenza, the sensitivity of nasopharyngeal PCR is only 50% in patients with severe influenza pneumonia.

A negative nasopharyngeal PCR does not exclude viral or bacterial infection.

Treatment

A.  Prevention

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

a.  A 23-valent pneumococcal polysaccharide vaccine (PPSV 23) and a 13-valent pneumococcal conjugate vaccine (PCV 13)

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

2.  Vaccine recommendations (ACIP)

a.  All adults aged ≥ 65 years: PCV 13 should be administered first followed 6–12 months later by PPSV23.

b.  Adults who previously received PPSV23 should receive PCV 13 at least 1 year later.

c.  Also indicated in adults ≥ 19 with any of the following: immunocompromise, asplenia, cerebrospinal fluid leak or cochlear implants, chronic heart or lung disease, advanced kidney disease.

B.  Evaluation

1.  Chest film is recommended in the evaluation of all patients with suspected 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 in patients with respiratory distress.

4.  Determining the causative agent:

a.  Although CAP is the most common pneumonia among outpatients, clinicians should always consider other less common pneumonia including aspiration, TB, PJP, and hospital-acquired pneumonia (see Figure 10-2), which may warrant additional testing and 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)  Known HIV, HIV risk factors or bilateral fluffy infiltrates increase the likelihood of PJP.

(4)  Recent hospitalization warrants coverage for hospital-acquired pneumonia.

(5)  Cavitary infiltrates, pleural effusions, and frank hemoptysis suggests an exotoxin-producing MRSA that has been increasingly identified in otherwise healthy outpatients with CAP. Patients may also have an erythematous rash and skin pustules.

b.  In the absence of clinical or radiographic clues that suggest other types of pneumonia, most patients should receive treatment covering the most common responsible organisms.

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

a.  The yield of these tests in outpatients with CAP is low and routine testing is optional in outpatients.

b.  Sputum cultures are often unreliable due to contamination by oral flora.

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

(2)  Positive in 14–19% of patients with S pneumoniae.

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

c.  Sputum Gram stains are also often unreliable due to poor quality, preparation, and interpretation.

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

(2)  Positive in 63–80% of patients with pneumococcal bacteremia

d.  Blood cultures positive in 5–14% of all patients with CAP and 39–57% of patients with S pneumoniae.

e.  Urinary antigen for S pneumoniae is positive in 30–89% of patients.

f.  The true sensitivity of each of these tests is likely to be lower due to the lack of a gold standard for diagnosis (eg, tissue culture). One study suggested that S pneumoniae caused the majority of cases of CAP in patients with negative conventional tests (sputum culture, blood culture, and urine antigen).

S pneumoniae is not ruled out with conventional testing.

g.  The IDSA has published guidelines for more extensive testing on select inpatients (Table 10-5). Some authorities also recommend influenza testing during the influenza season, especially in patients with CAP that may require ICU admission, or associated with liver disease, lung disease, or asplenia.

Table 10-5. IDSA guidelines for more extensive testing in persons with CAP.

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

i.  PCR testing: See above

6.  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).

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

C.  Determine the need for hospitalization

1.  Indications for admission

a.  Hypoxia or respiratory failure

b.  Sepsis

c.  Pleural effusion

d.  Multilobar infiltrates on chest film

e.  Failure of prior outpatient therapy

f.  Confusion

g.  Unable to tolerate oral intake

h.  Unreliable social situation (eg, substance abuse, homelessness, mental illness)

i.  Certain underlying diseases (sickle cell disease, immunocompromise, severe COPD, or heart failure)

j.  Suspicion of virulent pathogen (Staphylococcus, Legionella, etc)

2.  Prospective validated clinical tools can help predict mortality and guide the need for admission, including the pneumonia severity index and the CURB-65 score

a.  CURB-65 criteria are confusion (to person, place, or time), uremia (blood urea nitrogen [BUN] > 20 mg/dL), RR ≥ 30 breaths per minute, systolic BP < 90 mm Hg or diastolic BP ≤ 60 mm Hg, age ≥ 65.

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

c.  While validated scores can guide decisions, they should not be viewed as absolute and clinical judgment remains important. Patients with similar scores can have markedly different mortality rates. Among patients with the same CURB-65 score, the mortality rate in patients deemed to need admission was 1.7–26 times higher than patients not felt to need admission.

D.  Determine the need for ICU admission: The IDSA and the American Thoracic Society have published guidelines on ICU admissions for patients with severe pneumonia. ICU admission is recommended for patients with septic shock requiring vasopressors and those receiving 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).

E.  Antibiotics

1.  Neither the history and physical exam nor chest radiograph can reliably distinguish pyogenic (S pneumoniae) from atypical (Mycoplasma and Chlamydia) organisms and treatment must cover both.

2.  Penicillin-resistant S pneumoniae (PRSP)

a.  Increasing in the United States

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

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

3.  Empiric therapy

a.  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. Those patients include those 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%

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

c.  Administration within 3 hours of presentation is recommended and within 1 hour for patients in shock

d.  Procalcitonin to Guide Initiating antibiotics. Few studies have evaluated the decision to treat or withhold antibiotics in patients with CAP based on their procalcitonin level. There is insufficient evidence to warrant withholding antibiotics in patients with CAP based on a low procalcitonin level.

F.  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 reveal an underlying mass.

3.  Particularly important in patients at increased risk for lung cancer, including patients over 50 or current or ex-smokers.

4.  Chest film resolution lags behind clinical resolution.

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

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

MAKING A DIAGNOSIS

Have you crossed a diagnostic threshold for the leading hypothesis, CAP? Have you ruled out the active alternatives? Do other tests need to be done to exclude the alternative diagnosis?

The patient’s cough, fever, and abnormal radiograph are sufficient to make the clinical diagnosis of pneumonia. Referring to Figure 10-2, the next pivotal step considers other types of pneumonia (that occur in patients coming in from the community) by reviewing the clinical picture and radiograph for suggestive clues. Clinically, she has not been hospitalized recently (which would suggest hospital-acquired pneumonia) and has no known immunocompromise. She does not have influenza nor is her picture chronic which could suggest PJP, TB, or fungal pneumonia. Her radiograph does not suggest TB (no apical disease nor reticular nodular infiltrates nor cavities) nor Pneumocystis (bilateral diffuse disease). You review her alcohol and drug history to ensure she is not at risk for aspiration pneumonia.

CASE RESOLUTION

Ms. L reports drinking only an occasional glass of wine and denies recent intoxication, loss of consciousness, or substance abuse.

Ms. L lacks risk factors for aspiration pneumonia and she is clinically diagnosed with CAP (despite an initially normal chest exam!).

Ms. L’s WBC is 10,200 cells/mcL with 67% neutrophils and 5% bands. Her SaO2 is 96% on room air. An HIV test should be ordered, antibiotics must be chosen, and a decision must be made to admit or discharge Ms. L.

Ms. L’s CURB-65 score is 0 and she has no indications for admission (see above under CAP treatment). She is treated for CAP with azithromycin and instructed to call immediately if her fever increases or increasing shortness of breath or chest pain develop.

One week later, she reports feeling much better. A follow-up chest film 6 weeks later shows resolution of the pneumonia.

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

A high fever (temperature > 38°C) in a patient with cough should raise the suspicion of pneumonia.

CHIEF COMPLAINT

PATIENT

Mr. P is a 32-year-old man with 4 weeks of cough and progressive shortness of breath. He complains of a persistent cough productive of purulent sputum and low-grade fever. His past medical history is unremarkable.

On physical exam, Mr. P appears mildly short of breath. Vital signs are pulse, 95 bpm; temperature, 37.9°C; RR, 20 breaths per minute; BP, 140/90 mm Hg. He has temporal wasting. Lung exam reveals diffuse fine crackles bilaterally. Cardiac exam is normal.

At this point, what is the leading hypothesis, what are the active alternatives, and is there a must not miss diagnosis? Given this differential diagnosis, what tests should be ordered?

RANKING THE DIFFERENTIAL DIAGNOSIS

The first pivotal decision in patients with an acute cough identifies signs or symptoms that suggest pneumonia to distinguish common upper respiratory infection, acute bronchitis, and influenza from various pneumonias (see Figure 10-1). Mr. P has several concerning signs and symptoms that suggest pneumonia (rather than an upper respiratory infection or acute bronchitis) including his dyspnea and crackles. Clearly a chest radiograph is indicated.

PATIENT

His chest radiograph demonstrates bilateral diffuse infiltrates (Figure 10-5). No cardiomegaly is seen. A CBC is normal. SaO2 is 85%.

At this point, what is the leading hypothesis, what are the active alternatives, and is there a must not miss diagnosis? Given this differential diagnosis, what tests should be ordered?

Figure 10-5. Chest radiograph shows bilateral diffuse infiltrates. (Reproduced with permission from Elsayes KM, Oldham SA: Introduction to Diagnostic Radiology. New York, NY: McGraw-Hill Education; 2014.)

The cough, fever, and radiograph are diagnostic of pneumonia. Although CAP is the most common type of pneumonia in patients presenting from the community, the next pivotal step reviews the clinical history and radiograph searching for clues that might suggest other types of pneumonia including TB, aspiration pneumonia, and Pneumocystis pneumonia (see Figure 10-2).

PATIENT

Mr. P has no known exposures to TB and was born in the United States. He admits to drinking heavily, often a pint of gin per day, and occasionally losing consciousness. He does not remember any episodes of vomiting and aspirating. He denies injection drug use and reports that he has not been sexually active in several years. He denies having sex with men.

At this point, what is the leading hypothesis, what are the active alternatives, and is there a must not miss diagnosis? Given this differential diagnosis, what tests should be ordered?

Although CAP is most common, Mr. P has several clinical features that increase the likelihood of other types of pneumonia. His alcohol use clearly increases the likelihood of aspiration pneumonia (even in the absence of known frank aspiration). Alcoholism, substance abuse, and neurologic disorders are leading risk factors for aspiration, and make this the leading hypothesis. Another important clinical clue is his long duration of illness, which suggests more chronic processes such as TB or PJP. TB is also more common in alcoholic patients and malnourished patients. Given the public health risks, TB is a must not miss possibility.

His radiograph (Figure 10-5) reveals diffuse bilateral infiltrates, which is typical of PJP (and can also be seen in Mycoplasma and influenza pneumonia). The long duration of symptoms is more suggestive of PJP, which due to its life-threatening nature and requirement for specific therapy is another must not miss hypothesis. PJP affects immunocompromised patients, including patients on chemotherapy, other immunosuppressive medications, and HIV-infected patients. It is important to consider PJP even in patients without a history of immunosuppressive therapy or known HIV infection because PJP can be the presenting illness in patients with HIV infection. It is important to appreciate that the sexual history often fails to elicit high-risk sexual behavior. Table 10-6 lists the differential diagnosis.

Table 10-6. Diagnostic hypotheses for Mr. P.

Is the clinical information sufficient to make a diagnosis? If not, what other information do you need?

Leading Hypothesis: Aspiration Pneumonia

Textbook Presentation

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

Disease Highlights

A.  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 and usually unnoticed. It may be complicated by aspiration 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).

B.  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

C.  Aspiration pneumonitis

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

2.  Clinical syndrome

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

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

c.  Fever is usually low grade.

d.  Sputum may be putrid.

e.  Outcome varies

(1)  Rapid recovery within 24–36 hours (62%)

(2)  Bacterial superinfection (26%), which may lead to pneumonia, lung abscess, or empyema

(3)  Acute respiratory distress syndrome (12%)

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

4.  Organisms

a.  Pathogens commonly seen in patients coming from the community with aspiration pneumonia include anaerobes, aerobic streptococci, S pneumoniae, S aureus, and Haemophilus influenzae.

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

Evidence-Based Diagnosis

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

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

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

D.  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

A.  Prevention

1.  A recent Cochrane analysis concluded that food thickening strategies are ineffective in preventing aspiration.

2.  Tube feedings

a.  Decrease the incidence of aspiration pneumonia in patients with dysphagia (54% vs 13% with oral feeding).

b.  Main utility is in patients with short-term indications (eg, head and neck surgery).

c.  Despite tube feedings, patients can still aspirate from gastroesophageal reflux, vomiting, and aspiration of oropharyngeal contents.

d.  Not recommended by the American Geriatrics Society for the long-term care of patients with advanced dementia as they cause more agitation, use of physical and chemical restraints, require greater resource utilization, cause tube-related complications, and do not decrease the incidence of aspiration pneumonia or improve survival in these patients.

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 with brushing after each meal and professional oral health care each week decreased the incidence of pneumonia in elderly nursing home patients (18.6% vs. 11.4% NNT 14).

6.  Postprandial semi-recumbent positions decrease the rate of aspiration pneumonia compared with supine positions.

B.  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.

C.  Aspiration pneumonitis

1.  Antibiotics

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

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

c.  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.

D.  Aspiration pneumonia: antibiotics are indicated.

1.  Community-acquired aspiration: First-line options include ampicillin/sulbactam or amoxicillin/clavulanate or amoxicillin with metronidazole. Clindamycin can be used in penicillin-allergic patients.

2.  Hospital-acquired aspiration: Coverage requires addition of an antibiotic that is effective against gram-negative organisms, anaerobes, and S aureus.

MAKING A DIAGNOSIS

Although the patient’s CURB-65 score is 0, his hypoxia and alcohol use disorder make admission mandatory. Mr. P is admitted to an isolation bed on the general medical floor. He is empirically treated with clindamycin (for presumed aspiration pneumonia) as well as azithromycin and ceftriaxone (for CAP).

Have you crossed a diagnostic threshold for the leading hypothesis, aspiration pneumonia? Have you ruled out the active alternatives TB and PJP? Do other tests need to be done to exclude the alternative diagnosis?

At this point, it is appropriate to order blood cultures, sputum cultures, and Gram stain. Although he has risk factors for aspiration pneumonia, it remains important to consider the other must not miss hypotheses. The patient’s chest radiograph does not have any features that suggest TB (see below), which makes TB less likely. Nonetheless, PPD placement or QuantiFERON testing and obtaining sputum for acid-fast bacillus (AFB) stain and culture would be reasonable. However, the diffuse bilateral symmetric infiltrates are strongly suggestive of PJP, which must be considered (and HIV infection ruled out), despite the lack of obvious risk factors.

Alternative Diagnosis: PJP

Textbook Presentation

Patients with PJP are immunosuppressed, commonly due to previously diagnosed or undiagnosed advanced HIV disease. Patients commonly complain of progressive shortness of breath and dry cough of 1–3 weeks duration.

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

Disease Highlights

A.  PJP is caused by the ubiquitous opportunistic fungus P jirovecii. Colonization is present in > 50% of the adult population. In immunocompromised patients, it may cause a diffuse, bilateral, subacute but severe pneumonia.

B.  Epidemiology

1.  Pneumocystis causes pneumonia in immunocompromised persons including:

a.  HIV-infected persons with CD4 counts < 200 cells/mcL.

(1)  PJP is the most prevalent opportunistic infection in HIV-infected persons.

(2)  However, with the advent of antiretroviral therapy and PJP prophylaxis, the incidence of PJP has dropped dramatically among HIV-infected persons (> 10×) and the majority of PJP cases now occur in non–HIV-infected immunocompromised persons.

b.  Non–HIV-infected patients:

(1)  PJP may occur in patients who are receiving corticosteroids, chemotherapy, or other immunosuppressive therapies.

(2)  PJP may also occur in patients with idiopathic CD4 lymphocytopenia

(3)  Unlike HIV-infected patients, these patients often have a higher mean CD4 count when PJP develops (mean 302–487 cells/mcL).

A CD4 count > 200 cells/mcL does not rule out PJP in non–HIV-immunosuppressed persons.

(4)  Non–HIV-infected persons with PJP also experience higher mortality from PJP than HIV-infected persons (30–60% vs. 7%) probably secondary to a delay in diagnosis.

C.  The course is typically subacute in HIV-infected persons (over weeks) but may present more acutely (days) in patients with other immunocompromised states.

D.  The remainder of the discussion focuses on HIV-infected persons with PJP.

Evidence-Based Diagnosis

A.  History

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

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

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

B.  Physical exam

1.  Fever is present in 84%.

2.  Tachypnea is present in 62%.

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

C.  Chest film

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

Suspect PJP in patients with diffuse bilateral pneumonia, even in those without a diagnosis of HIV or known immunocompromise. PJP is a common mode of presentation in patients infected with HIV.

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

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

4.  Occasionally shows pneumothorax

5.  Normal in 10–25% of cases

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

D.  Specific diagnostic tests

1.  Although the chest radiograph and lactate dehydrogenase (see below) can increase or decrease the likelihood of PJP, patients require specific tests to confirm or exclude PJP.

2.  Clinical diagnosis (without confirmation by staining of sputum or BAL) is incorrect in 43% of patients.

3.  Induced sputum are typically the first test used to diagnose PJP.

a.  55–92% sensitive, 100% specific

b.  The addition of immunofluorescent monoclonal staining increases sensitivity.

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

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

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

c.  Sensitivity is 86–97%.

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

e.  PCR

(1)  Highly sensitive (100%) and specific

(2)  Identifies both PJP infection and colonization.

(3)  Quantitative cutoffs can help distinguish colonization from infection.

(4)  Since patients with PJP who are not HIV infected have lower fungal burdens, different cutoffs may be appropriate.

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

E.  Nonspecific diagnostic tests

1.  Serum 1,3-beta-D-glucan

a.  A cell wall component of Pneumocystis and other fungi (Candida, Aspergillus, but not Cryptococcus). Also found in Pseudomonas.

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

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

d.  Also can be elevated in invasive candidiasis and aspergillosis

2.  High-resolution chest CT scan

a.  In PJP, the CT typically shows patchy or nodular ground-glass appearance; ground glass most marked in perihilar regions. Cystic lesions may be seen.

b.  100% sensitive, 83–89% specific

c.  LR+, 5.9; LR–, 0

3.  Pulmonary function tests

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

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

Treatment

A.  Antimicrobial therapy

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

2.  Side effects are common including rash, fever, gastrointestinal symptoms, hepatitis, neutropenia, and hyperkalemia. CBC, liver biochemical tests, 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 of 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 PJP infections include clindamycin plus primaquine, dapsone plus TMP or atovaquone.

B.  Corticosteroids

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

2.  Initiate at time of PJP 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 PJP whose PaO2 < 70 mm Hg.

C.  Antiretroviral therapy should also be initiated within 2 weeks of treatment for PJP in HIV-infected patients (not already receiving antiretroviral therapy).

D.  Prophylaxis

1.  Indications

a.  HIV-infected persons with any of the following:

(1)  Prior PJP

(2)  CD4 counts < 200 cells/mcL or < 14%

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

(4)  Any AIDS defining illness

b.  Non–HIV-infected immunocompromised patients:

(1)  Patients with acute lymphoblastic leukemia, and those receiving solid organ or allogeneic bone marrow transplantation (NNT 19).

(2)  A Cochrane Review also recommended prophylaxis for patients with granulomatosis with polyangiitis and patients with solid organ malignancies taking corticosteroids.

(3)  Other groups have recommended PJP prophylaxis for a large number of other conditions requiring an array of immunosuppressive medications.

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.

4.  Dapsone, atovaquone, and inhaled pentamidine 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.  In HIV-infected persons, antiretroviral therapy can restore the CD4 count and allow for discontinuation of prophylaxis when CD4 count > 200 cells/mcL for approximately 3 months (unless PJP developed in patients with CD4 counts above 200 cells/mcL).

Because Mr. P’s radiograph was typical for PJP, an HIV and CD4 count were ordered. TMP-SMX and corticosteroids were added empirically to his antibiotic regimen pending results of the evaluation.

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

A.  Obligate aerobe that has predilection for lung apices.

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

C.  Common and serious

1.  Infects 33% of the world’s population

2.  8.6 million new cases per year (2014 data) and 1.5 million deaths (worldwide)

3.  95% of cases occur in developing countries.

D.  Epidemiology

1.  An estimated 11 million persons are infected with TB in the United States.

2.  Foreign-born persons have the highest rate of TB (13.4 times higher than US-born persons) and account for 66% of TB cases in the United States and 85% of multidrug-resistant TB (MDR-TB resistant to isoniazid and rifampin).

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

a.  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)  The presentation of pulmonary TB in early HIV infection is similar to that in immunocompetent persons; whereas, in advanced HIV infection, TB presents in more atypical ways.

b.  Alcoholics

c.  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)  Drug-dependent persons, homeless persons, prison inmates

E.  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, seeding more distant anatomic sites.

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. 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

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

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

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

d.  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%.

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

f.  PPD may be negative in these patients.

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

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

9.  Reactivation TB

a.  4–6% of patients with latent TB infection experience reactivation during their lifetime. The greatest risk is in the first 2 years following infection.

b.  Reactivation is often due to declining immune function. Risk factors include HIV, immunosuppressive therapy, diabetes mellitus, and silicosis. Children are also at higher risk.

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

d.  Due to the high rate of latent TB infection in foreign-born persons, they account for 71% of cases or reactivation TB.

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

f.  Reactivation TB progresses unless the patient is treated.

10.  Pleural TB: May cause either tuberculous empyema or tuberculous pleural effusions.

a.  Tuberculous empyema

(1)  Rare

(2)  Secondary to direct infection of pleural space (often from rupture of the neighboring tuberculous cavity)

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

b.  Tuberculous effusions

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

(2)  Usually associated with reactivation disease 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

A.  A variety of risk factors, symptoms, and radiographic findings can suggest TB (Table 10-7). Sensitivity is likely to be overestimated because TB was not systematically evaluated in all patients.

Table 10-7. Clinical and radiographic findings in TB.

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

a.  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.

b.  Hemoptysis was neither sensitive nor specific for TB.

c.  Fever is present in only 55%.

d.  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.

e.  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

a.  Pulmonary TB is very unlikely in patients with a normal chest film (97% sensitive).

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

c.  Most patients with TB have 1 of 3 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.

d.  Calcification can be seen in active lesions and does not exclude active disease unless comparison to prior films demonstrates stability.

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

B.  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:

a.  Immigrants from TB prevalent areas

b.  Positive TB history or history of positive PPD

c.  Homelessness, incarceration

d.  Weight loss

e.  Chest film with apical or cavitary infiltrates

C.  Testing for latent TB

1.  Tuberculin skin test (TST)

a.  Immune response to 0.1 mL intradermal PPD (from TB) injected into the volar forearm

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

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

d.  Turns positive 4–7 weeks after primary infection

e.  Significant reaction can be seen with either current infection or latent TB and does not diagnose active TB.

f.  Sensitivity (for active TB), 71–82%. False-negatives are more common in primary TB, immunosuppressed persons (including HIV), overwhelming illness, recent viral vaccination.

A negative TST does not rule out active TB.

g.  Specificity is 98–99% but is lower in patients with nontuberculous mycobacterial infection and 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.

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

(b)  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%).

h.  Booster phenomenon occurs when an initially negative TST is positive on recheck (without new infection).

(1)  In patients with latent TB, TST may revert to negative many years after infection.

(2)  In such patients, the initial TST may be negative but stimulate immune memory cells such that subsequent TST 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 TST.

(a)  Patients with initial negative PPD are retested 1–3 weeks later.

(b)  Patients in whom the second PPD test is positive should be treated as though the first test was positive.

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

2.  Interferon-gamma releasing assays (IGRAs)

a.  Current IGRAs include the QTF-GIT and T-SPOT.TB assays

b.  Patient’s blood (or other bodily fluid) is mixed with highly specific TB antigens that are not shared with BCG or most nontuberculous mycobacteria.

c.  Because of the high specificity of the antigens used, prior BCG vaccination does not cause false-positive IGRA results (unlike TST).

d.  The lymphocytes from TB-infected patients (latent or active) produce interferon gamma when exposed to TB antigens. The interferon gamma is measured.

e.  Unlike TST can be performed in a single visit.

f.  Highly sensitive and specific for active or latent TB infection.

(1)  Both IGRAs equal or superior sensitivity to TST (GFT-GIT 81–86%, T-SPOT 90–95%, TST (71–82%)

(2)  Less sensitive (as is TST) in patients with advanced HIV (CD4 count ≤ 200 cells/mcL)

(3)  GFT-GIT similar specificity to TST in patients without prior BCG vaccinations (GFT-GIT > 95%, TST 97%)

(4)  Both IGRAs more specific than TST in patients with prior BCG vaccination (GFT-GIT > 95%, T-SPOT 85–99%, TST (60%)

IGRA testing is far superior to TST in patients with prior BCG vaccination.

g.  Positive results do not distinguish latent from active TB. (A patient with pneumonia and a positive IGRA could have TB pneumonia or a nontuberculous pneumonia (eg, streptococcal) and latent TB infection.

h.  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).

Neither TST nor IGRA rule in or rule out active TB in patients with pneumonia.

3.  Strategy: Testing for latent TB infection (Figure 10-6)

Figure 10-6. Testing for latent tuberculosis infection (LTBI).

a.  Two factors should be considered when testing for LTBI

(1)  Risk of TB infection

(2)  Risk of progression to active TB if infected

b.  Major risk factors for infection include the following:

(1)  Household contacts of known TB (23% of TB contacts are TST positive).

(2)  Recent TST or IGRA converters

(3)  Work exposures (mycobacterial lab personnel or employees or residents of high-risk congregates)

(4)  Immigrants from high burden countries (Most of Sub-Saharan Africa and Asia (including China and India), Brazil and Russia

c.  Major risk factors for progression (if infected) include:

(1)  HIV infection

(2)  Immunosuppressive therapy

(3)  Chest film consistent with prior TB infection

(4)  Silicosis

(5)  Close contact of TB

(6)  Children < 5 years

d.  Patients without major risk factors for infection: testing for LTBI is not recommended

e.  Patients with major risk factors for infection:

(1)  Test if antituberculous therapy would be considered.

(2)  The appropriate testing strategy and criteria for positive results are stratified by their risk of progression. (Criteria for patients at low risk for infection is a positive IGRA and induration following TST > 15 mm; whereas, for those at highest risk, the criteria is only positive IGRA or induration following TST ≥ 5mm) (Figure 10-6).

(3)  Patients with positive results

(a)  Evaluate for active TB prior to starting latent TB treatment

(b)  Evaluation should include review of symptoms and chest film (regardless of symptoms).

(c)  Patients with evidence of active TB should be appropriately evaluated.

4.  Testing for active pulmonary TB

a.  Multiple tests are available and include microscopy (smear), NAAT (see below) and culture.

b.  All 3 tests recommended in patients evaluated for active TB by the American Thoracic Society/IDSA/CDC guidelines

(1)  TST and IGRAs can be done but do not distinguish active from latent TB infection nor are they sufficiently sensitive to rule out TB.

(2)  AFB stain and culture

(a)  Culture is the gold standard and specific but can take weeks to turn positive.

(b)  Sensitivity depends on the number of specimens (Table 10-8).

Table 10-8. Sensitivity of test according to the number of sputum specimens sent to the laboratory.

(3)  AFB smear (microscopy)

(a)  Ziehl-Neelsen (acid-fast stain) 70% sensitive, 90% specific.

i.  False-positive smears may occur due to nontuberculous mycobacteria.

ii.  False-negative smears may be seen in patients with inadequate specimens or small mycobacterial loads.

(b)  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.

(c)  Fluorochrome dyes can be used and are more sensitive but still detect nontuberculous mycobacteria.

(4)  NAAT

(a)  Specific NAATs for TB RNA or DNA

(b)  Specific for TB and can help distinguish TB from other mycobacteria. Particularly useful in patients with a low pretest probability of disease and positive microscopy. A negative NAAT in that situation would suggest nontuberculous mycobacterium.

(c)  Unlike culture, rapidly available within 1–2 days.

(d)  Inhibitors of NAAT present in 3–7% of sputum samples. Tests can detect inhibitors when suspected. Inhibitors render NAAT tests nondiagnostic.

(e)  Meta-analysis of the accuracy of NAATs report significant heterogeneity in part due to different references for the gold standard, specimen type, assays and cutoffs used, and inclusion of patients receiving treatment.

(f)  One meta-analysis reported 96% sensitivity in smear-positive patients, 66% sensitivity in smear-negative patients, and 97% specific (when analysis was limited to studies excluding treated patients).

5.  Diagnostic strategy: Recent guidelines suggest simultaneously testing using microscopy, NAAT, and culture.

a.  Consider testing in patients with risk factors, symptoms or typical radiographic findings suggestive of TB (Figure 10-7).

Figure 10-7. Evaluation for suspected pulmonary tuberculosis. (Recommendations for high resource, low incidence countries)

b.  While awaiting culture, the combined results of NAAT and microscopy can guide decisions.

c.  Patients with both negative microscopy and negative NAAT have a low likelihood of TB (< 5%) and can be observed pending culture.

d.  Patients with both positive microscopy and positive NAAT have a high likelihood of TB (> 90%) and should be treated pending culture.

e.  The likelihood of TB in patients with discordant smear and NAAT results is indeterminate with a wide and clinically significant range (2–75%)! Posttest probability is affected by the pretest probability of disease and which test was positive (NAAT or smear).

f.  Figure 10-7 illustrates an approach to the interpretation of smear microscopy and NAAT in patients evaluated for TB. The likelihood of TB is calculated using the sensitivities and specificities above and estimating the incidence of TB in patients with a low clinical suspicion at ≈ 5% and in patients with a high clinical suspicion ≈30%.

6.  Bronchoscopy: Bronchoscopy with BAL and brushings can be used to diagnose TB. Transbronchial biopsy can also be performed and is recommended in the following patients:

a.  Patients unable to induce sputum

b.  Patients with suspected miliary TB who are either unable to induce sputum or in whom the sputum is negative. Brushings and transbronchial biopsy are recommended in these patients.

7.  Tuberculous pleurisy with effusion

a.  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).

b.  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%

(6)  Adenosine deaminase: ADA ≥ 40 units/L; sensitivity, 88–99%; specificity, 88–97%.

(7)  Pleural fluid interferon gamma: 89% sensitive, 97% specific

Treatment

A.  Isolation: see above

B.  Principles of therapy

1.  Goals include clinical cure of the patient, halting disease transmission and preventing drug resistance to therapy.

2.  Drug-resistant TB is a significant problem. MDR-TB refers to resistance to isoniazid and rifampin with an estimated 500,000 cases worldwide. Extensively drug-resistant TB (XDR-TB) refers to resistance to isoniazid, rifampin, fluoroquinolone and 1 of 3 second-line drugs (amikacin, kanamycin, or capreomycin).

3.  Precise drug recommendations evolve due to resistance.

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

5.  Direct observed therapy (DOT)

a.  Premature discontinuation and nonadherence promote drug resistance and must be avoided.

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

c.  DOT is strongly recommended and the standard of practice in the United States.

6.  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.

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

7.  Effective therapy takes many months.

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

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

C.  MDR-TB

1.  Defined when organisms are resistant to isoniazid and rifampin

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

a.  60% of cases of MDR-TB worldwide are in India, China, and Russia.

b.  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 have 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.

D.  Treatment of active pulmonary TB in patients at low risk for MDR-TB

1.  Obtain baseline liver biochemical tests, 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 liver biochemical tests. Ophthalmology evaluation is recommended for patients receiving ethambutol.

2.  A rapid molecular test for drug resistance is recommended in patients at risk for drug resistance (see above).

3.  Treat for 2 months with isoniazid, rifampin, pyrazinamide, and ethambutol and then simplify the regimen to isoniazid and rifampin, if the organism is fully susceptible, for an additional 4 months. Ethambutol can be discontinued earlier if the organism is susceptible to both isoniazid and rifampin.

4.  Empiric therapy (prior to the results of microscopy, NAAT- and culture), should also be started in patients with a high likelihood of TB and those seriously ill with suspected TB. Therapy can then be continued or stopped depending on test results (Figure 10-7).

5.  More aggressive therapy is required for patients with cavitary TB.

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

7.  Visual acuity and color discrimination tests are recommended at baseline and monthly during ethambutol use to detect optic neuritis.

8.  See Chapter 5 for recommendations in HIV-infected persons.

9.  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.

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

F.  Treatment of latent TB

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

2.  Isoniazid is the most commonly used treatment option; rifampin for 4 months has recently been shown to be noninferior.

3.  Isoniazid

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

b.  Reduces subsequent development of active TB from 14.3% to 3.6% in individuals with radiographic evidence of healed TB.

c.  Side effects include hepatitis (0.1– 2.3%) and neuropathy (2%). Neuropathy can be prevented with pyridoxine (25–50 mg/day). Advised for pregnant or breastfeeding women, HIV-infected persons and those with diabetes mellitus, alcoholism, malnutrition, or chronic kidney failure taking isoniazid.

CASE RESOLUTION

Unfortunately, Mr. P’s HIV result was positive; his CD4 count was 100 cells/mcL, and PJP was strongly suspected. His PPD and AFB smears were negative. Sputum silver stain for PJP was negative and the following day he underwent bronchoscopy. The silver stain from the BAL confirmed PJP, and treatment with trimethoprim-sulfamethoxazole and corticosteroids was continued.

On day 3 of his hospitalization, he became agitated, tachycardic, and complained of visual hallucinations. He was treated for delirium tremens with high doses of IV benzodiazepines (see Chapter 11). By day 5, he was improving. He was afebrile and his appetite improved. Antiretroviral therapy was started and the PJP regimen was continued.

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

Consider PJP in patients with pneumonia and diffuse bilateral infiltrates, even in patients without known HIV or risk factors.

REVIEW OF OTHER IMPORTANT DISEASES

Hospital-acquired Pneumonia and Ventilator-associated Pneumonia

Textbook Presentation

Patients with hospital-acquired pneumonia 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 hospital-acquired pneumonia may be recovering from surgery when fever or delirium heralds the development of hospital-acquired pneumonia.

Disease Highlights

A.  Hospital-acquired pneumonia is defined as pneumonia that develops ≥ 48 hours after hospital admission.

B.  Ventilator-associated pneumonia is defined as pneumonia that develops ≥ 48 hours after endotracheal intubation.

C.  Pneumonia in such patients is often secondary to multidrug-resistant organisms, including MRSA and gram-negative bacilli including P aeruginosa. They may also be infected with organisms that commonly cause CAP (S pneumoniae and H influenzae).

Evidence-Based Diagnosis

A.  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.

B.  A lower respiratory tract culture is recommended. Samples may include expectorated sputum, endotracheal aspirate, or samples from bronchoscopy (BAL or protected brush specimen). Endotracheal aspirate is preferred in ventilated patients and sputum culture in nonventilated patients.

C.  Blood cultures are recommended for patients with hospital- acquired pneumonia or ventilator-associated pneumonia.

Treatment

A.  Antimicrobial coverage is designed to cover S aureus, P aeruginosa, and other gram-negative bacteria.

B.  The 2016 IDSA guidelines recommend coverage of S aureus, P aeruginosa, and gram-negative bacilli for all patients with hospital-acquired pneumonia or ventilator-associated pneumonia. Extended coverage should be given to patients with an increased risk for antibiotic resistance or at an increased risk of death.

1.  An increased risk of resistance should be assumed in areas with a > 10–20% local resistance on antibiogram, in patients receiving antibiotics within the preceding 90 days, and those hospitalized for ≥ 5 days prior to pneumonia.

2.  An increased risk of mortality should be assumed for patients with septic shock, those requiring ventilator support, or new-onset renal replacement therapy.

3.  Extended coverage includes vancomycin or linezolid for possible MRSA infection and 2 antipseudomonal antibiotics.

4.  Aerosolized antibiotics in addition to IV antibiotics may be useful in select patients.

5.  Culture data and susceptibility should guide antimicrobial therapy when it becomes available.

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

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

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

C.  Spread by aerosol droplets. Develops in about one-third of household contacts.

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

1.  Catarrhal stage lasts 1–2 weeks.

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

b.  The cough is usually mild.

c.  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.

a.  A deep inspiration may occur at the end of coughing (the “whoop”).

b.  Emesis may occur at the end of coughing.

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

d.  The cough may be severe and prevent sleeping.

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

Evidence-Based Diagnosis

A.  Among patients with cough lasting > 6–7 days, the prevalence of pertussis is 3–20%; however, the likelihood increases in adult patients with acute cough lasting > 3 weeks (12–32%).

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

C.  Clinical symptoms

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

a.  Paroxysmal cough: Sensitivity, 100%; specificity, 12%; LR+, 1.1; LR–, 0

b.  Posttussive gagging: Sensitivity, 100%; specificity, 28.7%; LR+, 1.4; LR–, 0

2.  No symptom is terribly specific or diagnostic.

a.  Whooping: sensitivity, 26%; specificity, 85.4%; LR+, 1.8; LR–, 0.9

b.  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.

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

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

c.  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

A.  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.

B.  Treatment

1.  Treatment usually started during the paroxysmal phase.

a.  Probably does not affect the course of illness

b.  Decreases spread to others. Without postexposure prophylaxis, the secondary attack rate is > 80% among susceptible persons.

c.  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.

REFERENCES

Burk M, El-Kersh K, Saad M, Wiemken T, Ramirez J, Cavallazzi R. Viral infection in community-acquired pneumonia: a systematic review and meta-analysis. Eur Respir Rev. 2016;25:178–88.

Call SA, Vollenweider MA, Hornung CA, Simel DL, McKinney WP. Does this patient have influenza? JAMA. 2005;293(8):987–97.

Centers for Disease Control and Prevention. Guidance for Clinicians on the Use of Rapid Influenza Diagnostic Tests. Available at: www.cdc.gov/flu/professionals/diagnosis/clinician\_guidance\_ridt.htm. Accessed 12/27/18.

Centers for Disease Control and Prevention. Updated guidelines for the use of nucleic acid amplification tests in the diagnosis of tuberculosis. MMWR. 2009 Jan 16;58(01):7–10.

Centers for Disease Control and Prevention. Updated guidelines for using interferon gamma release assays to detect Mycobacterium tuberculosis infection–United States, 2010. MMWR. 2010 June 25;59(5):1–25.

Chartrand C, Leeflang MMMG, Minion J et al. Accuracy of rapid influenza diagnostic tests. A meta-analysis. Ann Intern Med. 2012;156:500–11.

Chestow DS, Memoli MJ. Bacterial coinfection in influenza. JAMA. 2013;309(3):275–82.

Christ-Crain M, Stolz D, Bingisser R et al. Procalcitonin Guidance of Antibiotic Therapy in Community-acquired Pneumonia. Am J Respir Crit Care Med. 2006;174:84–93.

Claessens YE, Debray MP, Tubach F et al. Early chest computed tomography scan to assist diagnosis and guide treatment decision for suspected community-acquired pneumonia. Am J Respir Crit Care Med. 2015;192:974–82.

Cornia PB, Hersh AL, Lipsky BA, Newman TB, Gonzales R. Original article: does this coughing adolescent or adult patient have pertussis? In: Simel DL, Rennie D, eds. The Rational Clinical Examination: Evidence-Based Clinical Diagnosis. New York, NY: McGraw-Hill; 2012. http://www.jamaevidence.com/content/3498462.

Division of Tuberculosis Elimination, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, CDC. Updated Guidelines for the use of Nucleic Acid Amplification Tests in the Diagnosis of TB. MMWR. 2009 Jan 16;58(1):7–10.

Dobson J, Whitley RJ, Pocock S, Monto AS. Oseltamivir treatment for influenza in adults: A meta-analysis of randomized controlled trials. Lancet. 2015;385:1729–37.

Dosanjh DP, Hinks TS, Innes JA et al. Improved diagnostic evaluation of suspected tuberculosis. Ann Intern Med. 2008;148(5):325–36.

Dugas AF, Valsamakis A, Atreya MR et al. Clinical diagnosis of influenza in the emergency department. Am J Emerg Med. 2015;33(6):770–5.

Flynn E, Smith CH, Walsh CD, Walshe M. Modifying the consistency of food and fluids for swallowing difficulties in dementia. Cochrane Database Syst Rev. 2018;9:CD011077.

Greco S, Girardi E, Navarra A, Saltini C. Current evidence of diagnostic accuracy of commercially based nucleic acid amplification tests for the diagnosis of pulmonary tuberculosis. Thorax. 2006;61:783–90.

Grohskopf LA, Sokolow LZ, Broder KR, Walter EB, Fry AM, Jernigan DB. Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices—United States, 2018–19 Influenza Season. MMWR Recomm Rep 2018;67(No. RR-3):1–20.

Huijskens EG, Rossen JW, Kluytmans JA, van der Zanden AG, Koopmans M. Evaluation of yield of currently available diagnostics by sample type to optimize detection of respiratory pathogens in patients with community-acquired pneumonia. Influenza Other Respir Viruses. 2014;82(2):243–9.

Kalil AC, Metersky ML, Klompas M et al. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Inf Dis. 2016;63(5):575–82.

Kikawada M, Iwamoto T, Takasaki M. Aspiration and infection in the elderly: epidemiology, diagnosis and management. Drugs Aging. 2005;22(2):115–30.

Kunimoto D, Long R. Tuberculosis: still overlooked as a cause of community-acquired pneumonia–how not to miss it. Respir Care Clin N Am. 2005;11(1):25–34.

Le Bel J, Hausfater P, Chenevier-Gobeaux C et al. Diagnostic accuracy of C-reactive protein and procalcitonin in suspected community-acquired pneumonia adults visiting emergency department and having a systematic thoracic CT scan. Crit Care. 2015;19:366.

Lewinsohn DM, Leonard MK, LoBue PA et al. Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention Clinical Practice Guidelines: Diagnosis of Tuberculosis in Adults and Children. Clin Infect Dis. 2017;64(2):e1–e33.

Ling DI, Flores LL, Riley LW, Pai M. Commercial nucleic-acid amplification tests for diagnosis of pulmonary tuberculosis in respiratory specimens: meta-analysis and meta-regression. PLoS ONE 2008;2:e1536.

Llamas-Alvarez AM, Tenza-Lorano EM, Latour-Perez J. Accuracy of lung ultrasonography in the diagnosis of pneumonia in adults. Systematic Review and Meta-Analysis. Chest. 2017;151(2):374–82.

Mattoo S, Cherry JD. Molecular pathogenesis, epidemiology, and clinical manifestations of respiratory infections due to Bordetella pertussis and other Bordetella subspecies. Clin Micro Rev. 2005;18:326–82.

Merckx J, Wali R, Schiller I et al. Diagnostic accuracy of novel and traditional rapid tests for influenza infection compared with reverse transcriptase polymerase chain reaction. Ann Intern Med. 2017;167(6):394–409.

Metlay JP, Fine MJ. Testing strategies in the initial management of patients with community-acquired pneumonia. Ann Intern Med. 2003;138(2):109–18.

Metlay JP, Kapoor WN, Fine MJ. Does this patient have community-acquired pneumonia? Diagnosing pneumonia by history and physical examination. JAMA. 1997;278(17):1440–5.

Metlay JP, Schulz R, Li YH et al. Influence of age on symptoms at presentation in patients with community-acquired pneumonia. Arch Intern Med. 1997;157(13):1453–9.

Montalto NJ. An office-based approach to influenza: clinical diagnosis and laboratory testing. Am Fam Physician. 2003;67(1):111–8.

Moran GJ, Barrett TW, Mower WR et al. Decision instrument for the isolation of pneumonia patients with suspected pulmonary tuberculosis admitted through US emergency departments. Ann Emerg Med. 2009;53:625–32.

Nahid P, Dorman SE, Alipanah N et al. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis. Clin Infect Dis. 2016 Oct 1;63(7):e147–e195.

O’Brien WT Sr, Rohweder DA, Lattin GE Jr et al. Clinical indicators of radiographic findings in patients with suspected community-acquired pneumonia: who needs a chest x-ray? J Am Coll Radiol. 2006;3(9):703–6.

Onishi A, Sugiyama D, Kogata Y et al. Diagnostic accuracy of serum 1,3-β-D-glucan for Pneumocystis jiroveci pneumonia, invasive candidiasis, and invasive aspergillosis: systematic review and meta-analysis. J Clin Microbiol. 2012 Jan;50(1):7–15.

Pai M, Zwerling A, Menzies D. Systematic review: T-cell-based assays for the diagnosis of latent tuberculosis infection: an update. Ann Intern Med. 2008;149(3):177–84.

Rapid Diagnostic Testing for Influenza: Information for Health Care Professionals. (Accessed at http://www.cdc.gov/flu/professionals/diagnosis/rapidclin.htm.)

Role of Laboratory Diagnosis of Influenza. (Accessed at http://www.cdc.gov/flu/professionals/diagnosis/labrole.htm.)

Selwyn PA, Pumerantz AS, Durante A et al. Clinical predictors of Pneumocystis carinii pneumonia, bacterial pneumonia and tuberculosis in HIV-infected patients. AIDS. 1998;12(8):885–93.

Sharp AL, Jones JP, Wu I et al. CURB-65 performance among admitted and discharged emergency department patients with community-acquired pneumonia. Acad Emerg Med. 2016;23:400–5.

Stein J, Louie J, Flanders S et al. Performance characteristics of clinical diagnosis, a clinical decision rule, and a rapid influenza test in the detection of influenza infection in a community sample of adults. Ann Emerg Med. 2005;46(5):412–9.

Stern A, Green H, Paul M, Vidal L, Leibovici L. Prophylaxis for Pneumocystis pneumonia (PCP) in non-HIV immunocompromised patients. Cochrane Database Syst Rev. 2014;10:CD005590.

Strebel P, Nordin J. Population-based incidence of pertussis among adolescents and adults, Minnesota, 1995–1996. J Infect Dis. 2001;183:1353–9.

Syrjala H, Broas M, Ohtonen P, Pääkkö E. Chest magnetic resonance imaging for pneumonia diagnosis in outpatients with lower respiratory tract infection. Eur Respir J. 2017 Jan 11;49(1).

Tietjen PA. Clinical presentation and diagnosis of Pneumocystis carinii (P. jiroveci) infection in HIV-infected patients. In: UpToDate; 2008.

Van Gageldonk-Lafeber AB, Heijen ML, Barelds AI et al. A case-control study of acute respiratory tract infection in general practice patients in The Netherlands. Clin Infect Dis. 2005;41:490–7.

Woodring JH, Vandiviere HM, Fried AM et al. Update: The Radiographic Features of Pulmonary Tuberculosis. AJR. 1986;146:497–506.

Yang JH, Huang PY, Shie SS et al. Predictive symptoms and signs of laboratory-confirmed influenza. Medicine. 2015;94(44):e1952.