Bronchitis

David R. McBride

Key Points

Infections of the upper respiratory tract accounted for more than 36 million ambulatory medical visits in 2005, according to the National Ambulatory Medical Care Survey (Cherry et al., 2007). Although a large percentage of these infections are viral in origin, antibiotics are still prescribed for more than 50% of patients with acute respiratory tract infection (ARTI). Acute bronchitis, in the ARTI category, is defined as a respiratory infection in which cough is the predominant symptom and there is no evidence of pneumonia. Antibiotics are often prescribed despite limited evidence that they shorten the duration of acute bronchitis. With increasing incidence of antibiotic resistance, bronchitis allows physicians to practice “prescriptive restraint” and to provide supportive therapy. Consider using the phrase “chest cold” to help patients understand the viral and benign nature of this infection.

Chronic bronchitis is one of the manifestations of chronic obstructive pulmonary disease (COPD) and is defined clinically as cough and sputum production on most days for 3 months annually for 2 years. Chronic bronchitis is thought to be primarily inflammatory in origin, although infection may be associated with acute exacerbations; with increased sputum production and worsening dyspnea, antibiotics have proved effective in acute episodes. However, systemic corticosteroids are the mainstay of COPD exacerbation management.

The patient with acute bronchitis presents with cough, often productive. Patients may report clear or colored mucus in association with the presumed diagnosis of acute bronchitis. Despite what many patients believe, the color of sputum, even purulent sputum, is not predictive of bacterial infection. The cough of bronchitis can last up to 4 weeks, sometimes even longer. Typically, acute bronchitis is associated with other manifestations of infection, such as malaise and fever.

Respiratory viruses are thought to cause the majority of cases of acute bronchitis. Influenza A and B, parainfluenza, respiratory syncytial virus (RSV), coronavirus, adenovirus, and rhinovirus are common pathogens in the viral category. Clues to a specific virus may be found in the patient history; for example, RSV might be considered when there is household exposure to infected children. Influenza typically presents with sudden onset of symptoms, including fever, myalgias, cough, and sore throat.

Neuraminidase inhibitors are modestly effective in shortening the duration of influenza in ambulatory and healthy patients (by about 1 day), if initiated in the first 48 hours of illness. The resistance patterns of influenza A and B have shifted in the last several years and may vary based on yearly viral strains. Influenza B has remained, as of 2010, sensitive to zanamivir (Relenza) and oseltamivir (Tamiflu). Currently circulating strains of influenza A, both H1N1 and H3N2, and influenza B have generally remained sensitive to both oseltamivir and zanamivir (Fiore et al., 2011). Family physicians are advised to consider restraint in the prescribing of these agents, since resistance is of great concern. Yearly influenza immunization and cough etiquette and hygiene are likely the most useful techniques for influenza management.

Studies have identified other pathogens, such as Mycoplasma pneumoniae and Chlamydophila pneumoniae, in a small minority of cases of clinical acute upper respiratory illness with cough as the predominant symptom. No significant benefit has been found in treating these infections with antibiotics. An exception in the treatment of acute bronchitis-like illness with antibiotics is when confirmed or probable Bordetella pertussis is present. Early treatment with a macrolide antibiotic and patient isolation will likely decrease coughing paroxysms and limit spread of disease (Braman, 2006). Although common upper respiratory bacterial pathogens, such as Moraxella (Branhamella) catarrhalis, Streptococcus pneumoniae, and Haemophilus influenzae, may be isolated from patients with acute bronchitis, their relevance is questionable because these bacteria can be present in the respiratory tract of healthy individuals. Obtaining sputum for culture when bronchitis is the diagnosis generally is not useful.

Antibiotics may offer a modest benefit in the treatment of acute bronchitis, with many studies showing no statistical significance in the outcome of treated versus not-treated groups. Measures of function, such as duration of illness, loss of work, and limitation of activity, have not shown clinically significant improvement in those with acute bronchitis taking antibiotics. Coupled with cost and the potential for side effects, the use of antibiotics for acute bronchitis is not recommended. If a provider decides to use an antibiotic in a specific patient situation, narrow-spectrum respiratory agents are preferred, such as a first-generation macrolide or doxycycline.

Treating the symptom of cough in acute bronchitis is an important concern for patients. In adults with acute bronchitis with signs of airway obstruction, evidenced by wheezing on examination or decreased peak expiratory flow rate, beta-2 agonists may be helpful in alleviating cough. These agents are not helpful for children with acute cough or adults with cough and no evidence of airway obstruction. Side effects of tremor and an anxious feeling must be weighed against this benefit.

Patients often are primarily interested in alleviating symptoms caused by respiratory illness. Unfortunately, there is mixed evidence for the use of over-the-counter (OTC) and prescription cough medications. Dextromethorphan and codeine may be somewhat effective, although they have not been evaluated in randomized, double-blinded, placebo-controlled trials for acute bronchitis. Combination first-generation antihistamine-decongestant products may be effective for the cough associated with colds. Naproxen showed efficacy against cough in one upper respiratory model study (Sperber et al., 1992). Guaifenesin acts as an expectorant and may have some effect on cough by its mucus-thinning properties.

Pneumonia

Anthony Zeimet

Key Points

Community-acquired pneumonia (CAP) is defined as an acute infection of the pulmonary parenchyma and, along with influenza, is the seventh leading cause of death in the United States. Fever, cough, sputum production, pleuritic chest pain, and dyspnea are common symptoms of CAP. Nausea, vomiting, and diarrhea also may occur, and in elderly patients, CAP may present with mental status changes. Although its absence usually makes pneumonia less likely, fever can be absent in the elderly patient. Other physical examination findings include an elevated respiratory rate, conversational dyspnea, tachycardia, and rales. Egophony and dullness to percussion may be noted with focal consolidation. Typical laboratory findings include leukocytosis. The diagnosis of pneumonia is based on the presence of symptoms and the presence of an infiltrate on chest radiograph. If infiltrate is not present, consider obtaining a chest tomography scan (which has higher sensitivity) to rule in or rule out CAP. If negative, other diagnoses should be considered.

The most common microbiologic agent of pneumonia is often not isolated (Table 16-1). Furthermore, studies have shown that bacteriologic causes of pneumonia cannot be determined by radiographic appearance (i.e., “typical” vs. “atypical”). In the proper clinical setting, certain clinical microbes should be considered because they can affect treatment considerations and epidemiologic studies. These include Legionella spp., influenza A and B, and community-acquired methicillin-resistant Staphylococcus aureus (MRSA).

Table 16-1 Most Common Etiologies of Community-Acquired Pneumonia

∗ Influenza A and B, adenovirus, respiratory syncytial virus, and parainfluenza.

Certain diagnostic tests are performed based on clinical setting. Blood cultures are not routinely done in the outpatient setting but should always be done if the patient is being admitted to the hospital, ideally before antibiotics are given. The use of Gram stain and sputum culture remains controversial but can provide more evidence of a bacterial cause (e.g., many PMNs). If sputum cultures are being obtained, it is recommended that the physician have the patient expectorate directly into a specimen cup and have it sent immediately for processing. This can increase the yield of isolating Streptococcus pneumoniae among other respiratory pathogens. Other tests include urine antigen tests for S. pneumoniae, Legionella pneumophila serogroup 1, and nasal swab for influenza A and B. In young children, RSV, adenovirus, and parainfluenza in addition to influenza are common causes. Nasal swab for RSV and influenza can be rapidly done, but the other causes can be determined with viral cultures, serology, enzyme-linked immunosorbent assay (ELISA), and polymerase chain reaction (PCR), although results usually are received after resolution of the acute symptoms.

Perhaps the most important decision for clinicians is to determine the location of treatment. The American Thoracic Society (ATS) and the Infectious Diseases Society of America (IDSA) recommend use of the pneumonia severity index (PSI), which uses 20 variables to risk-stratify the patient into five mortality classes, or the CURB-65, which measures five clinical variables in this decision making. The CURB-65 may be the easiest and most convenient to use at the site of decision making. A score of 0 or 1 indicates treatment as an outpatient; a score of 2 requires hospital admission to the general medical ward; and a score of 3 or more indicates admission to an intensive care unit (ICU) (Box 16-1).

Treatment of CAP should be targeted toward the most likely etiology (Table 16-2). Outpatient therapy for patients who have no comorbidities and have not received antibiotics within the last 3 months includes doxycycline or a macrolide antibiotic. Use of a fluoroquinolone antibiotic (levofloxacin or moxifloxacin) should be reserved for patients with more complicated pneumonia and those requiring hospitalization. Patients who have comorbid conditions or recent antibiotic exposure, or who will be hospitalized, should receive a respiratory fluoroquinolone or combination therapy with a beta-lactam drug plus a macrolide, for 48 to 72 hours after fever abates (usually 5-7 days’ total therapy). If an organism is isolated, therapy may be narrowed to cover the causative agent. The clinician should consider longer therapy and appropriate antibiotics to cover for infection by less common organisms such as Staphylococcus aureus or Pseudomonas aeruginosa. If the patient has no more than one abnormal value (temperature <37.8° C, heart rate <100, respiratory rate <24, SBP >90, O₂ saturation >90%, Po₂ >60 on room air) and the patient is able to maintain oral intake and has a normal mental status, the clinician can safely switch to oral therapy and discharge the patient from the hospital. Unless the etiology of the pneumonia is known, the physician should switch to oral antibiotics in the same class as the intravenous antibiotics used.

Table 16-2 Guide to Empiric Choice of Antimicrobial Agent for Treating Patients with Community-Acquired Pneumonia (CAP)

∗ Azithromycin or clarithromycin.

† That is, the patient was given a course of antibiotic(s) for treatment of any infection within the past 3 months, excluding the current episode of infection. Such treatment is a risk factor for drug-resistant Streptococcus pneumoniae and possibly for infection with gram-negative bacilli. Depending on the class of antibiotics recently given, one or another of the suggested options may be selected. Recent use of a fluoroquinolone should dictate selection of a nonfluoroquinolone regimen, and vice versa.

‡ Moxifloxacin, levofloxacin, or gemifloxacin.

§ Dosage: 1 g orally (PO) three times daily (tid).

¶ Dosage: 2 g PO twice daily (bid).

∗∗ High-dose amoxicillin (1 g tid), high-dose amoxicillin-clavulanate (2 g bid), cefpodoxime, cefprozil, or cefuroxime.

†† Cefotaxime, ceftriaxone, ampicillin-sulbactam, or ertapenem.

‡‡ The antipseudomonal agents chosen reflect this concern. Risk factors for Pseudomonas infection include severe structural lung disease (e.g., bronchiectasis) and recent antibiotic therapy, health care–associated exposures or stay in hospital (especially in the ICU). For patients with CAP in the ICU, coverage for S. pneumoniae and Legionella species must always be considered. Piperacillin-tazobactam, imipenem, meropenem, and cefepime are excellent β-lactams and are adequate for most S. pneumoniae and H. influenzae infections. They may be preferred when there is concern for relatively unusual CAP pathogens, such as P. aeruginosa, Klebsiella spp., and other gram-negative bacteria.

§§ Piperacillin, piperacillin-tazobactam, imipenem, meropenem, or cefepime.

## Data suggest that older adults receiving aminoglycosides have worse outcomes.

¶¶ Dosage for hospitalized patients, 750 mg/day.

The U.S. Preventive Services Task Force (USPSTF) along with IDSA and ATS recommend annual influenza vaccinations to those over 50 years of age, those who are (or who reside with those who are) at high risk for influenza complications, and all health care workers. Furthermore, the pneumococcal vaccine should be given to all those over age 65. Smoking cessation is also important and should be discussed at each clinic visit.

Influenza

Anthony Zeimet

Key Points

• Concerns about development of resistant seasonal and H1N1 swine-derived influenza virus should be considered in the decision to administer antiviral medications to healthy patients with these infections.

• The abrupt onset of fever with chills, headache, malaise, myalgias, arthralgias, and rigors during “flu season” is sufficient to diagnose influenza.

• Prevention of influenza is generally with vaccination.

Influenza deserves special mention because it is an important cause of pneumonitis and can precede a bacterial pneumonia. Influenza viruses are medium-sized enveloped ribonucleic acid (RNA) viruses that consist of a lipid bilayer with matrix proteins with spiked surface projections of glycoproteins (hemagglutinins, neuraminidase) on the outer surface (Figure 16-1). Both influenza A and influenza B have eight segmented pieces of single-stranded RNA. The only difference between influenza A and B is that B does not have an M2 ion channel. Hemagglutinins, three types of which typically infect humans (H1, H2, H3), bind to respiratory epithelial cells and allow fusion with the host cell. Neuraminidase, consisting of two types (N1, N2), allows release of virus from the infected cells.

Figure 16-1 Schematic model of influenza A virus.

(From Treanor JJ: Influenza viruses, including avian influenza and swine influenza. In Mandell GL, Bennett JE, Dolin RD (eds). Mandell, Douglas, and Bennett’s Principles and Practices of Infectious Diseases, 7th ed. Philadelphia, Churchill Livingstone, 2010, p 2266.)

A unique aspect of influenza is that antigenic variation occurs annually. Antigenic shift is caused by a genetic reassortment between animal and human influenza strains, producing a novel virus that generally causes the worldwide pandemics. Influenza viruses circulate mostly among humans, birds, and swine. Sometimes; a human strain and an animal strain can intermingle and create a new, unique virus. This is what happened during spring 2009, heralding the most recent pandemic and creating “Novel H1N1 Influenza” (swine influenza). Genotype analysis of this strain determined that components came from an influenza virus circulating among swine herds in North America that combined with a virus circulating among ill swine in Eurasia, creating a new influenza strain capable of causing disease in humans. Because this virus had not previously infected humans, it had the potential to cause widespread morbidity and mortality worldwide. During pandemics, the U.S. Centers for Disease Control and Prevention (CDC) estimates an additional 10,000 to 40,000 deaths caused by influenza. Although higher than in nonpandemic years, mortality was significantly less than initially predicted in 2009.

The abrupt onset of fever, along with chills, headache, malaise, myalgias, arthralgias, and rigors during “flu season,” is sufficient to diagnose influenza. As the fever resolves, a dry cough and nasal discharge predominate. A rapid nasal swab or viral cultures can be used to confirm the diagnosis of influenza but is rarely needed. In fact, the sensitivity of these rapid tests can range from 50% to 70%, so a negative test does not rule out influenza. The primary care physician needs to determine if the patient has influenza or the common cold, because symptoms of both illnesses generally overlap (Table 16-3).

Table 16-3 Common Cold versus Influenza Symptoms

Symptom	Common Cold	Influenza
Fever	Rare	Abrupt onset
Cough	Frequent, usually hacking	Frequent, usually severe
Sore throat	Frequent	Rare
Nasal congestion	Frequent	Rare
Sneezing	Frequent	Rare
Myalgia	Rare	Frequent
Headache	Rare	Frequent
Fatigue	Mild	Severe

Treatment of influenza is generally not necessary because it is usually a self-limiting condition. Treatment should be reserved for those with comorbidities who present within 48 hours of symptom onset. Neuraminidase inhibitors (zanamivir and oseltamivir) prevent the release of virus from the respiratory epithelium and are approved for both influenza A and influenza B. The M2 inhibitors (amantadine and rimantadine) are approved by the U.S. Food and Drug Administration (FDA) for the treatment of influenza A because these drugs block the M2 ion protein channel, preventing fusion of the virus to host cell membrane (influenza B has no M2 ion channel). The use of M2 inhibitors is limited because of increasing resistance among influenza A viruses, as well as causing central nervous system (CNS) problems that are usually exacerbated in elderly persons, who are more likely to seek treatment for influenza (Table 16-4).

Table 16-4 Treatment and Chemoprophylaxis Recommendations for Influenza

Agent/Group	Treatment	Chemoprophylaxis
Neuraminidase Inhibitors
Oseltamivir
Adults	75-mg capsule twice daily (bid) for 5 days	75-mg capsule once daily (qd)
Children (age >12 mo)
<15 kg	60 mg/day divided into 2 doses	30 mg qd
15-23 kg	90 mg/day in 2 doses	45 mg qd
24-40 kg	120 mg/day in 2 doses	60 mg qd
>40 kg	160 mg/day in 2 doses	75 mg qd
Zanamivir
Adults	Two 5-mg inhalations (10 mg bid)	Two 5-mg inhalations (10 mg qd)
Children	Two 5-mg inhalations (10 mg bid)(age >7 yr)	Twp 5-mg inhalations (10 mg qd)(age >5 yr)
M2 Inhibitors (Adamantadines)∗
Rimantadine†
Adults	200 mg/day as either a single daily dose or divided into 2 doses	200 mg/day as either a single daily dose or divided into 2 doses
Children
1-9 yr	6.6 mg/kg/day (max, 150 mg/day) divided in 2 doses	5 mg/kg qd, not to exceed 150 mg
>10 yr	200 mg/day as either a single daily dose or divided into 2 doses	200 mg/day as either a single daily dose or divided into 2 doses
Amantadine
Adults	200 mg/day as either a single daily dose or divided into 2 doses	200 mg/day as either a single daily dose or divided into 2 doses
Children
1-9 yr	5-8 mg/kg/day divided into 2 doses or as a single daily dose (max, 150 mg/day)	5-8 mg/kg/day divided into 2 doses or as a single daily dose (max, 150 mg/day)
9-12 yr	200 mg/day divided into 2 doses	200 mg/day divided into 2 doses

∗ The amantadines should be used only when influenza A (H1N1) infection or exposure is suspected. The amantadines should not be used for infection or exposure to influenza A (H2N3) or influenza B.

† Rimantadine has not been approved by the U.S. Food and Drug Administration for treatment of children, although published data exist on safety and efficacy in the pediatric population.

Modified from Harper SA, Bradley JS, Englund JA, et al. Seasonal influenza in adults and children: diagnosis, treatment, chemoprophylaxis, and institutional outbreak management. Clinical Practice Guidelines of the Infectious Diseases Society of America. Clin Infect Dis 2009;48:1003-1032.

The major complication of influenza is a secondary bacterial pneumonia or exacerbation of underlying COPD. Initial improvement in clinical symptoms followed by deterioration usually suggests a secondary bacterial pneumonia, which can usually be confirmed with a chest radiograph showing an infiltrate. Other, less common complications of influenza include myositis, myocarditis, pericarditis, transverse myelitis, encephalitis, and Guillain-Barré syndrome.

Prevention of influenza is generally with vaccination. Box 16-2 outlines patients at risk for influenza complications who should be vaccinated yearly. Although anyone wanting an influenza vaccine should be vaccinated, during periods of vaccine shortage, high-risk groups have priority. A well-matched vaccine can prevent influenza among 70% to 90% of adults and decrease work absenteeism. Conversely, a poorly matched vaccine only prevents influenza in 50% of healthy adults. Proper hand hygiene and covering one’s cough are two additional important components in preventing the spread of influenza virus.

Box 16-2 Groups at risk for Influenza Complications^∗

Modified from Harper SA, Bradley JS, Englund JA, et al. Seasonal influenza in adults and children: diagnosis, treatment, chemoprophylaxis, and institutional outbreak management. Clinical Practice Guidelines of the Infectious Diseases Society of America. Clin Infect Dis 2009;48:1003-1032.

Unvaccinated infants age 12 to 24 months

Persons with asthma or other chronic pulmonary disease, such as cystic fibrosis in children or chronic obstructive pulmonary disease in adults

Patients with hemodynamically significant cardiac disease

Patients with immunosuppressive disorders or receiving immunosuppressive therapy

Patient with human immunodeficiency virus (HIV) infection

Patients with sickle cell anemia and other hemoglobinopathies

Patients with disease requiring long-term aspirin therapy (e.g., rheumatoid arthritis, Kawasaki disease)

Patients with chronic renal obstruction

Patients with cancer

Patients with chronic metabolic disease, such as diabetes mellitus

Patient with neuromuscular disorders, seizure disorders, or cognitive dysfunction that may compromise the handling of respiratory secretions

Adults older than 66 years

Residents of any age of nursing homes or other long-term care facilities

^∗ Data suggest that the highest risk of both mortality and serious morbidity (e.g., hospitalization) occurs in severely immunocompromised patients (e.g., hematopoietic stem cell transplant patients) and very elderly (>85 years) residents of nursing homes; infants under age 24 months also have high hospitalization rates but lower case-fatality rates than the other two groups.

KEY TREATMENT

Early treatment (within 48 hours of onset of symptoms) with oseltamivir or zanamivir is recommended for influenza A (Jefferson et al., 2006) (SOR: A).

Use of oseltamivir and zanamivir is not recommended for patients with uncomplicated influenza with symptoms for more than 48 hours (Kaiser and Hayden, 1999) (SOR: A).

Oseltamivir and zanamivir may be used to reduce viral shedding in hospitalized patients or to treat influenza pneumonia (Mandell et al., 2007) (SOR: C).

Systemic Viral Infections

Anthony Zeimet

Key Points

Vaccinations have dramatically decreased the incidence of a number of historically common viral infections; smallpox has been eradicated through widespread vaccination. However, recent outbreaks of measles and mumps on college campuses underscore the need to remain vigilant in administering vaccines at the population level, even though no vaccine is available for many common viruses.

Measles

In 2008, more measles cases were reported than in any other year since 1997 (CDC, 2010). Measles is the “first disease” of childhood from the history of medicine. In adults, measles infection may be acquired in the face of waning immunity from remote immunization. A booster dose of MMR vaccine is recommended before college entry.

Clinically, measles presents with cough, coryza (nasal irritation and congestion), and conjunctivitis. Fever is common several days before the onset of the rash. The rash of measles typically spreads from head to toe and has an erythematous, papular appearance with a “sandpaper” feeling. Koplik’s spots are erythematous papules with a bluish center on the oral mucosa and appear early in measles. Measles is highly contagious through droplets.

Lymphopenia and neutropenia are common laboratory findings with measles infection. Complications of measles include primary infections such as pneumonia, gastroenteritis, encephalitis, and the rare subacute sclerosing panencephalitis. Secondary infections such as otitis media, pneumonia, and adenitis may also occur.

Treatment is supportive, and the implications of measles infection are primarily in the public health realm. Patients with measles should be isolated for at least 4 days after the appearance of the rash. It is important to recognize that patients are contagious for 2 days before the development of symptoms. Careful verification of immunization status for close contacts is essential.

Epstein-Barr Virus and Cytomegalovirus

Clinical infectious mononucleosis is a common infection in adolescents and early adults. The clinical syndrome is most often caused by Epstein-Barr virus (EBV), although cytomegalovirus (CMV) may also be the source in this clinical syndrome, which includes fever, exudative tonsillitis, adenopathy (often including posterior cervical or occipital nodes), and fatigue. EBV is transmitted in oral secretions and may be transmitted sexually as well. B cells are infected with EBV either directly or after contact with epithelial cells, resulting in diffuse lymphoid enlargement.

The diagnosis of infectious mononucleosis is made by recognizing the clinical symptoms of fever, pharyngitis, and adenopathy along with the laboratory findings of greater than 50% lymphocytes with 10% or more atypical lymphocytes (Hoagland, 1952). Also, a positive serologic test for heterophile antibody assists the family physician in the diagnosis. To differentiate EBV from CMV mononucleosis, serology (IgG and IgM) may be obtained. Results of these tests are generally not available in time to have a significant benefit clinically.

Splenic enlargement as part of this lymphoid hypertrophy can lead to splenic rupture (0.1% risk) (Dommerby et al., 1986). Athletes with infectious mononucleosis must be managed carefully to avoid their participation in sports that could result in abdominal trauma. Other risks associated with infectious mononucleosis include upper airway obstruction, asymptomatic transaminase elevation, thrombocytopenia, and rash after the administration of ampicillin or amoxicillin. Routinely obtaining transaminase levels in patients without clinical hepatitis is of little value and can increase the overall cost of management.

Treatment of infectious mononucleosis is largely supportive. Patients should be instructed to treat fever with antipyretics, rest, and expect symptom duration of 2 to 4 weeks, although symptoms can last for several months. The use of steroids, such as prednisone, has shown limited benefit. Data suggest an initial benefit 12 hours after steroid administration, although this is lost within several days (Candy and Hotopf, 2006). Combination of steroid and an antiviral (valacyclovir) may have some positive effect on fatigue.

Tuberculosis

David McCrary

Key Points

Tuberculosis (TB) is a disease that has plagued humans since antiquity, with evidence of spinal TB in neolithic and early Egyptian remains. At present, TB affects approximately one third of the world’s population. TB is the world’s second most common cause of death from infectious disease after human immunodeficiency virus or acquired immunodeficiency syndrome (HIV/AIDS). Tuberculosis is caused by Mycobacterium tuberculosis, an acid-fast bacillus. TB is acquired by inhalation of respiratory droplets. These respiratory droplets are spread by coughing. Brief contact carries little risk for acquiring TB, and infection generally does not occur in open air; open-air sanatoriums were the cornerstone of TB treatment before antimicrobial therapy.

Presentation

Tuberculosis is most frequently manifested clinically as pulmonary disease, but it can involve any organ. Extrapulmonary TB accounts for about 20% of disease in HIV-seronegative persons but is more common in HIV-seropositive persons. Pulmonary TB typically manifest with fever, night sweats, chronic cough, sputum production, hemoptysis, anorexia, and weight loss. Chest radiographs in patients with pulmonary TB typically reveal upper-lobe cavitary lesions and can reveal infiltrates or nodular lesions, as well as lymphadenopathy (Figure 16-2). TB in the setting of advanced HIV co-infection does not generally manifest in the typical manner (Table 16-5).

Figure 16-2 Chest radiograph showing right apical infiltrate typical of a patient with primary tuberculosis.

(From Fitzgerald D, Sterling T, Haas D. Mycobacterium tuberculosis. In Mandell GL, Bennett JE, Dolin R (eds). Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases, 7th ed. Philadelphia, Churchill Livingstone, 2010, p 3141.)

Table 16-5 Clinical Manifestations of Active Tuberculosis in Early verus Late^∗ Human Immunodeficiency Virus Infection

Sign	Early	Late
Tuberculin test	Usually positive	Usually negative
Adenopathy	Unusual	Common
Pulmonary distribution	Upper lobe	Lower and middle lobes
Cavitation	Often present	Typically absent
Extrapulmonary disease	10%-15% of cases	50% of cases

∗ For practical purposes, “early” and “late” may be defined as CD4+ cell counts >300 cells/mm³ and <200 cells/mm³, respectively.

Modified from Murray JF. Cursed duet: HIV infection and tuberculosis. Respiration 1990;57:210-220.

Treatment

Patients with AFB positive smears from sputum samples should be started on anti-TB therapy while awaiting results of PCR and cultures. The treatment of TB always uses multiple agents with anti-TB activity. Single agents should never be used. The standard first-line agents are isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB) (Figure 16-3 and Table 16-6). If administered, INH should be given with pyridoxine (vitamin B₆; 25-50 mg orally daily) to prevent neuropathy. Treatment of active pulmonary TB is generally for 6 months regardless of HIV status, but treatment may need to be extended in certain situations.

Figure 16-3 Treatment algorithm for tuberculosis. Patients in whom TB is proved or strongly suspected should have treatment initiated with isoniazid, rifampin, pyrazinamide, and ethambutol for the initial 2 months. A repeat smear and culture should be performed when 2 months of treatment has been completed. If cavities were seen on the initial chest radiograph or the acid-fast smear is positive at completion of 2 months of treatment, the continuation phase of treatment should consist of isoniazid and rifampin daily or twice weekly for 4 months to complete a total of 6 months of treatment. If cavitation was present on the initial chest radiograph and the culture at completion of 2 months’ therapy is positive, the continuation phase should be lengthened to 7 months (total of 9 months of treatment). If the patient has HIV infection and the CD4+ cell count is less than 100/mm³, the continuation phase should consist of daily or three-times-weekly isoniazid and rifampin. In HIV-uninfected patients having no cavitation on chest radiograph and negative acid-fast smears at completion of 2 months of treatment, the continuation phase may consist of either once-weekly isoniazid and rifapentine, or daily or twice-weekly isoniazid and rifampin, to complete a total of 6 months (bottom). Patients receiving isoniazid and rifapentine, and whose 2-month cultures are positive, should have treatment extended by an additional 3 months (total of 9 months).

^∗EMB may be discontinued when results of drug susceptibility testing indicate no drug resistance.

^†PZA may be discontinued after it has been taken for 2 months (56 doses).

^‡RPT should not be used in HIV-infected patients with TB or in patients with extrapulmonary TB. Therapy should be extended to 9 months if 2-month culture is positive.

AFB, Acid-fast bacilli; CXR, chest radiograph (x-ray); EMB, ethambutol; INH, isoniazid; PZA, pyrazinamide; RIF, rifampin; RPT, rifapentine.

From Centers for Disease Control and Prevention (CDC). Treatment of tuberculosis. American Thoracic Society, CDC, and Infectious Diseases Society of America. MMWR 2003;52(RR-11):1-88.

Table 16-6 Recommended Treatment Regimens for Pulmonary Tuberculosis

Directly observed therapy (DOT) is the preferred mechanism of administration to ensure compliance. Many local county and state health departments have systems for DOT. Treatment of HIV-seropositive patients with TB who are receiving an antiretroviral (ARV) regimen that contains a protease inhibitor is complicated by the latter’s interaction with rifamycins (particularly rifampin). Management of such patients should be coordinated with an infectious diseases specialist, who also should manage drug-resistant TB treatment.

Latent Tuberculosis Infection and Purified Protein Derivative

In the United States, latent tuberculosis infection (LTBI) is the most prevalent form of tuberculosis. LTBI is the term given to patients with a positive purified protein derivative (PPD) skin test without evidence of active TB. PPD has been used for more than 100 years and relies on delayed-type hypersensitivity (DTH) to M. tuberculosis cellular proteins. Because PPD relies on DTH, any factor that reduces the DTH affects the host response to PPD. The most common clinical example is use of corticosteroids, which blunt the DTH response and can complicate PPD interpretation. Therefore, PPD testing should not be performed while a patient is taking corticosteroids. Also, TB testing should be targeted to those with higher risk of infection and should not routinely be done in those with low risk (ATS/CDC, 2000).

The PPD can also give false-positive results in patients with previous bacille Calmette-Guérin (BCG) vaccination or with infection by other mycobacterial infections. In the United States, this may cause difficulties in testing immigrants from countries who routinely use BCG vaccination programs. However, previous BCG vaccination should not change the interpretation of the PPD or willingness to treat such individuals accordingly.

The DTH response can wane over time. To overcome this problem, nonreacting patients may undergo repeat PPD 1 week after their initial PPD. The diagnosis of LTBI is made by interpretation of a PPD and by ascertaining the patient’s risk factors for progression to active TB if left untreated (Box 16-3). Interpretation of the PPD should be based on the area of induration and not the area of surrounding erythema. Persons whose PPDs have converted from negative to positive within 2 years are presumed to have been infected recently. The decision to use PPD means treating the patient for LTBI if the PPD test is positive.

Box 16-3 Criteria for Tuberculin Positivity by Risk Group

Modified from Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection. American Thoracic Society. MMWR 2000;49(RR-6):1-51.

Reaction ≥5mm of Induration

HIV-positive persons

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