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I have an HIV-positive patient with a cough and fever. How do I determine the cause🚧 施工中
I have an HIV-positive patient with a cough and fever. How do I determine the cause?
CHIEF COMPLAINT
PATIENT
Mr. L is a 35-year-old man who is HIV-positive. His chief complaints are cough and fever lasting for 4 days.
What is the differential diagnosis of cough and fever in HIV-positive patients? How would you frame the differential?
CONSTRUCTING A DIFFERENTIAL DIAGNOSIS
The most common pneumonias in HIV-infected patients are bacterial pneumonia, PJP, and pulmonary TB. Taken together, they account for 91% of pulmonary infections in HIV-positive patients. Three pivotal features aid in the diagnosis of these common pneumonias in HIV-infected persons. First, the CD4TL count gauges the level of immunocompromise. Virulent infections, such as pulmonary TB or bacterial pneumonia, may occur in patients with any CD4TL count. On the other hand, less virulent infections, such as PJP, are seen almost exclusively in patients with CD4TL < 200 cells/mcL.
The second pivotal feature is that certain diseases present acutely (bacterial pneumonia), but other diseases present subacutely or chronically (pulmonary TB or PJP).
The final pivotal feature that aids in the diagnosis of these complaints is the pattern on chest radiograph. Lobar infiltrates suggest bacterial pneumonia, whereas diffuse or interstitial infiltrates are seen in PJP and TB. Patterns that suggest pulmonary TB include apical or cavitary infiltrates (if CD4TL > 200 cells/mcL), hilar lymphadenopathy, or nodular infiltrates. The chest radiographic pattern in pulmonary TB varies depending on the patient’s degree of immunosuppression. Table 5-4 summarizes the typical CD4TL count, acuity, and chest radiographic pattern and approach to pulmonary infection in HIV-positive patients.
Table 5-4. Summary of findings in pulmonary infection in HIV-positive patients.
Tumors may also cause pulmonary complaints. Not surprisingly, aggressive neoplasms, such as lung cancer, may occur at any CD4TL count, whereas pulmonary lymphoma usually develops in patients with CD4TL counts < 500 cells/mcL, and Kaposi sarcoma usually develops in patients with CD4TL < 200 cells/mcL.
As noted above, the most common pneumonias in HIV-infected patients are bacterial pneumonia, PJP and pulmonary TB. PJP is reviewed in Chapter 10 and will be mentioned here only briefly. There are a large number of less common causes of pneumonia in HIV-infected patients that will not be reviewed here including endemic or geographically limited fungi (blastomycosis, coccidioidomycosis, and histoplasmosis), opportunistic fungi (cryptococcosis and, in late AIDS, aspergillosis), uncommon bacterial pathogens (Nocardia, Rhodococcus equi, M kanasii) and CMV. The remainder of this section will focus on bacterial pneumonia, pulmonary TB, and M avium infection in HIV-infected patients.
Differential Diagnosis of Pulmonary Processes in Patients with HIV
A. CD4TL count > 500 cells/mcL
1. Bacterial pneumonia
2. Pulmonary TB
1. Lung cancer
B. CD4TL count 200–499 cells/mcL: all of the above plus lymphoma
C. CD4TL count 100–199 cells/mcL: all of the above plus PJP
D. CD4TL count < 100 cells/mcL: all of the above plus the following:
1. Fungal infections (blastomycosis, coccidioidomycosis, cryptococcosis, histoplasmosis, and aspergillosis)
2. CMV: when found in bronchoalveolar lavage culture, it usually reflects asymptomatic reactivation rather than the etiology of pneumonia, although CMV is occasionally responsible for pneumonia in advanced AIDS.
3. Nontuberculous mycobacteria, especially MAI and M kansasii
4. Kaposi sarcoma
PATIENT
Mr. L reports that he was feeling well until 4 days ago when he developed the sudden onset of fever 38.8°C, cough productive of green sputum, and right-sided chest pain with inspiration. He feels moderately short of breath with exertion. Medical history is remarkable for sexually acquired HIV infection diagnosed 2 years ago. His last CD4TL cell count 1 month ago was 400 cells/mcL. At that time, his viral load was undetectable. He is compliant with ART.
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
There are 2 key features to Mr. L’s presentation. The first pivotal feature is that his CD4TL count is only moderately reduced. This makes a variety of OIs unlikely (PJP, MAI, CMV, and cryptococcosis). On the other hand, pulmonary TB, bacterial pneumonia, and blastomycosis are sufficiently virulent to present in patients with normal or mildly impaired immune systems. The second pivotal feature is the rapid development of the pulmonary process, which strongly favors bacterial pneumonia over pulmonary TB. The differential diagnosis is summarized in Table 5-5.
Table 5-5. Diagnostic hypotheses for Mr. L.
PATIENT
Physical exam reveals temperature, 38.6°C; BP, 120/75 mm Hg; HR, 110 bpm; RR, 18 breaths per minute. Lung exam reveals crackles over the lower one-third of posterior right chest. Chest radiograph reveals a right lower lobe consolidation. No effusion is seen. WBC is 8000/mcL with 15% bands. Sputum Gram stain reveals numerous PMNs and gram-positive diplococci. The initial AFB smear is negative. Blood cultures are sent.
Is the clinical information sufficient to make a diagnosis? If not, what other information do you need?
Leading Hypothesis: Bacterial Pneumonia
Textbook Presentation
Typical onset is acute (< 1 week) with productive cough and fever. Patients may produce purulent sputum and complain of pleuritic chest pain. Presentation is similar to bacterial pneumonia in HIV-negative patients.
Disease Highlights
A. Bacterial infection is the most common cause of pneumonia associated with HIV and AIDS. HIV should therefore be considered in any patient with severe or recurrent community-acquired pneumonia.
B. Recurrent bacterial pneumonia (> 2 episodes within 1 year) is an AIDS-defining condition.
C. May occur at any time during course of HIV infection
D. Risk of bacterial pneumonia increases as CD4TL count falls. IDU further increases the risk.
1. CD4TL count
a. Rate of bacterial pneumonia in HIV-negative patients: 0.9%/year
b. Rate of bacterial pneumonia in HIV-positive patients
(1) CD4TL > 500 cells/mcL: 2.3%/year
(2) CD4TL 200–500 cells/mcL: 6.8%/year
(3) CD4TL < 200 cells/mcL: 10.8%/year
(4) Two-thirds of cases in HIV-infected patients developed in those with CD4TL < 200 cells/mcL.
2. IDU
a. Pneumonia incidence in HIV-infected patients who are IDUs is twice that in HIV-infected patients who are not IDUs.
b. Increased rate of septic emboli from infective endocarditis contribute to the increased risk of pneumonia.
3. ART significantly reduces the risk of bacterial pneumonia (45%).
E. Etiology
1. S pneumoniae is the most common cause of bacterial pneumonia. Other common bacterial etiologies are H influenzae; Mycoplasma pneumoniae; Legionella; S aureus, including community-acquired methicillin-resistant S aureus; and Pseudomonas aeruginosa.
2. S pneumoniae is associated with higher WBC than P aeruginosa (12,400/mcL vs 5000/mcL) and higher average CD4TL count (106 cells/mcL vs 19 cells/mcL).
3. P aeruginosa is the reported causative pathogen in up to 38% of hospital-acquired pneumonias and 3–25% of community-acquired pneumonias; it is associated with 33% in-hospital mortality rate.
4. Concomitant PJP is present in 13% of patients with bacterial pneumonia.
F. Complications and prognosis
1. Bacterial pneumonia progresses more rapidly and is more often complicated in HIV-infected persons than in Non-HIV infected persons.
2. 30% of bacterial pneumonias are associated with bacteremia; bacteremia is more common with S pneumoniae.
3. Among hospitalized patients, overall mortality is 9.3–27%.
a. 6–13 times higher mortality than general US population (and 1.2–2.4 times higher than population > 65 years)
b. 5 predictors of mortality include septic shock, CD4TL count < 100 cells/mcL, significant pleural effusion (extending beyond costophrenic angle), cavities and multilobar infiltrates. Mortality is proportional to number of risk factors (Table 5-6).
Table 5-6. Mortality among HIV-positive patients with bacterial pneumonia.
c. Mortality increases during influenza season. Influenza infection may result in either severe influenza virus pneumonia or bacterial pneumonia, most often due to S pneumoniae or S aureus.
G. Pyogenic bacterial bronchitis with productive cough, fever, and absence of infiltrates is more common in HIV-infected patients.
Evidence-Based Diagnosis
A. Initial evaluation
1. Should include a chest radiograph, blood and sputum cultures, sputum Gram stain, and WBC
2. Urinary pneumococcal and Legionella pneumophila serogroup 1 Ag testing is performed routinely and often helpful.
B. Airborne precautions should be followed in all HIV-infected patients with pneumonia.
1. They should be placed in a negative-pressure isolation room.
2. 3 sputum acid-fast stains should be done to rule out pulmonary TB.
C. Toxic appearance is uncommon but suggests bacterial pneumonia over PJP or pulmonary TB (sensitivity, 10.6%; specificity, 97.8%; LR+, 4.8)
D. Pneumococcal pneumonia
1. Common symptoms include cough (93%), subjective fever (90%), pleural pain (52–91%), and chills (74%); 51% of patients have hemoptysis and 63% have temperature > 38°C.
2. The median duration of symptoms is 4 days.
3. Sputum Gram stain is 58% sensitive and more frequently positive if collected within 24 hours of antibiotics.
4. Sputum culture is 56% sensitive: the real pathogen is more often isolated if sputum culture is performed before starting antibiotics. When sputum culture is delayed > 24 hours after starting antibiotic, respiratory colonizers are more often isolated; for example, a respiratory sample obtained from a person with severe pneumonia caused by S pneumoniae who has been intubated in the ICU for 48 hours may grow P aeruginosa that colonizes the ventilator tubing without causing pneumonia.
5. Blood cultures are positive in 31–95%.
6. Pneumococcal urinary Ag: ≈79% sensitive and 94% specific (LR+, 13; LR–, 0.2). The test may be also be positive due to colonization or upper respiratory infections with S pneumoniae.
Antibacterial coverage should not be limited to S pneumoniae in HIV-infected patients with pneumonia and a positive pneumococcal urinary Ag.
E. Legionella pneumonia
1. One study reported that certain findings were more common in patients with Legionella pneumonia than S pneumoniae, including extra-respiratory symptoms (57% vs 24%), hyponatremia (57% vs 13%), and elevated creatine phosphokinase (57% vs 17%).
2. Respiratory failure is more common with Legionella than S pneumoniae (33% vs 2%).
F. M pneumoniae is usually diagnosed by IgM ELISA, 4-fold change in IgG, or the presence of cold agglutination.
G. Chest radiograph
1. Standard imaging includes posteroanterior plus lateral chest radiograph.
2. Typically demonstrates lobar or multifocal consolidation.
3. Lobar consolidation is not always seen but strongly suggests bacterial pneumonia over PJP or pulmonary TB (sensitivity, 54%; specificity, 90%; LR+, 5.6; LR–, 0.51).
4. Lobar infiltrates in patients with fever for < 1 week strongly suggests bacterial pneumonia (sensitivity, 48%; specificity, 94%; LR+, 8.0; LR–, 0.55).
5. Chest radiographic patterns did not distinguish S pneumoniae from P aeruginosa or Legionella infection.
6. One report found that 82% of HIV-infected persons with pulmonary complaints had abnormalities, including pleural effusions, cavities and abscess, on high-resolution CT scans that were not detected on chest radiograph.
High-resolution CT scanning should be considered for HIV-infected patients who do not respond to therapy and for ill patients with respiratory symptoms or signs but an unexpectedly normal chest radiograph.
H. Bronchoscopy
1. Indicated in patients who do not respond to therapy or when concomitant infection is likely.
2. Sensitivity of bronchoalveolar lavage for bacterial pneumonia: 70% (if performed early)
Treatment
A. Prevention
1. TMP-SMX PJP prophylaxis in patients with a CD4TL count < 200 cells/mcL also decreases the incidence of bacterial pneumonia by 67%.
2. Pneumococcal vaccines
a. Two pneumococcal vaccines are recommended in HIV-infected persons: the 13-valent conjugated pneumococcal vaccine (Prevnar-13) and the 23-valent polysaccharide pneumococcal vaccine (Pneumovax). Both decrease pneumococcal disease significantly, but the combination is superior.
b. The 23-valent polysaccharide pneumococcal vaccine covers 86% of serotypes but is not as immunogenic as the 13-valent conjugated pneumococcal vaccine.
c. CDC recommends pneumococcal vaccine use as early as possible in HIV infection.
(1) Vaccination should be delayed 4 weeks in individuals initiating ART to allow for immune reconstitution.
(2) Usually, the more immunogenic conjugated pneumococcal vaccine is administered first, and the less immunogenic polysaccharide vaccine is administered 2 months later, although it may be preferable to wait for the latter until CD4 > 200 cells/mcL.
d. A polysaccharide pneumococcal vaccine booster is recommended every 5 years. A booster may also be useful in patients whose initial CD4TL is < 200 cells/mcL after significant immune reconstitution occurs (an increase of CD4TL > 100 cells/mcL).
3. Therapy for typical bacterial pneumonia is usually initiated empirically.
4. Inappropriate antimicrobial therapy is associated with markedly increased mortality in patients with shock (85.7% compared with 25% with appropriate therapy).
5. Antibiotics must cover common pathogens (S pneumoniae, S aureus, H influenzae, M pneumoniae, and P aeruginosa). Local resistance patterns should be considered.
6. A common strategy includes azithromycin and ceftriaxone.
7. There should be a low threshold for including anti-methicillin-resistant S aureus coverage, particularly in patients with a history of IDU; patients undergoing hemodialysis; MSMs; and patients with severe, presumably bacterial, pneumonia during influenza season.
8. Pseudomonas infection
a. Should be considered when the CD4TL is low.
b. Treat with an antipseudomonal beta-lactam antibiotic
(1) Piperacillin/tazobactam, cefepime, ceftazidime, meropenem
(2) Ceftazidime/avibactam or ceftolozane/tazobactam for multidrug-resistant P aeruginosa isolates
c. An aminoglycoside (usually tobramycin) may be added initially pending susceptibility data, but there is no benefit of continuing tobramycin if Pseudomonas is susceptible to the antipseudomonal beta-lactam.
9. Patients with uncomplicated pneumonia have a time course of clinical and radiologic response to therapy similar to non–HIV-infected persons.
MAKING A DIAGNOSIS
Serial sputum samples are sent for acid-fast bacilli (AFB) smear and culture. All AFB stains are negative.
Have you crossed a diagnostic threshold for the leading hypothesis, bacterial pneumonia? Have you ruled out the active alternatives? Do other tests need to be done to exclude the alternative diagnoses?
A critical decision at this point in the evaluation of an HIV-infected patient with pulmonary complaints is whether the patient needs bronchoscopy with bronchoalveolar lavage to establish the causative pathogen. In HIV-positive patients with infiltrates, bronchoalveolar lavage is highly sensitive (86%) if performed within 24 hours of starting antibiotics. Transbronchial biopsy increases the sensitivity further but is rarely performed. Due to the large number of potential pathogens, empiric treatment for community-acquired bacterial pneumonia is often inappropriate except in the cases in which bacterial pneumonia is strongly suspected. Acute onset and focal infiltrates suggest bacterial pneumonia whereas subacute/chronic progression, diffuse infiltrates, and cavitary lesions suggest other etiologies. Bronchoscopy is often necessary in such cases unless sputum analysis is diagnostic (positive AFB or rarely positive silver stain). Mr. L’s acute illness, and focal findings on the chest radiograph strongly suggest bacterial pneumonia. You wonder if pulmonary TB would present similarly in an HIV positive patient with this CD4TL count.
Alternative Diagnosis: Pulmonary TB in AIDS Patients1
Textbook Presentation
Pulmonary TB typically presents subacutely with cough and fever that have gone on for over a week (and often much longer) and systemic symptoms of night sweats and weight loss are common. In patients with CD4TL > 200 cells/mcL, the chest radiographic pattern is similar to the one seen in non–HIV-infected patients—that is, with apical, cavitary, or nodular infiltrates. In patients with CD4TL < 200 cells/mcL, the pattern on chest radiograph is often atypical: lower lobe infiltrates, miliary infiltrates, and lymphadenopathy are more common. Extrapulmonary TB is also more common in AIDS.
Disease Highlights
A. There are currently more worldwide cases of TB than at any time in human history: per CDC data, in 2017, there were an estimated 10.0 million people with new TB and 1.3 million TB-related deaths worldwide. Latent TB infection affects a quarter of the world population.
B. HIV-infected persons are at highest risk for TB (170 times higher incidence).
1. Risk increases further in patients from endemic areas and among IDUs.
2. 9000 TB cases were reported in 2017 in the United States, a 1.6% decrease from 2016.
C. TB in turn increases both HIV replication and the risk of death.
D. Worldwide, TB accounts for 30% of HIV-related deaths.
E. Epidemic in sub-Saharan Africa and parts of Asia
F. 50% of cases secondary to recent infection (progressive primary TB)
G. TB may be the first manifestation of HIV infection and is an AIDS-defining illness.
All patients with TB should be tested for HIV.
H. Clinical characteristics
1. Early HIV infection: pulmonary TB is fairly typical.
2. Advanced HIV infection
a. Extrapulmonary TB more frequent
(1) More common in the AIDS population (30%) than in patients without AIDS (15%)
(2) Most common sites of extrapulmonary TB include blood, lymph nodes, bone marrow, genitourinary tract, CNS, and liver. 19% of patients had cervical or supraclavicular lymph node involvement.
(3) Other syndromes seen in these patients include weight loss, fever of unknown origin, and TB meningitis.
b. Chest radiographic pattern more frequently atypical (see below).
Extrapulmonary TB is common in HIV-infected patients and extrapulmonary sites of infections may provide a target for diagnostic procedures.
Evidence-Based Diagnosis
A. Prolonged fever (> 7 days) is more common in HIV-infected persons with pulmonary TB than in PJP or bacterial pneumonia (sensitivity, 56%; specificity, 78%; LR+, 2.5; LR–, 0.57).
B. Weight loss is also more common with pulmonary TB than with PJP or bacterial pneumonia (sensitivity, 67%; specificity, 68%; LR+, 2.1; LR–, 0.49).
C. Standard tests in patients with suspected pulmonary TB should include chest radiograph (with posteroanterior and lateral views), 3 sputum AFB stains and cultures, PPD or IGRA, and blood and urine cultures.
D. Chest radiography
1. Certain radiographic findings, including cavitary lesions, hilar lymphadenopathy, and nodular lesions, are infrequent but suggestive of pulmonary TB (Table 5-7).
Table 5-7. Diagnostic accuracy of radiographic findings in HIV-infected patients for tuberculosis.
The chest radiograph in HIV-infected patients with pulmonary TB may be typical or atypical. Pulmonary TB should be considered in patients with apical or cavitary disease, nodular infiltrates, or lymphadenopathy.
2. However, the radiographic manifestations of pulmonary TB vary with degree of immunosuppression (Table 5-8).
Table 5-8. Frequency (%) of radiographic manifestations in HIV-infected patients with TB: Influence of CD4 count.
a. Early HIV infection (CD4TL > 200 cells/mcL): chest radiograph usually shows the typical reactivation pattern: upper lobe disease or apical segment of lower lobe with or without cavitation.
b. Advanced HIV infection (CD4TL count < 200 cells/mcL):
(1) Middle and lower lobe consolidation, lymph node enlargement, pleural effusions, and miliary patterns more often seen.
(2) Pleural involvement more common
(a) Often accompanied by fever (85%), cough (77%), and chest pain (36%). Weight loss is common (74%).
(b) Unilateral exudative effusion
(c) Concomitant lower lobe parenchymal infiltrate present in 44–73%
Pleural effusions without an infiltrate can be a manifestation of TB in HIV-infected patients.
3. Cavitary lesions with night sweats or prolonged fever (> 7 days) not sensitive for pulmonary TB but highly predictive (sensitivity, 8–11%; LR+, ∞).
4. Hilar lymphadenopathy with weight loss or with prolonged cough (> 7 days) was not sensitive for pulmonary TB but highly suggestive (sensitivity, 8%; LR+, 8–∞).
5. Chest radiograph is normal in 10–21% of patients with pulmonary TB and advanced disease.
Pulmonary TB can be present despite a normal chest radiograph and should be considered in HIV-positive patients with CD4TL < 200 cells/mcL and pulmonary symptoms. Such patients require isolation in a negative-pressure room.
E. PPD and IGRA: sensitivity depends on the degree of immunosuppression.
1. CD4TL > 300 cells/mcL: 90% sensitive
2. CD4TL < 100 cells/mcL:
a. PPD (≥ 5 mm) 0% sensitive.
b. IGRA test interpretation is complex in patients CD4TL < 100 cells/mcL. Most such patients have indeterminate IGRA results, which are not diagnostic. However, a negative result makes the diagnosis of TB less likely.
F. Sputum analysis
1. AFB smear results
a. Poor sensitivity (29–60%) is often due to the patient’s inability to produce adequate sputum. Sensitivity is 67% in patients able to produce adequate sputum.
b. Specificity falls at lower CD4TL counts due to increasing incidence of MAI but remains remarkably high in this group (92%).
2. AFB culture: Sensitivity ranges from 43% to 100%. Sensitivity approaches 100% in patients able to produce adequate sputum.
G. Mycobacterium tuberculosis PCR testing of sputum
1. Helps distinguish pulmonary TB from MAI, M kansasii, or colonizing/contaminating nontuberculous mycobacteria (often Mycobacterium gordonae)
2. Primarily used when AFB stains positive
3. Particularly useful if suspicion of pulmonary TB is low
a. Positive rapid tests help confirm pulmonary TB, negative tests make pulmonary TB less likely
b. 95% sensitive and specific in this situation
4. Also useful when clinical suspicion is high and smear negative
a. Rapid tests reported 53% sensitive, 93% specific.
b. Positive tests suggest pulmonary TB
c. Cultures still required to test drug susceptibility
5. A diagnostic algorithm is shown in Figure 5-10.
Figure 5-10. Diagnosis of pulmonary tuberculosis: role of rapid diagnostic tests.
H. Blood culture for mycobacteria
1. Blood cultures are positive in 26–42% of HIV-positive patients with TB.
2. Sensitivity increases to 49% in patients with CD4TL < 100 cells/mcL.
I. Bronchoscopy
1. Smear sensitivity: 50–57%; specificity: 99% in endemic area
2. Culture sensitivity: nearly 100%
3. Some studies report similar sensitivities to induced sputum.
4. Bronchoscopy associated with increased transmission of M tuberculosis to medical personnel. Risk is minimal if bronchoscopy is performed in a negative-pressure room.
5. Induced sputum is preferred.
6. If bronchoscopy is performed for suspected miliary TB, transbronchial biopsy is recommended.
J. Pleural evaluation
1. Pleural fluid smear positive in 15%
2. Culture of pleural fluid positive in 33–90%
3. Sputum smear or culture in patients with pleural TB is positive in 33–50%. Sputum may be positive in patients without parenchymal infiltrate.
Obtain sputum for AFB stain and culture in HIV-infected patients with pleural effusions, even in those without infiltrates
4. Effusion is unilateral and exudative with lymphocyte predominance.
5. Pleural biopsy
a. Positive smear: 44–69%
b. Positive pathology (granuloma): 88%
Treatment
A. Chemoprophylaxis
1. Indicated for HIV-infected patients who have either a positive PPD (induration ≥ 5 mm) or a positive IGRA; also indicated for HIV-infected patients who have had a recent and significant exposure to persons with infectious pulmonary TB regardless of PPD/IGRA results
2. A chest radiograph should be performed and the patient evaluated to rule out active TB (pulmonary or extrapulmonary). In addition, even in patients with a normal chest radiograph but CD4TL < 200 cells/mcL, sputum AFB stain and culture should be obtained.
3. Isoniazid prophylaxis for 9 months decreases the rate of progression from latent to active TB from 7.4% to 2.6% in HIV-infected patients.
4. Patients should be evaluated monthly to monitor adherence and side effects of therapy.
5. Isoniazid liver toxicity
a. Elevation of transaminases in 10–20% of patients, but symptomatic hepatitis much less common
b. Isoniazid should be stopped if transaminase elevation exceeds 5× the upper limit of normal, even if the patient is asymptomatic.
c. Patients with alcohol abuse, chronic liver disease, or coinfection with hepatitis B or C virus should have monthly liver biochemical tests to rule out isoniazid-induced hepatitis. All HIV-infected patients are at higher risk for hepatotoxicity (NASH, drug adverse effects) and should receive monthly liver biochemical tests.
6. Rifampin prophylaxis for 4 months is an alternative when isoniazid cannot be used or to shorten the duration of prophylaxis; however, drug interactions have to be carefully reviewed. Adverse effects include hepatitis, blood dyscrasias, rash, and hypersensitivity.
7. Recently rifapentine plus isoniazid weekly for 12 weeks has become an acceptable alternative for HIV-infected patients with latent TB infection.
B. Active TB
1. Active TB is usually treated with rifabutin, isoniazid, pyrazinamide, and ethambutol (RIPE). If the isolate is susceptible to rifampin and isoniazid, ethambutol is stopped. After 2 months of therapy, pyrazinamide is stopped. Rifabutin and isoniazid are continued to complete 6 months of therapy.
2. Treating TB in HIV is complicated by clinically important drug interactions; consultation is recommended. Rifampin is rarely used in HIV-infected patients in the United States because rifabutin interactions are easier to manage. Unfortunately, rifabutin is expensive and not used extensively in low-income countries.
3. Directly-observed therapy is recommended for all patients with active TB, including HIV-positive patients.
a. Decreases relapse rate from 20% to 5%
b. Decreases development of multidrug-resistant TB from 6% to 1%
4. Monthly follow-up sputum cultures are obtained: if the 2-month culture remains positive, treatment is extended from 6 to 9 months.
5. Multidrug resistance is a major health problem.
a. Definitions
(1) Drug-resistant TB is resistant to any of the first-line drugs (rifampin, isoniazid, pyrazinamide, or ethambutol).
(2) Multidrug-resistant TB is defined as resistance to both rifampin and isoniazid.
(3) Extensively drug-resistant TB is defined as resistance to rifampin, isoniazid, fluoroquinolones (ciprofloxacin, moxifloxacin, levofloxacin) and one of the injectable second-line antituberculous drugs (capreomycin and aminoglycosides).
(4) Drug-resistant TB is more common in HIV patients, but multidrug-resistant TB is uncommon in the United States.
b. Drug-resistant TB arises in nonadherent patients.
c. Suspect drug-resistant TB in patients with prior TB treatment, contact with known multidrug-resistant TB, or immigrants from countries where multidrug-resistant or extensively drug-resistant TB is prevalent.
d. Case fatality rate is high in patients with multidrug resistant or extensively drug-resistant TB and HIV.
e. Multidrug-resistant TB typically requires 5 to 6 drugs, including 3 drugs to which TB is susceptible. Expertise in treating multidrug-resistant TB is required. Therapy is recommended for at least 2 years. Surgical resection of localized disease is required in some patients.
C. IRIS and pulmonary TB
1. Infiltrates worsen in 36% of patients upon institution of ART due to immunologically mediated reactions (ie, IRIS).
2. Increasing fever, infiltrates, and adenopathy may be seen.
3. A second OI, poor adherence, drug resistance, or low potency of TB regimen needs to be excluded.
4. IRIS is usually self-limited with pulmonary TB, but more severe reactions benefit from corticosteroids.
D. BCG
1. BCG is a live-attenuated Mycobacterium bovis strain with limited efficacy: it may prevent TB meningitis and miliary TB, but does not prevent the more common presentations of primary or reactivation TB.
2. BCG is contraindicated in HIV-positive patients due to increased incidence of active infection or dissemination of the BCG strain.
CASE RESOLUTION
Mr. L’s acute presentation and chest radiograph suggest bacterial pneumonia. PJP and MAC are unlikely given his high CD4TL count. Similarly, pulmonary TB would be unlikely with such an acute presentation. Furthermore, at this CD4TL level, pulmonary TB would be expected to present more typically (ie, with upper lobe or apical segment of lower lobe disease). The LR+ of bacterial pneumonia given the acuity of symptoms and lobar infiltrate is 8.0. Therefore, empiric therapy for bacterial pneumonia would be appropriate. Bronchoscopy should be performed if Mr. L does not respond promptly to antibiotic therapy to rule out an alternative diagnosis like blastomycosis.
Mr. L is given ceftriaxone (a third-generation cephalosporin) and azithromycin. Urinary Ag is positive for S pneumoniae and blood cultures return in 36 hours positive for S pneumoniae, highly susceptible to penicillin and ceftriaxone. Mr. L. is treated with IV ceftriaxone because of the convenience of once a day administration, improves over the next 3–4 days, and is given oral amoxicillin and discharged.
Table 5-9 summarizes the predictive value of clinical, radiologic, and combined findings for the diagnosis of PJP, pulmonary TB, and bacterial pneumonia in HIV-infected patients.
Table 5-9. The predictive value of clinical, radiologic, and combined findings for the diagnosis of bacterial pneumonia, Pneumocystis pneumonia, and tuberculosis in HIV-infected patients.
REVIEW OF OTHER IMPORTANT DISEASES
Mycobacterium avium/intracellulare (MAI)
Textbook Presentation
MAI typically presents with constitutional symptoms, including fever, drenching sweats, and weight loss.
Disease Highlights
A. MAI (also known as Mycobacterium avium complex (MAC)) refers to M avium and M intracellulare. M avium is by far the most common nontuberculous mycobacteria in AIDS patients.
B. M avium is acquired through inhalation or ingestion.
C. No human-to-human transmission
D. Infection is common in immunocompetent persons, and pulmonary MAI disease may be progressive and require treatment.
E. Disseminated MAC
1. Usually occurs in patients with profound immunosuppression.
a. CD4TL < 50 cells/mcL in almost all disseminated MAC cases
b. Mean CD4TL: 7 cells/mcL
2. Disseminated MAC involves the liver, spleen, gastrointestinal tract, lungs, and bone marrow.
a. Cultures of blood, bone marrow, and urine may be positive.
b. Predominantly pulmonary or gastrointestinal disease is uncommon.
c. Constitutional symptoms predominate.
3. MAI detection in sputum and stool often indicate colonization rather than disease.
4. Pulmonary disease occurs in < 5% of patients with disseminated disease. Nodules, infiltrates, lymphadenopathy, and cavities may be seen.
F. Marked decreased incidence of disseminated MAC since the introduction of ART.
Evidence-Based Diagnosis
A. Signs and symptoms
1. Fever: 18–87%
2. Night sweats: 78%
3. Cough: 78%
4. Diarrhea: 32–47%
5. Weight loss: 32–100%
6. Hepatosplenomegaly: 24%
B. Laboratory findings
1. Anemia: 85%
2. Increased alkaline phosphatase: 45–53%
C. Culture
1. Blood culture for AFB: 50–95% sensitive
2. Bone marrow culture: 82% sensitive
D. Sputum
1. Smears may be positive for AFB.
2. Rapid PCR testing can distinguish MAI from TB in patients with positive AFB smears.
E. Chest radiograph
1. Usually normal
2. May demonstrate patchy consolidation, nodules, or cavities
Treatment
A. Therapy of disseminated MAC includes clarithromycin and ethambutol, plus rifabutin, especially in sicker patients. Drug interactions are complex and infectious disease consultation is recommended.
B. Susceptibility testing to macrolides should be performed at baseline and whenever patients do not respond to the treatment regimen.
C. Therapy may be discontinued after 1 year in patients responding to ART with CD4TL > 100 cells/mcL for more than 6 months.
D. Pulmonary infiltrates, hepatosplenomegaly, lymphadenopathy, or systemic symptoms may develop anew or worsen during institution of ART (IRIS).
Kaposi Sarcoma
Textbook Presentation
Patients are typically HIV-positive MSM who present with a rash composed of nodular, nontender, pink to violaceous papules and nodules.
Disease Highlights
A. Caused by human herpes virus 8 (HHV 8) associated with HIV
B. Most affected patients are MSMs. Individual lesions are pink, red, or purple, and nontender in most cases.
C. Lesions on the extremities, trunk and face (Figure 5-11)
Figure 5-11. Kaposi sarcoma in an AIDS patient.
D. With decreasing CD4TL, the number of lesions increases.
E. Skin involvement is almost always present in Kaposi sarcoma.
F. Extracutaneous involvement includes oral cavity, gastrointestinal tract, lymph nodes and lungs (Figure 5-12).
Figure 5-12. Involvement of oral cavity in AIDS patient with Kaposi sarcoma.
G. Gastrointestinal involvement is common (40%) but usually asymptomatic. Bleeding and bowel perforation are uncommon complications.
H. Pleuro-pulmonary involvement common in advanced Kaposi sarcoma
1. Presentations of pulmonary Kaposi sarcoma include lung nodules, infiltrates, dyspnea, large pleural effusions, and respiratory failure.
2. Patient survival is shortened.
I. The incidence of Kaposi sarcoma has decreased dramatically, only in part due to the introduction of effective ART. A change in sexual behavior has also contributed to this decline.
Evidence-Based Diagnosis
A. Skin biopsy shows the typical angioproliferation with slit-like vascular spaces and spindle cells.
B. Immunohistochemistry detects HHV 8 in infected endothelial cells.
C. Gastrointestinal Kaposi sarcoma: endoscopy is clinically suggestive, but the submucosal location of lesions makes tissue diagnosis difficult.
D. Pulmonary Kaposi sarcoma: high-resolution chest CT suggestive; bronchoscopy may show the lesions
Treatment
Effective ART is highly effective in early Kaposi sarcoma, but chemotherapy is required in pulmonary involvement.
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1 TB in the non–HIV-infected patients is covered in Chapter 9, Cough, Fever, and Respiratory Infections.