Infectious Diseases

Pulmonary Disease in the HIV Patient

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OVERVIEW: What every practitioner needs to know

Are you sure your patient with human immunodeficiency virus has pneumonia? What should you expect to find?

Patients with pneumonia typically present with a number of cardinal symptoms and signs, which are listed below. The presentation may vary depending on the degree of immunosuppression or the organism causing the pneumonia; some organisms may even present with a normal physical exam.

  • Cough—Cough is one of the most common indicators of pneumonia and may be productive or nonproductive, depending on the organism.

  • Dyspnea—Dyspnea is frequently present in pneumonia, ranging from mild exertional shortness of breath to severe dyspnea at rest. The onset is typically progressive and may be subacute and insidious in the case of fungal pneumonia or Pneumocystis pneumonia (PCP). Acute onset of severe dyspnea should raise concern for another process, such as myocardial infarction, pulmonary embolus, or cardiogenic edema.

  • Chest pain—Pleuritic chest pain may accompany pneumonia, particularly in the case of a necrotizing process or an associated pleural effusion or empyema. Musculoskeletal chest pain may develop in the setting of relentless cough. Severe chest pain in the absence of radiographic abnormalities should raise concern for pulmonary embolus or cardiac process.

  • Fever—Fever typically accompanies pneumonia, but may not be present in a patient with severe immunosuppression.

  • Abnormal lung exam—Patients with bacterial pneumonia typically have physical findings of lobar consolidation, including rhonchi, bronchial breath sounds, and egophany. Dullness to percussion in the absence of egophany suggests an associated pleural effusion. Patients with fungal pneumonia or PCP may have inspiratory crackles; however, the lung exam in PCP may be completely normal.

  • Hypoxemia—Oxygen saturation may be assessed rapidly with pulse oximetry; decreased saturations correlate with more severe disease. (A minor point regarding assessment of saturation is that patients who are using dapsone for PCP prophylaxis may rarely have falsely decreased pulse oximetry values secondary to methemoglobinemia; this will be readily apparent on arterial blood gas.)

  • Extrapulmonary signs and symptoms may coincide with and suggest particular infections, though they are not present in every case of disseminated disease (see below for a review of extrapulmonary signs and symptoms).

Typical presentations of respiratory pathogens

  • Bacterial pneumonia is usually associated with a cough productive of purulent sputum, and possibly pleuritic chest pain. The duration of symptoms prior to presentation is usually 3 to 5 days. Physical exam findings may include rhonchi and bronchial breath sounds. In the case of associated pleural effusion, there will be dullness to percussion.

  • PCP usually presents with a subacute course, with symptoms present for 2 to 4 weeks prior to presentation. Cough is nonproductive, patients are usually dyspneic, and fever may be present. The most common lung exam finding is inspiratory crackles, but the lung exam may be normal.

  • Influenza pneumonia is most commonly encountered during the winter season in temperate climates. Patients typically present with a rapid onset of a "flu-like syndrome" consisting of dry cough, myalgias, headache, and high fever. Pneumonia, when it develops, follows the initial symptoms by 12 to 36 hours; either crackles or lobar findings may be present. New hemoptysis, pleuritic pain, or clinical worsening that develop during the course of influenza pneumonia may signify bacterial superinfection (particularly with Staphylococcus aureus).

  • Cytomegalovirus (CMV) pneumonitis presents with a subacute course (2–4 week symptom duration) and complaints of nonproductive cough, dyspnea, and fever. The lung exam may demonstrate crackles, but may be normal. CMV pneumonitis is rarely found in isolation; it typically presents in the setting of disseminated disease, with the most common signs and symptoms related to retinitis, colitis, or esophagitis.

  • Fungal pneumonia other than PCP (histoplasmosis, blastomycosis, coccidiomycosis, penicillosis) may present subacutely with cough and dyspnea or may follow a more fulminant course with symptoms similar to acute bacterial pneumonia. Pleuritic chest pain may be present. Lung exam may demonstrate crackles. Disease is frequently disseminated, and therefore may be accompanied by constitutional symptoms (weight loss, lethargy, fever) or symptoms in other organ systems, namely the central nervous system, skin, and liver.

  • Invasive aspergillosis presents similarly to bacterial pneumonia, with high fever, cough, and dyspnea. Pleuritic chest pain may be present. Hemoptysis (occasionally massive) may be present, particularly with angioinvasive disease.

  • Tuberculosis has protean manifestations and may present at any cluster of differentiation 4 (CD4) count. In patients with preserved CD4 counts, tuberculosis (TB) has a similar presentation to what would be expected in an immunocompetent person (fever, chills, night sweats, anorexia, productive cough, and occasional hemoptysis). Persons with advanced human immunodeficiency virus (HIV) are more likely to present with symptoms consistent with primary infection or with disseminated disease (lymphadenopathy, central nervous system involvement).

  • Mycobacterium avium very rarely presents as isolated pulmonary infection in HIV-positive persons; however, M. kansasii may present with symptoms and signs very similar to TB.

Extrapulmonary signs and symptoms of certain pathogens

The extrapulmonary signs and symptoms of certain pathogens are summarized in Table I.

Table I.

Extrapulmonary signs and symptoms of certain pathogens.
Disease Extrapulmonary signs/symptoms
Mycobacterium avium complex Constitutional symptoms (fever, weight loss, anorexia)Hepatosplenomegaly, lymphadenopathyAbdominal pain, chronic diarrheaCytopenias may be present secondary to bone marrow involvement
Cryptococcosis Meningeal signsMultiple, polymorphic skin lesions (papules, pustules, nodules, plaques) found most commonly on the head and neck
Histoplasmosis (endemic region: Mississippi, Ohio, and St Lawrence river valleys) Consitutional symptoms (fever, weight loss)Lymphadenopathy, hepatomegalyOral mucosal ulcersErythema nodosum or erythema multiformeMultiple skin lesions (pustules, crusted papules)Cytopenias may be present secondary to bone marrow involvement
Coccidiomycosis (endemic region: southwestern United States, west Texas, southern California, northern Mexico) Constitutional symptoms (fever, weight loss)Meningeal signsLymphadenopathyPolymorphic skin lesions (papules, pustules, erythematous nodules, plaques)
Blastomycosis (endemic region: Mississippi and Ohio river valleys, Great Lakes regions) Bone lesionsSkin lesions resembling neoplasmsGenitourinary involvement, particularly in males
Toxoplasmosis Meningeal signsLocalizing neurologic exam
Cytomegalovirus RetinitisColitis, esophagitis, or abdominal pain
Aspergillosis Sinus symptoms and nasal dischargeMucosal hemorrhage (including the gastrointestinal tract) may complicate angioinvasive disease

Which individuals are of greater risk of developing pneumonia?

The risk of developing pneumonia from various organisms will vary with the CD4 count and with the use of appropriate prophylactic therapy and antiretroviral therapy (ART). Bacterial pneumonia may develop at any CD4 count, though the risk is lower when the patient is on combination ART and increases with degree of immune suppression. Similarly, as the CD4 cell count declines, the incidence of TB increases, but TB can present at any CD4 count. The diseases that are associated with various CD4 counts are summarized in Table II.

Table II.

Infectious agents associated with various degrees of immune suppression.
CD4 count Disease
ANY CD4 COUNT Mycobacterium tuberculosisBacterial pneumoniaSeasonal influenza
<200 Pneumocystis jirovecii pneumonia (particularly in absence of prophylaxis)Cryptococcal pneumoniaExtrapulmonary tuberculosisBlastomycosis
<50–100 Toxoplasmosis (particularly in absence of TMP-SMX prophylaxis)Histoplasmosis, coccidiomycosis, penicillosisCytomegalovirusMycobacterium avium, Mycobacterium kansasiiInvasive aspergillosisRhodococcus equi
  • A general principle is that prior infection with any opportunistic infection is associated with increased risk of recurrence.

  • Injection drug use and cigarette smoking increase the risk of bacterial pneumonia.

  • Emerging data suggest that risk of methicillin-resistant S. aureus (MRSA) colonization is increased in HIV-positive individuals, particularly intravenous drug users, men who have sex with men, and those with low CD4 cell counts. MRSA may be a pathogen in pneumonia.

  • Chronic corticosteroid use increases the risk of PCP.

  • Broad-spectrum antibiotics, steroids, and neutropenia predispose to disseminated aspergillosis. Marijuana smoking is also a risk factor for aspergillosis.

  • Exposure to domestic cats or eating undercooked meats increases risk for toxoplasmosis.

  • Prior Mycobacterium avium complex (MAC) colonization increases the risk of disseminated MAC.

Residence or travel in certain endemic regions increases the risk for fungal pathogens, see Table III.

Table III.

Residence or travel in certain endemic regions increases the risk for fungal pathogens.
Fungal pathogen Endemic area
Histoplasma capsulatum Ohio, Mississippi, and St Lawrence river valleys
Coccidioides immitis Southwestern United States, west Texas, southern California, northern Mexico
Blastomyces dermatitidis Ohio and Mississippi river valleys and regions around the Great Lakes

Beware: there are other diseases that can mimic pneumonia

The differential diagnosis of respiratory symptoms in an HIV-positive patient includes several conditions that are seen in the general population, as follows:

  • Pulmonary embolus (PE): The clinical manifestations of PE are highly nonspecific. The classic presentation includes acute onset of dyspnea, hypoxemia, pleuritic chest pain, and sinus tachycardia with or without hemoptysis. Pleural effusion is common. Massive embolus may precipitate acute hypoxemic respiratory failure or hemodynamic collapse. Risk factors include immobility, recent surgery, thrombophilia, or underlying malignancy.

  • Cardiogenic pulmonary edema: Pulmonary edema presents with dyspnea and occasionally cough. The primary physical exam findings are pulmonary crackles in concert with other signs of heart failure, including lower extremity edema, an elevated jugular venous pressure, an S3 or S4, or a cardiac murmur. The chest radiograph may show ground glass opacities, Kerley B and A lines, and pleural effusions.

  • Chronic obstructive pulmonary disease (COPD): HIV infection is an independent risk factor for COPD, and this association persists in the era of combination ART. A primary risk factor for COPD, as in the general population, is smoking. The prevalence of smoking is higher in the HIV-positive population than the general population. COPD exacerbation typically presents with cough and dyspnea. Physical exam findings include diminished air entry, prolonged expiratory phase, and expiratory wheeze. Chest radiograph may demonstrate increased lung volumes if emphysema is present, but may be normal.

  • Pulmonary hypertension: The prevalence of pulmonary arterial hypertension (PAH) is increased in the HIV-positive population, particularly in those who acquired HIV through intravenous drug use. PAH may present at any degree of immunosuppression, although highly active ART may have a favorable effect. The classic presentation of PAH includes subacute onset of dyspnea with signs of right heart failure, in the absence of left-heart failure. Physical exam may demonstrate pedal edema, an elevated jugular venous pressure, a loud pulmonic S2, a tricuspid murmur, or a right-sided S3 or S4. The chest radiograph is usually clear, but the pulmonary arteries may be pronounced in advanced disease. While the diagnosis may be supported by elevated pulmonary arterial systolic pressure on echocardiogram, pulmonary hypertension can neither be confirmed or ruled out without a right heart catheterization.

HIV is specifically associated with a number of noninfectious pulmonary conditions, as follows:

  • Immune reconstitution inflammatory syndrome (see also the separate chapter on IRIS): IRIS is a syndrome that develops in the context of recovery of CD4 cell counts following the initiation of ART. IRIS is believed to represent an excessive inflammatory response to an antigen, most frequently a subclinical or recently treated opportunistic infection. It is most commonly seen in conjunction with such infections as TB, PCP, MAC, and Cryptococcus, but can also occur in association with malignancy (Kaposi sarcoma) or sarcoidosis. Manifestations include fevers, lymphadenopathy, meningeal symptoms, and pulmonary infiltrates. Most cases occur in the first few weeks after starting ART, though cases of IRIS have been reported up to 12 months following the initiation of therapy. Risk factors include low CD4 count prior to initiation of ART and opportunistic infection treatment proximal in time to ART initiation. There are unfortunately no definitive diagnostic criteria for IRIS, which remains a diagnosis of exclusion. A high index of suspicion is imperative in the appropriate clinical setting, as treatment with corticosteroids can be life-saving in severe cases. ART should be continued during IRIS if at all possible.

  • Interstitial lung diseases (ILDs): Nonspecific interstitial pneumonitis (NSIP) is an inflammatory condition characterized by a lymphocytic infiltrate in the peribronchial and perivascular tissue and interlobular septae. It is relatively commonly found in HIV-positive persons. NSIP may be asymptomatic or may present with fever, cough, and dyspnea. It can radiographically resemble PCP, with presence of a reticular pattern and ground glass opacities seen on a chest computed tomography (CT) scan. Lymphocytic interstitial pneumonia (LIP) is a lymphoproliferative interstitial lung disease characterized by infiltration of the pulmonary parenchyma with lymphocytes and plasma cells. Its presentation is similar to NSIP, and radiographic findings are similar, though LIP more frequently presents with poorly defined small nodules in a peribronchial distribution. Both ILDs require tissue for diagnosis. Transbronchial diagnosis can frequently identify LIP, but surgical lung biopsy may be required.

  • Malignancy:

    • Kaposi sarcoma (KS) is an angioproliferative malignancy that was very common in HIV patients prior to ART. Although the incidence of KS has declined dramatically in the current era, it is still encountered clinically. The primary risk factor is low CD4 count (particular <50, very rare with CD4 >200), and incidence is higher in men who have sex with men. Although most patients with pulmonary KS have concomitant mucocutaneous lesions, up to 15% may have isolated pulmonary disease. Presenting symptoms of pulmonary KS include dyspnea, cough, and fever; hemoptysis may be present. Characteristic radiographic findings include bilateral central or perihilar nodular or linear opacities, thickening of bronchovascular bundles, or thickening of the interlobular septa. Pleural effusions are common. KS frequently occurs with concomitant opportunistic pulmonary infection (particularly PCP), for which a careful evaluation should be undertaken.

    • Non-Hodgkin lymphoma (NHL) is also associated with HIV and has declined in the ART era. The median CD4 cell count at diagnosis is 100. Most patients have B-cell subtype and present with disseminated nodal and extranodal disease, of which the thorax is one affected site. Pulmonary symptoms include cough, dyspnea, and pleuritic chest pain. Thoracic imaging findings most commonly include single or multiple parenchymal nodules, lobar infiltrates, and pleural effusion.

    • Recent studies have suggested an increase in the incidence of Hodgkin lymphoma in the HIV-positive population following the introduction of ART. Symptoms and radiographic findings are similar to NHL. Mediastinal lymphadenopathy is almost invariably present in pulmonary Hodgkin lymphoma.

Substance abuse, which remains common in the HIV-positive population, may predispose the patient to a number of pulmonary conditions. A careful substance history may suggest one of the following conditions:

  • Noncardiogenic pulmonary edema can be seen in association with almost any opiate and also occasionally with cocaine use. Typical features include acute dyspnea, pulmonary crackles on lung exam, and bilateral ground glass opacities. The presentation is identical to cardiogenic pulmonary edema, but occurs in the absence of cardiac dysfunction.

  • Septic emboli secondary to right-sided endocarditis or peripheral thrombophlebitis may present with symptoms suspicious for pneumonia, including fever, dyspnea, and cough. Chest radiograph may show multiple cavities or peripheral shaggy nodules. Both embolic foci and pulmonary infarcts may be confused with lobar or patchy pneumonia on plain imaging of the chest. Sepsis at presentation, a new cardiac murmur, or evidence of peripheral thrombophlebitis should raise the index of suspicion.

  • Crack lung is an acute alveolar syndrome characterized by eosinophilic inflammation that develops in the setting of inhaled cocaine use. The syndrome usually presents with hypoxemia, diffuse alveolar infiltrates, and pulmonary obstruction. Alveolar hemorrhage is common and may manifest as hemoptysis. Crack lung may rapidly progress to respiratory failure.

  • Pulmonary talcosis, a granulomatous reaction to foreign bodies, may be seen when pills are pulverized and either inhaled or peripherally injected. The radiographic findings typically include a fine nodular infiltrate, but may also include centrilobular nodules or ground glass opacities.

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

  • Peripheral white blood cell count with differential: an acute infectious pneumonia will usually present with a leukocytosis (and occasionally leukopenia). Bacterial pnuemonia frequently causes a left shift, with or without bandemia. Profound bandemia should raise suspicion for concomitant bacteremia or pleural space infection. The total white blood cell count should be considered relative to the patient's baseline; a "normal" count may be falsely reassuring in a patient who is chronically leukopenic.

  • A recent CD4 count should be obtained and reviewed, as the range of the CD4 count is associated with a risk for certain pathogens.

  • An arterial blood gas should be obtained in all patients who have evidence of hypoxemia on pulse oximetry, who have apparent respiratory distress, or have signs of sepsis. A reduction in the arterial pH (<7.35) correlates with increased disease severity. Severe hypoxemia or respiratory alkalosis or acidosis are signals of impending respiratory failure and should prompt consideration for intensive care unit admission.

Results that confirm the diagnosis

  • Sputum culture: A sputum Gram stain and culture should be obtained on all patients who can expectorate sputum (or obtained from deep respiratory suctioning through an endotracheal tube), ideally before the initiation of antibiotics. An important caution is that empiric therapy should not be narrowed on the basis of a sputum Gram stain alone. Sputum fungal cultures can be diagnostic of Cryptococcus or Coccidioides but are of less value for Histoplasma and Blastomyces, which are more reliably diagnosed by bronchoscopy.

  • Induced sputum: Induced sputum samples should be obtained on any patient for whom PCP is being considered and should be sent to cytology for histologic or immunofluorescent staining. Induced sputum has a broad range of sensitivity (from <50 to >90%) for PCP identification, depending on the adequacy of the sample and the experience of the laboratory. Spontaneously expectorated sputum has a low sensitivity for organism identification and should not be used to rule out the diagnosis.

  • Bronchoscopy: Many patients with HIV will require bronchoscopy to make a definitive diagnosis. It is prudent to perform bronchoscopy with bronchoalveolar lavage (BAL) in patients requiring intubation and mechanical ventilation. Bronchoscopic evaluation is also appropriate when empiric therapy is failing, when the diagnosis remains unknown despite less invasive testing, or when specific diagnoses are being sought. While BAL is sufficient for diagnosis of many infections, including PCP, transbronchial biopsy is necessary to confirm a diagnosis of invasive aspergillosis, CMV pneumonitis, or noninfectious disorders such as non-Hodgkin lymphoma or sarcoidosis.

  • Sputum acid-fast bacillus (AFB) smears: AFB smears and culture in patients with suspected pulmonary TB should ideally be obtained on three separate days. If three smears are negative and the index of suspicion remains high (or if sputum cannot be obtained), bronchoscopy with BAL is required.

  • Nucleic acid amplification tests (NAATs) are available for the identification of mycobacteria from respiratory samples. They are more sensitive than AFB staining. When positive, the result is more likely to represent TB than a nontuberculous mycobacterial infection.

  • Influenza nasopharyngeal reverse transcription polymerase chain reaction swab is >90% sensitive for the diagnosis of influenza and should be obtained during flu season when the virus is suspected.

  • Blood culture: Patients with bacterial pneumonia and a CD4 count of less than 200 frequently have bacteremia, and the organism may be identified on blood cultures.

  • Mycobacterial blood cultures should be obtained in patients with suspected TB or MAC and a CD4 count of less than 200. All positive cultures should be submitted for susceptibility testing.

  • Fungal blood cultures should be obtained in patients with suspected fungal disease. The slow growth of fungal cultures limits diagnostic utility, but susceptibility testing may be used to guide therapy.

  • Urine antigens (pneumococcal antigen and Legionella antigen) may be obtained in patients with suspected community-acquired bacterial pneumonia.

  • Serum cryptococcal antigen should be obtained when cryptococcosis is suspected, but patients with isolated pulmonary disease may have a negative result.

  • Histoplasma polysaccharide antigen (HPA)testing of the blood or urine may diagnose disseminated histoplasmosis; HPA testing of BAL fluid can rapidly diagnose pulmonary histoplasmosis.

  • Skin biopsy of new skin lesions can be diagnostic of disseminated fungal disease or extrapulmonary TB.

  • Lymph node biopsy may be diagnostic of disseminated fungal or mycobacterial disease when widespread peripheral lymphadenopathy is present.

  • Bone marrow biopsy may be diagnostic of disseminated fungal or mycobacterial disease when signs of marrow involvement (i.e.cytopenias) are present.

Pleural fluid studies: HIV-positive patients presenting with pleural effusion should undergo diagnostic thoracentesis, as the incidence of complicated parapneumonic effusion and empyema in association with bacterial pneumonia is higher in the HIV-positive population than in the general population. Pleural fluid should be sent for Gram stain, culture, cell count and differential, lactate dehydrogenase (LDH), protein, glucose, and pH.

  • The presence of a transudate (pleural fluid LDH/serum LDH <0.6, pleural fluid protein/serum protein <0.5, AND pleural fluid LDH <2/3 normal serum value) argues against infectious cause of pleural effusion.

  • Pleural fluid pH less than 7.3 and glucose less than 60 suggest infectious process.

  • Pleural fluid pH less than 7.2 suggests empyema.

  • Purulent fluid = empyema.

  • Lymphocyte predominance on cell count highly is suggestive of TB.

  • TB may be supported by pleural fluid adenosine deaminase level greater than 40.

Emerging diagnostic methods for PCP

The following three tests are research tools and not widely available to clinicians:

Polymerase chain reaction (PCR): Assays detect Pneumocystis DNA in BAL fluid, induced sputum, and oral washes and has potential advantages, i.e. rapid turn-around time and ability to reliably detect PCP using a noninvasive method (e.g.oral wash). Sensitivities are reported from 88 to 98%, however, specificities are lower as the assay detects Pneumocystis colonization in patients without clinical pneumonia. Therefore, clinical utility is limited.

1→3-β-D-glucan (β-glucan): β-glucan is a polysaccharide component of the walls of most fungi, including Pneumocystis, and has been studied as a possible noninvasive biomarker of PCP. In studies of HIV-infected patients, median β-glucan levels are significantly higher in patients with PCP than in non-PCP controls. Because β-glucan may also be increased in other fungal infections, and possibly in some bacterial infections, it is best used as an ancillary test.

S-Adenosylmethionine: S-Adenosylmethionine is an intermediate molecule important for methylation reactions and polyamine synthesis. Pneumocystis cannot synthesize this molecule and therefore must scavenge it from the host. Investigators have hypothesized that decreased plasma levels of S-adenosylmethionine may correlate with Pneumocystis infection, but studies have shown varying results.

Selected studies may be found in the references section.

What imaging studies will be helpful in making or excluding the diagnosis of pneumonia?

  • All patients with suspected pneumonia should have a posteroanterior and lateral chest X-ray (CXR) scan, if possible.

  • Many patients will benefit from noncontrasted chest computed tomography (CT)—particularly if there is no focal abnormality on the CXR scan and the patient appears ill.

CXR findings (CD4 >200):

  • Alveolar pattern with acute onset of symptoms suggests bacterial pneumonia.

  • Alveolar pattern with subacute onset of symptoms (>5 days) suggests atypical pneumonia, fungal pneumonia, or mycobacterial infection (including TB).

  • Cavitary infiltrate is strongly suggestive of TB; patient should be placed in respiratory isolation (Figure 1).

  • Nodules or masses are associated with an alternative diagnosis, such as malignancy, and a CT chest scan should be obtained.

Figure 1:

Typical chest X-ray and computed tomography findings of right upper lobe cavitary disease in tuberculosis.

CXR findings (CD4 <200):

  • A normal CXR does NOT rule out pulmonary disease, particularly PCP; high-resolution CT is warranted for further evaluation.

  • Alveolar, reticular, or interstitial pattern with acute onset (3–5 days) suggests bacterial pneumonia.

  • Alveolar pattern with subacute onset may suggest PCP, fungal pneumonia, TB, or a noninfectious process.

  • Reticular or interstitial pattern with subacute onset may suggest PCP or other fungal pneumonia, particularly Cryptococcus.

  • Nodular pattern may suggest fungal or bacterial pneumonia, TB (nodules <1cm), or neoplasm (nodules >1cm).

Most common radiographic manifestations of specific opportunistic infections

The most common radiographic patterns associated with opportunistic infections are described in Table IV, but it should be noted that the radiographic findings are protean; no particular pattern should be considered pathognomonic for any disease.

Table IV.

The most common radiographic manifestations of specific opportunistic infections.
Organism Radiographic manifestations (most common)
Pneumocystis Bilateral, symmetric ground glass opacitiesReticulation and thickening of interlobular septae ("crazy paving")Thin-walled cysts (pneumatoceles), present in 10 to 35% of cases (see Figure 2, Figure 3)
Cryptococcus Diffuse bilateral infiltrateReticular or reticulonodular interstitial patternDiscrete nodules
Histoplasma Diffuse small nodular or irregular linear opacitiesPatchy consolidation
Coccidioides Focal or diffuse areas of alveolar consolidationNodules (may be cavitary or noncavitating), lymphadenopathy
Blastomyces Focal consolidationDiffuse interstitial or miliary patternNodules, cavitation, lymphadenopathy
Aspergillus (invasive) Cavitary lung disease, upper lobe predominantBilateral alveolar or interstitial opacities
Cytomegalovirus Ground glass opacities

Figure 2:

Representative chest film from a patient with Pneumocystis pneumonia, demonstrating diffuse bilateral ground glass opacities.

Figure 3:

Computed tomography slice demonstrating severe Pneumocystis pneumonia in a patient with human immunodeficiency virus. Note the bilateral dense ground glass infiltrates and the presence of pneumatoceles.

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

An HIV specialist should be consulted for most patients with suspected opportunistic infections, particularly when tuberculosis is suspected, when disseminated or invasive fungal disease is being treated, when treatment failure is encountered, and/or when the initiation of combination ART is being entertained.

A pulmonary consult is necessary if bronchoscopy is being considered.

If you decide the patient has pneumonia, what therapies should you initiate immediately?

As with pneumonia in the general population, the cornerstones of therapy include prompt initiation of appropriate antibiotics and assurance of adequate oxygen delivery. Oxygen should be administered to maintain saturations greater than 92%, and patients should be intubated if necessary to maintain either oxygenation or a patent airway. Empiric antimicrobial therapy should be selected based on the patient's clinical history, with particular attention given to the recent CD4 count, if available. Patients with a presentation consistent with TB should be placed in respiratory isolation until the diagnosis can be definitively ruled out.

If I am not sure what pathogen is causing the infection, what type of anti-infective should I order?

The most likely diagnoses, as determined based on the constellation of history/physical finding, laboratory test results, and radiographic findings, should be covered empirically pending the results of confirmatory tests. Strong consideration should be given to the empiric coverage of TB in the appropriate clinical setting. Coverage for bacterial pneumonia and TB can be initiated simultaneously if strong clinical suspicion exists for both. Similarly, if PCP is suspected, therapy should be started empirically rather than waiting for confirmation of the organism.

Empiric coverage of community-acquired bacterial pneumonia

The most frequently encountered community-acquired bacterial pathogens in the HIV-positive population are the same as in the general population. Streptococcus pneumoniae is the most frequently identified organism, followed by Haemophilus influenzae. Similar to the general population, macrolide-resistant S. pneumoniae is increasingly encountered, and the frequency of macrolide-resistant organisms is higher in the HIV-positive population. Additionally, there have been several studies which have suggested that trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis may predispose to the development of TMP-SMX resistant S. pneumonia in the HIV-positive population.

HIV patients are also at increased risk for community-acquired Pseudomonas aeruginosa and S. aureus, including MRSA. Pseudomonas is particularly common in patients with a CD4 count greater than 100, structural lung disease, neutropenia, or corticosteroid use. Additional risk factors for S. aureus/ MRSA include recent viral infection, history of injection drug use, or men who have sex with men. Cavitating disease or severe necrotizing pneumonia should raise the index of suspicious for Psuedomonas or Staphylococcus.

Atypical pathogens, including Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydophila, occur with the same frequency as in the general population.

Two important caveats:

  • Do not use an empiric macrolide alone in an HIV-positive patient, as there is increased risk of macrolide-resistant S. pneumoniae in the HIV population.

  • Only use a fluoroquinolone alone if the presentation strongly suggests bacterial pneumonia, and not TB (to avoid inadvertant monotherapy in the case of tuberculosis).

Treatment options are summarized in Table V.

Table V.

Treatment options for community-acquired bacterial pneumonia in the HIV population.
Treatment setting Preferred regimen Alternative regimen (allergy OR received β-lactam within last 90 days)
Outpatient Oral β-lactam (amoxicillin 1g orally three times a day or amoxicillin-clavulanate 875mg orally twice a day) AND azithromycin 500mg orally daily Moxifloxacin* 400mg orally daily or levofloxacin* 750mg orally daily orgemifloxacin* 320 mg PO dailyMacrolide allergy: oral β-lactam AND doxycycline 100mg orally twice a day
Inpatient (non-ICU) Intravenous β-lactam (ceftriaxone 1g IV every 24 hours, cefotaxime 1g IV every 8 hours, or ampicillin-sulbactam 3g IV every 6 hours) AND azithromycin 500mg IV every 24 hours for two doses, then 500mg orally every 24 hours Moxifloxacin* 40mg IV every 24 hours or levofloxacin* 750mg IV every 24 hoursMacrolide allergy: intravenous β-lactam AND doxycycline 100mg orally twice a day
ICU Intravenous β-lactam (ceftriaxone 1g IV every 24 hours, cefotaxime 1g IV every 8 hours, or ampicillin-sulbactam 3g IV every 6 hours) AND azithromycin 500mg IV every 24 hours for two doses, then 500mg orally every 24 hoursIntravenous β-lactam (ceftriaxone 1g IV every 24 hours, cefotaxime 1g IV every 8 hours, or ampicillin-sulbactam 3g IV every 6 hours) AND moxifloxacin 400mg IV every 24 hours or levofloxacin 750mg IV every 24 hoursConsider therapy of Pseudomonas and Staphylococcus Aztreonam 2g IV every 8 hours AND intravenous fluoroquinolone (moxifloxacin 400mg IV very 24 hours or levofloxacin 750mg IV every 24 hours)
Suspicion for Pseudomonas (for both non-ICU and ICU) Intravenous extended-spectrum β-lactam (piperacillin-tazobactam 4.5g IV every 8 hours, cefepime 1g IV every 8 hours, imipenem 500mg IV every 6 hours, or meropenem 1g IV every 8 hours) AND ciprofloxacin 400mg IV every 12 hours or levofloxacin 750 mg IV every 24 hoursAddition of aminoglycoside may be necessary, depending on the regional antibiogram Aztreonam 2g IV every 8 hours AND intravenous fluoroquinolone (moxifloxacin 400mg IV every 24 hours or levofloxacin 750mg IV every 24 hours)
Suspicion for Staphylococcus aureus (for both non-ICU and ICU) Vancomycin 15–20mg/kg every 12 hours (in addition to standard regimen) Linezolid 600mg IV every 24 hours (in addition to standard regimen)

Empiric coverage of health care associated pneumonia or hospital-acquired pneumonia

When health care associated pneumonia (HCAP)/hospital-acquired pneumonia (HAP) is suspected, it should be treated with empiric broad-spectrum coverage because of the increased risk for extended spectrum pathogens. These include aerobic gram-negative rods (particularly resistant Pseudomonas, Acinetobacter, and extended-spectrum β-lactamase-producing Klebsiella) and MRSA. The factors that define HCAP and HAP are reviewed below. Treatment options are summarized in Table VI.

Table VI.

Treatment options for health care associated pneumonia or hospital-acquired pneumonia.
If HCAP/HAP is suspected, antibiotic regimen should include:
One of these* Antipseudomonal cephalosporin:    •  cefepime 1–2g IV every 8 to 12 hours    •  ceftazidime 2g IV every 8 hours
Carbapenem:    •  imipenem 500mg IV every 6 hours    •  meropenem 1g IV every 8 hours
Piperacillin-tazobactam 4.5g IV every 6 hours
AND one of these* Antipseudomonal fluoroquinolone:    •  levofloxacin 750mg IV every 24 hours    •  ciprofloxacin 400mg IV every 8 hours
Aminoglycoside:    •  gentamicin 7mg/kg IV every 24 hours (trough <1mcg/mL)    •  tobramycin 7mg/kg IV every 24 hours (trough <1mcg/mL)    •  amikacin 20mg/kg IV every 24 hours (trough <4–5mcg/mL)
AND one of these* Vancomycin 15mg/kg every 12 hours (trough 15–20mcg/mL)
Linezolid 600mg IV every 12 hours

Risk factors for healthcare associated pneumonia or hospital-acquired pneumonia

  • Antibiotic therapy in the preceding 90 days

  • Hospitalization for 2 days or more in the preceding 90 days

  • Residence in nursing home or extended care facility

  • Chronic hemodialysis within the preceding 30 days

  • Home wound care

  • Home infusion therapy

  • Family member/household contact with known multidrug-resistant pathogen

  • Current hospitalization for 5 days or more

Coverage of Pneumocystis pneumonia

If PCP is suspected, therapy should be started empirically rather than waiting for confirmation of the organism. Diagnostic yield of bronchoscopy will not be reduced by immediately initiating therapy, as BAL will remain positive for Pneumocystis for at least several days after starting TMP-SMX.

  • TMP-SMX is first-line therapy for PCP (intravenous, dosed as trimethoprim at 15–20mg/kg daily, divided every 6–8 hours)

  • Patients with a sulfa allergy or other intolerance to TMP-SMX can be treated with intravenous pentamidine (3–4 mg/kg every 24 hours)

If PCP is suspected and the patient is hypoxemic (A-a gradient greater than or equal to 35mm Hg or PaO2 less than or equal to 70mm Hg on room air), adjunctive corticosteroids should be started at the same time as Pneumocystis antimicrobials regardless of confirmation of diagnosis. Treatment options are summarized in Table VII.

Table VII.

Treatment options for Pneumocystis pneumonia.
Pneumocystis pneumonia adjunctive corticosteroids Days 1–5 Days 6–10 Days 11–21
Prednisone (if tolerating orally) 40mg orally every 12 hours 40mg orally every 24 hours 20mg orally every 24 hours
Methylprednisolone (if not tolerating orally or concern for malabsorption) 30mg intravenously every 12 hours 30mg intravenously every 24 hours 15mg intravenously every 24 hours

Coverage of tuberculosis

Patients with suspected TB should receive standard four-drug therapy (isoniazid, rifampicin or rifabutin, pyrazinamide, and ethambutol) until the organism's sensitivities are available. Pyridoxine should always be given in conjunction with isoniazid. If there is clinical suspicion for M. avium, clarithromycin or azithromycin may be added to the regimen. Therapy may be narrowed when culture results are available. As there may be interactions with antiretroviral therapy, consultation with an HIV specialist should be sought if patients are receiving TB therapy and ART simultaneously.

Initial treatment for specific pathogens

All treatment decisions should be made with attention to possible drug interactions (with ART regimens and other medications). Hepatic and renal impairment may require alteration of dosing regimen or drug choice. Many antimicrobials are contraindicated in pregnancy. The antimicrobials listed are considered initial therapy; TB and most fungi will require extended periods of "consolidation" therapy following initial treatment. Alternative regimens must be initiated in the event of either drug resistance or treatment failure. Treatment options are summarized in Table VIII.

Table VIII.

Treatment options for the initial treatment of specific pathogens.
Organism First-line antibiotic Alternative
Pneumocystis Mild disease (room air PaO2 >70 and A-a gradient <35): oral TMP-SMX two double-strength tablets (160mg TMP/800mg SMX) every 8 hoursModerate to severe disease: intravenous TMP-SMX (15–20mg/kg TMP daily, divided every 6 to 8 hours) Mild disease: TMP 15–20mg/kg daily, divided every 6 to 8 hours with dapsone 100mg orally dailyClindamycin 1,800mg daily, divided every 6 to 8 hours AND primaquine 30mg orally dailyAtovaquone 750mg orally every 8 hoursModerate to severe disease: Pentamidine 3–4mg/kg intravenously every 24 hoursClindamycin 600–900mg intravenously every 8 hours AND primaquine 30mg orally daily
Mycobacterium avium Clarithromycin 500mg orally twice a day AND ethambutol 15mg/kg/day*the addition of a third (rifabutin 300–600mg orally daily) or fourth (streptomycin 15mg/kg intramuscularly three times weekly or amikacin 15mg/kg three times weekly) agent may be considered in cases with advanced immunosuppression and high mycobacterial loads Azithromycin 500mg orally daily may be used in place of clarithromycin
Cytomegalovirus Ganciclovir 5mg/kg intravenously every 12 hours Foscarnet 90mg/kg intravenously every 12 hours
Influenza Oseltamavir 75mg orally twice a day Zanamavir 10mg inhaled twice daily (not for use in patients with underlying structural lung disease or asthma)
Toxoplasma Pyrimethamine 200mg loading then 50mg orally every 24 hours/folinic acid 20mg orally every 24 hours AND sulfadiazine 1.5g orally every 6 hours Clindamycin 1,200mg (orally or intravenously) every 6 hours may be given in place of sulfadiazine
Histoplasma Amphotericin B (liposomal) 3–5mg/kg intravenously every 24 hours if disseminatedItraconazole 300mg orally twice a day for 3 days, then 200mg orally twice a day may be used when lung is only site of infection
Coccidioides Amphotericin B (deoxycholate) 1mg/kg intravenously daily if disseminatedfluconazole 400mg orally daily or itraconazole 200mg orally twice a day may be used when lung is only site of infection
Cryptococcus Amphotericin B (deoxycholate 0.7mg intravenously every 24 hours or liposomal 3–5mg/kg every 24 hours) AND flucytosine 100mg/kg daily in divided dosesFluconazole 400mg orally daily plus flucytosine if lung is confirmed to be the only site of infection
Aspergillus (invasive) Voriconazole 6mg/kg intravenousy every 12 hours for two doses, then 200mg orally twice a day Amphotericin B deoxycholate 1mg/kg daily or caspofungin 50mg daily

What other therapies are helpful for reducing complications?

  • Adjunctive steroid therapy is indicated in the treatment of PCP with hypoxemia (room air PaO2 <70 or A-a gradient >35); steroids should be initiated in conjunction with antimicrobials.

  • Pneumonia from any source may progress to respiratory failure, and in severe cases, development of acute lung injury (ALI) or the acute respiratory distress syndrome (ARDS). When ALI or ARDS is suspected (PaO2/FiO2 ratio <300 or <200, respectively, diffuse bilateral airspace disease, no evidence of elevated left ventricular filling pressures), lung protective ventilation strategies should be followed according to ARDS Network guidelines. Control of plateau pressures is particularly important in patients with PCP and pneumatoceles, who are at increased risk for iatrogenic pneumothorax.

  • When complicated parapneumonic effusion or empyema is confirmed, the collection should be drained with an appropriately sized pleural drainage catheter or chest tube.

  • Intravenous fluids should be used with caution in patients with PCP, in whom alveolar transudate should be minimized.

  • The initiation or continuation of combination ART during hospitalization in patients who are diagnosed with opportunistic infections has been found in several studies to improve survival. Starting ART in critically ill patients with opportunistic pneumonias remains controversial and is guided by expert opinion. A recent retrospective study (Croda et al) has suggested a potential benefit of ART, but prospective data are lacking.

What complications could arise as a consequence of pneumonia?

  • Respiratory failure, including ARDS, is a potential complication of any pneumonia in an HIV-positive patient.

  • Pneumothorax is a potential complication of PCP due to the frequent presence of pneumatoceles.

  • Pleural effusion or empyema may develop in conjunction with bacterial, fungal, or mycobacterial pneumonia.

  • Sepsis may complicate pneumonia in the HIV-positive patient, particularly when there is associated bacteremia or disseminated disease.

What should you tell the family about the patient's prognosis?

  • Bacterial pneumonia is associated with increased mortality in HIV-positive patients, with case fatality rates reported as high as 20%. Radiographic progression of disease, a low baseline CD4 count, and presence of shock are independent predictors of mortality.

  • Mortality in PCP has been reported from 15 to 50% in the current era, with risk factors for higher mortality including poor baseline functional and nutritional status, high A-a gradient at presentation, pneumothorax, and requirement for mechanical ventilation.

  • Fungal disease localized to the lung has a relatively good prognosis, but disseminated disease has a very high mortality rate. Invasive aspergillosis in HIV also has a poor prognosis, with at least 50% mortality.

What if the patient is not improving?

There are a number of reasons why a patient may worsen or fail to improve on initial therapy.

  • Alternative diagnosis: Is there a chance your patient does not have pneumonia? The mimics of pneumonia should be reviewed in light of the patient's clinical scenario, and possible differential diagnoses (as covered above) should be explored.

  • Inadequate treatment: Is there a chance the culprit organism is not covered? A patient who was initially treated with narrow therapy for community-acquired bacterial pneumonia may fail to respond because they are harboring community-acquired Pseudomonas or MRSA. TB should be reconsidered in patients who have failed to respond to adequate therapy for suspected bacterial pneumonia.

  • Concomitant infection: Is there a coinfection which has not been treated? For instance, patients with PCP are frequently coinfected with another organism (20% prevalence), including bacteria, CMV, and TB.

  • New infection: Has your patient contracted a hospital-acquired pathogen? Patients who have been hospitalized for 5 days or greater are at risk for hospital-acquired organisms, which have broad resistance patterns and may not be covered by initial empiric therapy for community-acquired pneumonia.

  • Treatment failure: Treatment failure is a consideration with a number of conditions, including PCP and TB.

    • In the case of PCP, treatment failure should not be considered until at least 8 days into the antibiotic course, as clinical response may not be apparent until days 4 to 8. If the patient has worsening respiratory function after that time, the drug class may be changed to pentamidine or clindamycin/primaquine. Coinfection and new infection must also be investigated, ideally via bronchoscopy. Bronchoscopy will remain positive for Pneumocystis throughout treatment and detection on BAL does not indicate treatment failure.

    • In the case of TB, treatment failure is secondary to drug resistance and should be managed in conjunction with an HIV specialist.

  • IRIS: Did your patient recently initiate ART? As previously stated, there are no definitive diagnostic criteria for IRIS, which is therefore a diagnosis of exclusion. If other processes have been ruled out, a trial of corticosteroids may be warranted.

How can pneumonia be prevented in HIV-positive patients?

The 23-valent polysacharrhide pneumococcal vaccine decreases the risk of pneumococcal pneumonia, and also reduces the risk of pneumococcal bacteremia in HIV patients who do develop pneumonia. All patients with a CD4 count greater than 200 should be given the vaccine, and it should be repeated every 5 years. Patients with a CD4 count less than 200 may have a less robust vaccine response secondary to immunosuppression, but the vaccine can still be offered. Revaccination in this group may be offered if the CD4 count rises above 200 after initiation of ART. Pneumococcal conjugate vaccines, including Prevnar-7 and Prevnar-13, are also available, but the use in HIV-infected adults is controversial. Ongoing studies may be useful for informing future recommendations.

All patients with HIV should receive the seasonal influenza vaccine on a yearly basis. Live attenuated influenza vaccine is contraindicated in HIV-infected persons.

Primary PCP prophylaxis should be initiated in any patient with a CD4 count less than 200 or a history of oral thrush (regardless of CD4 count). Prophylaxis may also be considered in patients with a CD4 cell percentage of less than 14% or with a history of any acquired immunodeficiency syndrome-defining illness. The preferred prophylactic agent is TMP-SMX, one double strength tablet daily. TMP-SMX has the additional benefit of offering protection from Toxoplasma.

Patients with a CD4 count less than 50 should receive primary prophylaxis for Mycobacterium avium. Preferred prophylactic agents are azithromycin or clarithromycin.

Patients with latent TB should be treated with isoniazid to prevent progression to active TB.

Prophylaxis for fungi or CMV are not routinely recommended.

Respiratory isolation of any patient with suspected TB should be performed to prevent spread both to staff and to other patients. Although there is some suggestion of person-to-person transmission of PCP, current guidelines do not recommend placing patients in isolation.

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

The following references provide a comprehensive overview of the infectious and noninfectious pulmonary complications of HIV:

Crothers, K, Morris, A, Huang, L, Mason, R, Broaddus, VC, Martin, TR, King, TE, Shraufnagel, DE, Murray, JF, Nadel, JA. "Pulmonary complications of human immunodeficiency virus infection.". Murray and Nadel's textbook of respiratory medicine. Saunders. 2010. pp. 1914-49.

Kaplan, JE, Benson, C, Holmes, KH, Brooks, JT, Pau, A, Masur, H. "Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America". MMWR Recomm Rep. vol. 58. 2009. pp. 1-207.

Huang, L, Crothers, K. "HIV-associated opportunistic pneumonias". Respirology. vol. 14. 2009. pp. 474-85.

The current Infectious Diseases Society of America/American Thoracic Society guidelines for the management of community-acquired and health care associated pneumonias:

Mandell, LA, Wunderink, RG, Anzueto, A. "Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults". Clin Infect Dis. vol. 44. 2007. pp. S27-72.

"American Thoracic Society, Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and health care-associated pneumonia". Am J Respir Crit Care Med. vol. 171. 2005. pp. 388-416.

The study referenced below forms the basis for the low-tidal volume ventilatory strategy in patients with acute lung injury and acute respiratory distress syndrome:

http://www.ardsnet.org/system/files/vent-w_hipeepcard_0.pdf.

"Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome". N Engl J Med. vol. 342. 2000. pp. 1301-8.

The references below provide further reading on selected issues mentioned in the text:

Huang, L, Schnapp, LM, Gruden, JF, Hopewell, PC, Stansell, JD. "Presentation of AIDS-related pulmonary Kaposi's sarcoma diagnosed by bronchoscopy". Am J Respir Crit Care Med. vol. 153. 1996. pp. 1385-90.

Croda, J, Croda, MG, Neves, A, De Sousa dos Santos, S. "Benefit of antiretroviral therapy on survival of human immunodeficiency virus-infected patients admitted to an intensive care unit". Crit Care Med. vol. 37. 2009. pp. 1605-11.

These references discuss emerging detection methods for P. jirovecii:

De Boer, MG, Gelinck, LB, van Zelst, BD. "β-D-glucan and S-adenosylmethionine serum levels for the diagnosis of Pneumocystis pneumonia in HIV-negative patients: a prospective study". J Infect. vol. 62. 2011. pp. 93-100.

Held, J, Koch, M, Reischl, U, Danner, T, Serr, A. "Serum (1-->3)-β-D-glucan measurement as an early indicator of Pneumocystis jirovecii pneumonia and evaluation of its prognostic value". Clin Microbiol Infect. vol. 17. 2010. pp. 595-602.

Larsen, HH, Huang, L, Kovacs, JA. "A prospective, blinded study of quantitative touch-down polymerase chain reaction using oral-wash samples for diagnosis of Pneumocystis pneumonia in HIV-infected patients". J Inf Dis. vol. 189. 2004. pp. 1679-83.

A review of pulmonary hypertension in HIV infection:

Janda, S, Quon, BS, Swiston, J. "HIV and pulmonary arterial hypertension: a systematic review". HIV Med.. vol. 11. 2010. pp. 620-34.

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