A reassessment of indications and diagnostic algorithms Bronchoscopy in HIV disease: An update in the era of HAART key words: HIV/AIDS, Bronchoscopy, PCP, Kaposi sarcoma, Lung cancer

June 1, 2007

abstract: The use of fiberoptic bronchoscopy (FOB) in HIV- infected patients has sharply declined since the availability of highly active antiretroviral therapy and the resulting decrease in the incidence of opportunistic infections. Nevertheless, FOB continues to be an important diagnostic tool in this patient population. For example, FOB is useful in evaluating for Pneumocystis jiroveci (formerly carinii) pneumonia (PCP) in patients with CD4+ cell counts of less than 200/µL who have diffuse pulmonary infiltrates and in whom sputum induction has not been performed or is nondiagnostic. It is also useful for evaluating patients who have not responded adequately to empiric therapy for bacterial pneumonia or PCP. Other applications include the visual diagnosis of endobronchial Kaposi sarcoma or the assessment of suspected lung cancer. (J Respir Dis. 2007;28(6): 244-252)

Fiberoptic bronchoscopy (FOB) has been an important diagnostic procedure throughout the HIV pandemic.1 The use of FOB for diagnosing HIV-related pulmonary disorders escalated soon after the beginning of the pandemic in the early 1980s. It was rapidly found to be an effective procedure for diagnosing opportunistic lung infections and a less invasive alternative to open lung biopsy.

As the HIV pandemic spread, most institutions found that the sensitivity of FOB for Pneumocystis jiroveci (formerly carinii) pneumonia (PCP), the most common HIV-related infection at the time,was at least 90%. This garnered widespread acceptance for FOB as the gold standard procedure for diagnosing PCP.

The major role of FOB in patients with HIV infection has been to obtain specimens for diagnosing pulmonary infections. Visual inspection of the airways can be diagnostic of Kaposi sarcoma or reveal other endobronchial lesions, including primary lung malignancies. The indications for FOB have been refined in many institutions with the use of screening instruments and ultrasonic nebulizer sputum induction with hypertonic saline to document PCP.

Since the mid-1990s, the widespread use of highly active antiretroviral therapy has dramatically changed the approach to the care of patients with HIV disease. Patients who respond to such therapy have preservation or reconstitution of immunological function, dramatically fewer opportunistic infections, and increased survival. A substantial decline in the use of FOBin patients with HIV disease has been observed since highly active antiretroviral therapy has become available.

In this article, I will describe the current indications for FOB in patients with HIV disease. Then I will outline diagnostic algorithms applicable to specific clinical settings.

The spectrum of pulmonary disease

Between 1988 and 1994, the NIH-funded multicenter Pulmonary Complications of HIV Infection Study observed a large cohort of HIV-infected persons at all stages of disease.2 The respiratory disorders that occurred during this study period before the advent of highly active antiretroviral therapy can be divided into 3 groups according to the usefulness of FOB for diagnosis:

•Disorders for which FOB has a high degree of usefulness, such as PCP; infiltrative disorders, such as nonspecific interstitial pneumonitis or lymphoid interstitial pneumonitis; neoplasms (including Kaposi sarcoma); and other less common infections, including aspergillosis and cryptococcosis.

•Disorders for which FOB can isolate a causative organism, but for which the diagnosis usually is made clinically or by sputum specimens, such as bacterial pneumonia and tuberculosis.

•Disorders such as bronchitis or pulmonary hypertension, which cannot be diagnosed by FOB.

In the NIH-funded cohort of HIV-infected persons at all stages of disease, about one fourth of the respiratory disorders were ones for which FOB would have a high degree of diagnostic usefulness. For patients with advanced HIV disease, the proportion of disorders diagnosed by FOB, especially PCPand other pulmonary opportunistic infections, was higher, but even in this group, a large proportion of respiratory infections were acute bronchitis or bacterial pneumonia.

The availability of highly active antiretroviral therapy has clearly influenced the profile of lung disorders that complicate HIV disease. The incidences of PCP and other opportunistic infections have dramatically declined among patients receiving highly active antiretroviral therapy.3-5 The incidence of bacte-rial pneumonia has also decreased, although one report suggested that the risk of bacterial pneumonia may be higher in patients receiving antiretroviral therapy who present with symptoms or abnormal chest radiographic findings, possibly because of the lower risk of opportunistic infections.4,6

The incidence of tuberculosis has decreased,7 but it is not known whether the frequency of pulmonary fungal infections has been affected by highly active antiretroviral therapy. There has been a sharp decline in the risk of noninfectious conditions, such as non-Hodgkin lymphoma and Kaposi sarcoma, with such therapy; however, the impact on the frequency and course of pulmonary involvement is less clear.8-10

Disorders that may have increased in incidence since the availability of highly active antiretroviral therapy include primary lung cancer and chronic obstructive pulmonary disease (COPD).11 HIV-infected persons, especially those who smoke, are at increased risk for lung cancer, airway disease, and emphysema. Two recent studies have suggested an even higher risk of lung cancer in the HIV-infected population since the introduction of highly active antiretroviral therapy.12,13

Possible explanations for the increased incidence in lung cancer include more years of tobacco exposure concomitant with increased life expectancy for patients receiving antiretroviral therapy, a greater opportunity for the development of lung cancer with the decline in deaths from opportunistic infections, and a greater pool of older HIV-infected persons who are at higher risk for cancer. These conditions, along with the effects of prolonged latent infection with agents such as Pjiroveci, may also result in greater prevalence of COPD.14

Immune reconstitution syndromes may complicate the initiation of antiretroviral therapy in patients with latent pulmonary infections such as tuberculosis or PCP.15 Reactivation of sarcoidosis and a sarcoid-like pulmonary disorder coincident with commencement of antiretroviral therapy have also been reported.16

The current use of FOB

The use of FOB for the diagnosis of HIV-related pulmonary disorders has decreased over the past 2 de- cades.17,18 In one academic center, the decline began before the introduction of highly active antiretroviral therapy. It was coincident with PCP prophylaxis and better screening for lung disorders that require diagnosis by FOB.

Another sharp decline in the use of FOB has been seen since the availability of highly active antiretroviral therapy. This reduction in use does not seem to be a consequence of a change in diagnostic approach or diagnostic yield. It most likely reflects a more immunocompetent HIV-infected population that is less likely to present with a pulmonary process that requires diagnostic FOB.

Nevertheless, FOB continues to be an effective diagnostic tool for the evaluation of pulmonary disorders in some HIV-infected patients (Table 1). Despite the lower frequency of opportunistic infections, these infections continue to be important complications of HIV disease. For example, PCP remains the leading AIDS-defining opportunistic infection.19

Highly active antiretroviral therapy has affected different patients to a different degree. Not all patients tolerate or have access to such therapy, and some present with a pulmonary complication as the first manifestation of HIV infection. Thus, although the procedure is being performed less frequently, there has been little change in the indications for FOB.18

Several clinical and radiographic characteristics are useful in deciding when FOB will be helpful. In general, FOB is useful for patients with CD4+ cell counts of less than 200/µL and diffuse pulmonary infiltrates that are either of the alveolar filling or interstitial pattern typical of PCP or of the atypical nodular or miliary patterns. It is also useful for patients with risk factors for lung cancer who have radiographic evidence of a lung mass or focal volume loss suggestive of lung cancer.

A visual diagnosis of endobronchial Kaposi sarcoma is often made in patients with typical skin lesions and consistent chest radiographic or CT findings. FOB is less useful for patients who produce purulent sputum with focal infiltration, who usually have bacterial pneumonia, or for those with normal chest radiographic findings, who often have acute bronchitis.

Diagnostically useful bronchoscopic specimens

The most useful bronchoscopic procedures in the diagnosis of HIV- related pulmonary disease have been bronchoalveolar lavage (BAL) and transbronchial biopsy (TBB). BAL has a diagnostic yield for PCP of up to 90%.20,21 When combined with TBB, the yield may approach 100%.20 When Pneumocystis is not found in either BAL fluid or TBB specimens, the negative predictive value has been greater than 93%.21

These bronchoscopic procedures retain their usefulness even after empiric therapy has been initiated, if the duration of the therapy has not exceeded 1 to 2 weeks.20 Because BAL has a high diagnostic yield for PCP and because it poses a lower risk of complications, such as pneumothorax or excessive bleeding, than does TBB, BAL alone is often performed when PCP is suspected in patients with HIV disease.

FOB is useful for diagnosing lung cancer in HIV-infected patients. Which specimens provide the best diagnostic yield depends on whether an endobronchial lesion can be visualized.22 When it can, endobronchial biopsy, with a minimum of 4 to 6 biopsy specimens, is most useful.

The usefulness of brushings and washings in this situation is unclear. When there is no visible endobronchial abnormality, diagnostic material may be obtained by fluoroscopically guided TBB or needle aspiration, brushings, or washings, with a considerably lower diagnostic yield that varies according to the size of the lesion. Newer methods to guide sampling, such as endobronchial ultrasound and electromagnetic tracking, may improve the diagnostic yield for tumors without accessible endobronchial involvement. For very peripheral lesions, transthoracic needle aspiration or core biopsy is often preferred over FOB as the initial diagnostic procedure.

Sputum induction

Some institutions use sputum induction with an ultrasonic nebulizer as a first attempt to recover a diagnostic specimen from patients at high risk for PCP. Initial sputum induction is less invasive and less costly than FOB, but its sensitivity is widely variable.23 Huang and associates24 have shown that sputum induction is a useful screening procedure for PCP, but it can miss other diagnoses, confirming the need for FOB to complete the evaluation if the findings are negative.

At institutions that have low sputum induction sensitivity or low PCP prevalence, most patients with a diagnosis of PCP have been evaluated with both sputum induction and FOB, a practice that is less efficient and more costly than if FOB is the initial procedure. Glenny and Pierson25 determined that when the prevalence of PCP and the sensitivity of sputum induction are sufficiently high, sputum induction followed by FOB is economically advantageous. With the dramatic decline in PCP since the availability of highly active antiretroviral therapy, sputum induction may no longer be a cost-effective first procedure at many institutions.

Diagnostic algorithms

As experience has been gained with the spectrum of HIV-related pulmonary disorders, the decision to use FOB to confirm specific diagnoses has been based on various clinical, laboratory, and radiographic screening criteria (Table 2).

•Diffuse radiographic abnormalities: In general, FOB is useful for patients whose CD4+ cell counts are less than 200/µL and in whom diffuse bilateral pulmonary infiltrates are evident radiographically. These diffuse patterns usually have an alveolar-interstitial pattern characteristic of PCP or, less commonly, perihilar or atypical nodular patterns that may occur with Kaposi sarcoma or opportunistic infections other than PCP.

For patients with diffuse disease, empiric therapy for PCP is usually started while awaiting the results of sputum stain and culture for mycobacteria if the patient is at risk for tuberculosis (Figure 1).Some clinicians continue empiric treatment as long as there is clinical improvement. Others routinely do sputum induction or FOB to make a definitive diagnosis.

At Olive View Medical Center, patients with clinically suspected PCP are referred for pulmonary consultation and assigned to a high-, moderate-, or low-risk group, primarily based on CD4 count, lactate dehydrogenase level, and chest radiographic findings (Table 3). Our sputum induction sensitivity is about 58%, and the PCP prevalence is sufficiently high in our high- and moderate-risk groups so that sputum induction followed by FOB is less costly than initial FOB. Most low-risk patients are observed or treated for other pulmonary infections, especially bacterial pneumonia or acute bronchitis. For the rare cases that are further evaluated for PCP, we go directly to FOB.

•Focal radiographic findings: FOB is usually not useful for the diagnosis of bacterial pneumonia in patients who produce purulent sputum and have focal consolidation on the chest radiograph. For focal disease, empiric treatment of bacterial pneumonia is started after blood, sputum, and pleural effusions are cultured, and sputum is stained and cultured for mycobacteria. Sputum induction and FOB to look for other causes are done only if there is not sufficient clinical improvement.

•Normal or equivocal chest radiographic findings: Most patients with purulent sputum and no radiographically apparent infiltrates have acute bronchitis and improve with a course of broad-spectrum antibiotics. In addition to the typical diffuse bilateral alveolar filling or interstitial pattern, HIV-related PCP can cause a variety of atypical radiographic presentations, including normal or equivocal chest radiographic findings.

High-resolution CT (HRCT) is a highly sensitive means of screening for PCP in patients with normal or equivocal chest radiographic findings. PCP may manifest as patchy areas of ground-glass attenuation. The diagnosis can be reliably excluded if the ground-glass attenuation is absent.26 Furthermore, findings of centrilobular opacities arranged in a tree-in-bud pattern that represent bronchioles impacted with inflammatory secretions and focal regions of air trapping may suggest bronchitis or bronchiolitis, especially in patients with purulent sputum.

The experience of Gruden and associates26 suggests a diagnostic algorithm for patients with suspected PCP whose chest radiographic findings are normal or equivocal (Figure 2). HRCT can be used to exclude PCP or suggest acute bronchitis, which can be treated with antibiotics. When ground-glass opacities are present, sputum induction or FOB can be performed to obtain diagnostic specimens.

•Lung mass: As with patients without HIV disease, bronchoscopy should be the initial procedure if radiographic studies indicate that the mass can be reached by the bronchoscope. Transthoracic needle aspiration or core biopsy is almost always preferable to FOB for smaller peripheral lesions. For both FOB and the transthoracic approaches, the diagnostic yield declines substantially as the size of the lesion falls below 2 to 3 cm and video- assisted thoracoscopy may be required to obtain a diagnostic specimen. For any of these procedures, it is particularly important to process diagnostic specimens for fungal, bacterial, and mycobacterial stains and cultures especially when immunocompromise is evident.

•Mediastinal masses or lymphadenopathy: Several of the well-recognized pulmonary complications of HIV-disease may present as a mediastinal mass or lymphadenopa-thy, including tuberculous or nontuberculous mycobacterial infection, coccidioidomycosis, histoplasmosis, Kaposi sarcoma, primary lung malignancies, and lymphoma. FOB with transbronchial needle aspiration is an excellent first diagnostic approach in that it has a high diagnostic yield for fungal and mycobacterial infections, as well as for lung cancer. Direct sampling of the mediastinum via a surgical approach may be required in cases where FOB is nondiagnostic.

Empiric therapy for PCP

The role of empiric therapy for PCP has been debated for years. It has been suggested that for patients presenting with typical features of PCP, a trial of empiric therapy may be more cost-effective than early FOB, and it may provide the opportunity for outpatient management for patients with mild disease who are compliant with therapy and who can tolerate oral medications.27

The significant decline in incidence of HIV-related PCP since the introduction of highly active antiretroviral therapy may be grounds for rethinking the indications for empiric therapy. With less experience in diagnosing and treating PCP, it may be more difficult for clinicians to recognize typical cases for which empiric therapy is most likely to be effective. Empiric therapy may be particularly hazardous in settings where pulmonary infections such as tuberculosis, coccidioidomycosis, and histoplasmosis may present in a manner similar to that of PCP.

CONCLUSIONS

Since the availability of highly active antiretroviral therapy, pulmonary opportunistic infections have continued to complicate HIV disease, but at a lower rate. Thus, although bronchoscopic procedures have continued to have an important role in diagnosing these infections, remarkably fewer of these procedures are being performed. Considering the more recent evidence of a higher risk of pulmonary malignancy in HIV-infected patients, clinicians should also consider FOB as an initial diagnostic procedure for lung cancer in cases where radiographic studies indicate a reasonable diagnostic yield (Table 4).

In light of the lower incidence of PCP, less experience with sputum induction may translate to lower sensitivity and cost-effectiveness, and FOB may be the initial diagnostic procedure at some institutions. Furthermore, clinicians may become more reluctant to treat PCP empirically. Finally, other, less common pulmonary opportunistic infections will continue to occur in patients with advanced HIV disease, and FOB will remain a highly effective diagnostic procedure for many of them.

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