Acute respiratory failure secondary to PCP remains a frequent cause of ICU admission among HIV-infected individuals. Despite this, the initial diagnostic workup of patients with acute pulmonary disease always should consider less frequent causes, among them fungal, bacterial, mycobacterial, and viral infections. Other infections that may mimic PCP both clinically and radiologically include various causes of “atypical” pneumonia (influenza, Mycoplasma pneumoniae), miliary tuberculosis, disseminated histoplasmosis, cryptococcosis, coccidioidomycosis, and acute respiratory distress syndrome (ARDS). Although severe acute respiratory syndrome (SARS) has not been reported in HIV-infected patients, its progression to diffuse pulmonary infiltrates in association with lymphopenia17 would resemble PCP in an HIV-positive patient. Among 19 AIDS patients hospitalized together with 95 SARS patients on the same floor of a hospital in the Province of Guangdong, none developed SARS, in contrast to 6 of 28 medical staff who did.18 This has raised the questions of whether HIV-1 interferes with SARS virus replication in the same host or combination antiretroviral regimens may prevent SARS.18 Although Kaposi's sarcoma (KS) can result in ARF, this seldom occurs in the absence of overt mucocutaneous disease. Progression to ARF in KS patients is usually a reflection of overwhelming disease.
Patients who have ARF present with varying degrees of hypoxemia, hypocapnia, and other nonspecific abnormalities related to the underlying HIV disease, as discussed earlier.19 If available, the CD4 count can aid in the differential diagnosis because the occurrence of PCP when the CD4 count is greater than 250 cells/μL would be unusual. An elevated lactic dehydrogenase (LDH) concentration in a patient with known HIV infection and respiratory distress is typical of PCP, and the LDH level tends to correlate with the severity of the episode. Furthermore, changes in the LDH level tend to parallel the course of PCP.23 However, an elevated LDH concentration is nonspecific because this enzyme also can be elevated in various other settings, including other pneumonias, pulmonary embolism, lymphoma, megaloblastic anemia, liver disease, shock liver, and hemolysis (commonly seen among HIV-infected patients receiving dapsone treatment or prophylaxis for PCP) or during long-term AZT therapy.
By the time ARF secondary to PCP requiring ICU admission develops, the chest radiograph usually has evolved to a diffuse alveolar pattern characteristic of ARDS. However, a careful review of previous radiographs can, at times, aid in the differential diagnosis, as shown in Table 48-2.20,21 The clinical, laboratory, and radiologic pattern is seldom specific enough to establish the diagnosis, which should be confirmed using appropriate laboratory examinations. This is particularly important when the patient does not yet carry a diagnosis of AIDS because of the serious prognostic and therapeutic implications of this diagnosis. If sputum is available, this should be cultured for bacteria, fungi, and mycobacteria. Blood cultures also should be obtained, and in selected patients, mycobacterial and fungal blood cultures should be obtained. The key to the etiologic diagnosis relies on obtaining tracheobronchial secretions.19 In the ICU setting, particularly in ventilated patients, bronchoscopic bronchoalveolar lavage (BAL) is the preferred approach. This should be performed by an experienced specialist. Bronchoscopy should be performed using appropriate cardiorespiratory monitoring, including pulse oximetry and an electrocardiogram (ECG).
The sensitivity of BAL for P. carinii and other treatable pathogens commonly found in AIDS patients exceeds 95%. BAL specimens should be concentrated to increase sensitivity. Aliquots should be referred for viral, bacterial, fungal, and mycobacterial studies. P. carinii screening should be requested specifically because this is not performed routinely in most laboratories. Sputum induction and transbronchial biopsies, although valuable techniques in the routine evaluation of less critically ill patients, are not recommended in critically ill and ventilated patients. In the few patients for whom the initial BAL does not provide a diagnosis, a transbronchial or open lung biopsy should be considered.20 However, the appropriateness of such intervention is best decided on a case-by-case basis after careful assessment of the general status of the patient, as well as the likelihood of diagnosing a treatable condition.
P. carinii, recently reclassified as a fungus but having some properties of protozoa, is a ubiquitous organism that produces human disease throughout the world, usually in the setting of severe immunosuppression. Asymptomatic primary infection generally occurs early in life. Rarely, P. carinii can be found incidentally at autopsy in the absence of symptoms. It is not clear whether this represents late infection or early disease not yet manifested clinically.
PCP was the index disease that facilitated the clinical recognition of AIDS. Since then, it also has become the first major AIDS-related opportunistic infection for which development of effective therapy has led to important improvement in survival. Despite these advances, PCP remains a serious opportunistic infection among those infected with HIV, typically occurring among those who do not get tested for HIV or who have problems with access or adherence to antiretroviral and prophylactic therapies. PCP is generally a late event in the evolution of HIV infection, usually occurring when the CD4 count is below 200 cells/μL.22 Therefore, it is recommended that all HIV-infected individuals with CD4 counts below 200 cells/μL or those who have had an episode of PCP should receive lifelong PCP prophylaxis unless immune reconstitution occurs owing to antiretroviral therapy (sustained increase in absolute CD4 count to more than 200 cells/μL for at least 3 months)22 (Table 48-3).
Table 48–3. Guidelines for Discontinuation of Primary and Secondary Prophylaxis for Selected Opportunistic Infections Following Antiretroviral-Induced Immune Reconstitution ||Download (.pdf)
Table 48–3. Guidelines for Discontinuation of Primary and Secondary Prophylaxis for Selected Opportunistic Infections Following Antiretroviral-Induced Immune Reconstitution
|Opportunistic Infection||Initiate Primary Prophylaxis||Discontinue Primary Prophylaxis||Discontinue Secondary Prophylaxis|
|Pneumocyctis carinii Pneumonia||• CD4 <200 cells/μL or history ororpharyngeal candidiasis||• CD4 >200 cells/μL for ≥3 months||• CD4 >200 cells/μL for ≥3 months|
|Toxoplasma encephalitis||• Toxoplasma seropositive and CD4 <100 cells/μL||• CD4 >200 cells/μL for ≥3 months||• CD4 >200 cells/μL for ≥6 months‡|
Complex||• CD4 <50 cells/μL||• CD4 >100 cells/μL for ≥3 months||• CD4 >100 cells/μL for ≥6 months*|
|Crypotcoccus neoformans||not indicated||not applicable||• CD4 >100–200 cells/μL for ≥6 months¶|
Clinical and Radiologic Features
Dyspnea, nonproductive cough, and fever are the classic features of PCP. In critically ill patients, the physical examination usually demonstrates evidence of acute respiratory distress, with surprisingly few adventitious sounds on auscultation of the chest. Acute hypoxemic respiratory failure requiring mechanical ventilation has been reported to occur in as many as 20% of hospitalized patients.23 Most often this occurs within the first 3 days of starting antimicrobial therapy; less frequently acute hypoxemic respiratory failure develops as a complication of diagnostic bronchoscopy and rarely as the initial presentation to the emergency room.23
Clinically overt PCP usually develops over a period of several days to weeks, and in this time, the radiologic picture tends to progress from a normal chest radiograph to a diffuse bilateral interstitial pattern. Varying degrees of alveolar involvement can be seen; even frank consolidation may occur, as seen in Figs. 48-1, 48-2, and 48-3. A number of atypical radiologic presentations have been described, including cystic changes, pneumothoraces (Fig. 48-4), nodular or masslike opacities, and even cavities.20 Upper lung field involvement, as seen in Fig. 48-5, also has been recognized increasingly, particularly (but not exclusively) in the context of aerosol pentamidine prophylaxis. To what extent aerosol pentamidine prophylaxis is responsible for the apparent increased frequency of PCP-related pneumothoraces remains controversial.
Posteroanterior chest x-ray of PCP patient demonstrating interstitial disease preferentially localized to the right hilum and lower lung zone.
Posteroanterior chest x-ray of PCP demonstrating extensive bilateral basilar lung involvement.
Anteroposterior chest x-ray demonstrating diffuse bilateral lung disease secondary to PCP in a patient with respiratory failure immediately prior to intubation. Air bronchograms can be seen throughout the lung, particularly in the upper lung fields bilaterally.
Posteroanterior chest x-ray of a patient with PCP who presented with a left-sided pneumothorax.
Posteroanterior chest x-ray of a patient with PCP who presented with bilateral upper lung disease.
As discussed earlier, given the nonspecific nature of the clinical, laboratory, and radiologic picture of PCP, diagnostic confirmation is desirable. BAL is a rapid, safe, and effective means of obtaining tracheobronchial secretions to provide an adequate diagnostic specimen. Lung biopsy is seldom required to confirm the diagnosis of PCP. As seen in Fig. 48-6, the usual pathologic picture of PCP consists of a mild to moderate interstitial inflammatory reaction with predominance of lymphocytes and alveolar macrophages and the presence of a foamy alveolar exudate (as seen with hematoxylin and eosin [H&E] staining). The foamy appearance of the alveolar exudate is caused by the presence of the cystic form of the organism, which is not stained with H&E but can be easily recognized using readily available special stains (Fig. 48-7). As seen in Fig. 48-8, BAL allows clear identification of the organism if the specimen is concentrated and stained appropriately.19,20 The composition of the alveolar exudate has not been established conclusively. However, BAL studies suggest that this is an inflammatory exudate rich in immunoglobulins, macrophages, and suppressor cytotoxic lymphocytes.24 Although P. carinii infection usually is confined to the lungs, systemic pneumocystosis (involving liver, spleen, lymph nodes, adrenals, and eyes), has been reported occasionally.25 Polymerase chain reaction (PCR) methodology has been applied to the diagnosis of PCP using blood, sputum, and BAL but is not widely available and remains investigational.
Characteristic foamy honeycomb material seen in alveolar spaces in Pneumocystis pneumonia (H&E stain, × 3100).
Cup-and-saucer–shaped Pneumocystis organisms seen on BAL (GMS 3 100).
BAL specimen showing characteristic granular material found in Pneumocystis pneumonia infection (H&E stain, × 3100).
PCP Immune Reconstitution Syndrome
Immune reconstitution syndrome (IRS; also known as immune reconstitution inflammatory syndrome) is the clinical deterioration or “paradoxical reaction” that may develop in almost any organ system as a result of augmented immune response to preexisting clinical or subclinical infection.26,27 Among HIV-negative patients, this phenomenon occurs occasionally during the course of chronic hepatitis B and during treatment for borderline lepromatous leprosy (reversal reaction, Lepra type I) or tuberculosis (e.g., central nervous system tuberculomas) and is due to improvement in cell-mediated immunity.28 A similar pathogenesis is believed to account for IRS among HIV-infected patients. IRS has been reported increasingly since the introduction of highly active antiretroviral therapy (HAART) in 1996. IRS has been described as both an unmasking of subclinical latent infection or a worsening of already documented preexisting disease. Most of the reports have been related to CMV retinitis, tuberculosis (TB), MAC, PCP, cryptococcosis, progressive multifocal leukoencephalopathy, and herpes zoster infection.
A diagnosis of IRS begins with a suspicion of clinical events occurring usually within weeks or months after initiating or revising an antiretroviral regimen. The differential diagnosis may include adverse drug effects and coexisting unrecognized infections (nosocomial or community-acquired). Some opportunistic infections show atypical features in the context of IRS, particularly MAC, CMV retinitis, and cryptococcal meningitis.29 The diagnosis cannot be made without convincing evidence of a response to the antiretroviral regimen (e.g., ≥1 log10 reduction in HIV RNA and usually a CD4 increase). For preexisting opportunistic infections (e.g., TB), the diagnosis of IRS is one of exclusion. In contrast, MAC IRS is usually an unmasking of subclinical infection, and when the organism is recovered from a normally sterile body site, the diagnosis is established. It is important to make the diagnosis of IRS in order to avoid inappropriate therapy (e.g., chemotherapy for suspected multidrug resistant TB).
Initiation of combination antiretrovirals during therapy for PCP has been associated with a paradoxical worsening of the pulmonary infiltrates and lung function in up to 5% to 18% of patients.30 Among the 17 patients with PCP immune reconstitution syndrome reported to date, the clinical worsening was observed 3 to 17 days after starting the antiretroviral regimen. Flow cytometry of BAL specimens in such patients may show a higher CD4/CD8 ratio than usually observed in PCP owing to an influx of CD4 cells during immune reconstitution.31 Transbronchial lung biopsy may reveal a prominent alveolar infiltrate consisting of lymphocytes, macrophages, and neutrophils with few or no demonstrable PCP organisms.32 The diagnosis is established by endoscopy and transbronchial biopsy in order to demonstrate the above-mentioned findings and exclude other possible opportunistic diseases. Any diagnosis of IRS should be supported by evidence of a virologic (HIV viral load reduction of usually ≥1 log10) and/or immunologic (CD4 count increase) response to the antiretroviral regimen. Some patients with PCP IRS have developed respiratory failure and appeared to respond to systemic corticosteroids. The incidence of this complication may be reduced by delaying the initiation of antiretrovirals until after PCP therapy has been completed because reported cases usually have developed within the first few weeks following the dagnosis of PCP.
Trimethoprim-sulfamethoxazole (TMP-SMX) is effective against P. carinii, as well as various gram-negative and gram-positive bacterial organisms. TMP-SMX is administered intravenously or orally at a dose of 15 and 75 mg/kg daily, respectively, in three divided doses for 14 to 21 days. Poor tolerance of TMP-SMX among HIV-infected patients is a significant problem, with adverse drug reactions occurring in 60% to 100% of patients. These include rash, fever, liver dysfunction, renal dysfunction, leukopenia, thrombocytopenia, hyponatremia, anemia, and gastrointestinal upset. Less common but at times severe are mucocutaneous reactions, occurring generally at the end of the first week of treatment. A number of reports have documented successful desensitization of TMP-SMX-allergic patients using progressively larger doses of the drug. Hypersensitivity-type reactions such as fever or rash also can be treated with diphenhydramine or corticosteroids.33,34
Pentamidine isethionate was used initially for the treatment of African trypanosomiasis. Since 1958, it has been known to be effective against P. carinii. Pentamidine usually is administered intravenously once daily at a dose of 4 mg/kg diluted in 250 mL of 5% dextrose and water for 14 to 21 days. Adverse reactions are common, occurring in up to 100% of patients in some series. Common adverse drug reactions include renal and liver dysfunction, neutropenia, thrombocytopenia, hyponatremia, rash, fever, and gastrointestinal upset. Hypotension is commonly associated with pentamidine infusion. This can be minimized by administering the drug slowly over several hours; if severe or long-lasting hypotension occurs, this should be treated supportively because it is readily reversible. Occasionally, carbohydrate metabolism abnormalities (hypo- or hyperglycemia) may develop, including insulin-dependent diabetes mellitus. Ventricular arrhythmias and pancreatitis also have been reported. Finally, observations suggest an increased risk of pancreatitis among patients receiving didanosine and systemic pentamidine concomitantly. Coadministration of these two drugs therefore is contraindicated. Owing to delayed elimination of intravenous pentamidine, ddI should not be coadministered for several weeks after stopping IV pentamidine. Because adverse reactions to pentamidine are related to its systemic concentration, and because of its poor absorption through the alveolar surface, aerosol therapy has been investigated. In a pilot study, a high cure rate with no significant systemic toxicity was achieved using 5 mg/kg daily via a nebulizer in a highly selected group of patients with mild PCP. The only reported adverse effects were cough and bronchospasm in the majority of patients; however, these adverse effects were easily prevented by premedication with a β2-agonist bronchodilator. However, because of variable efficacy and increasing concern regarding the possibility of uneven drug distribution, early relapse, and extrapulmonary pneumocystosis, aerosol pentamidine therapy is not recommended; it should be reserved for use as a prophylactic agent only.35–37
Dapsone (DPS), a sulfone used for the treatment of leprosy and dermatitis herpetiformis, has been shown to be effective against P. carinii, particularly when DPS, 100 mg by mouth daily, is combined with trimethoprim (TMP), 320 mg by mouth q8h (or 15 mg/kg daily, divided q8h). DPS-TMP has been shown to have similar efficacy and better tolerability than TMP-SMX.38 Adverse reactions are common, including hemolytic anemia with methemoglobinemia, thrombocytopenia, neutropenia, liver dysfunction, rash, and gastrointestinal upset, which often interferes with oral administration. The DPS-induced methemoglobinemia and hemolytic anemia are particularly severe among individuals with glucose-6-phosphate dehydrogenase deficiency. It is also important to note that the hemolytic anemia will produce an increase in LDH that should not be misinterpreted as a sign of worsening PCP.19
Atovaquone, a newly developed hydroxynaphthoquinone, has been shown to be a useful second-line agent for the treatment of PCP. Although slightly less effective than TMP-SMX, atovaquone has shown similar efficacy to IV pentamidine, with a very favorable safety profile. This agent is available only in an oral formulation. Furthermore, the drug is not to be used in the presence of moderate to severe diarrhea. For these reasons, atovaquone does not lend itself well to use in the critical care setting.39
Clindamycin-primaquine also has been shown to be effective in the treatment of PCP. This regimen usually is reserved for those who fail or are intolerant to TMP-SMX and IV pentamidine. Clindamycin is given orally or intravenously at doses of 450 to 600 mg four times daily, and primaquine is given orally at a dose of 15 to 30 mg daily.40 Finally, trimetrexate has failed to find a place in the therapeutic armamentarium against PCP despite early favorable reports.41
Prospective, randomized placebo-controlled studies have demonstrated a beneficial short-term effect of adjunctive corticosteroid therapy,42 which prevents the characteristic early deterioration in gas exchange seen in untreated patients and results in a faster resolution of the episode (as measured by respiratory rate, temperature, heart rate, PaO2, and LDH). Adjuvant corticosteroids also have been shown to decrease mortality significantly among patients with PCP-related ARF in a prospective, placebo-controlled trial.43 Systemic corticosteroids are recommended routinely as adjuvant therapy for moderate and severe PCP if no contraindications are present.44 A regimen consisting of oral prednisone 40 mg twice daily for the initial 7 days followed first by 40 mg orally daily for 7 days and then by 20 mg orally daily for the final 7 days is recommended.44 Corticosteroids should be started early in the course of the disease, and to this end, a PaO2 threshold of 70 mm Hg has been proposed.44 It must be emphasized that adjuvant corticosteroid therapy should be continued while patients are on anti-PCP antimicrobials to avoid the rapid deterioration often seen following premature discontinuation of adjuvant corticosteroids. Adjuvant corticosteroids also may exert a similarly beneficial effect even among patients with milder forms of PCP.45
The initial selection of the antimicrobial agent usually occurs outside the ICU. Patients with mild to moderate PCP generally are started on dapsone-trimethoprim or TMP-SMX orally. If there is a concern regarding superimposed bacterial infection, additional antibacterial coverage should be added for community-acquired pneumonia.46Pentamidine generally should be reserved for in-patients with PCP and documented intolerance to TMP-SMX. If the patient is first diagnosed in the ICU, TMP-SMX intravenously generally will be the preferred antimicrobial. Corticosteroids should be started at once in any patient whose PaO2 is below 70 mm Hg while breathing room air. Response to antimicrobials generally is slow, and significant improvement usually does not occur until after 5 to 7 days.33 With the use of adjunctive corticosteroids, however, significant improvement can be observed within the first 3 days of treatment.42 Patients who fail to improve within the first 5 days of therapy should be reviewed thoroughly to rule out potential intercurrent infections (such as ventilator-associated pneumonia) or other complications, including pneumothorax and fluid volume overload. Evidence of P. carinii resistance to sulfamethoxazole has been demonstrated in patients with prior sulfonamide exposure by the presence of mutations in the gene of sulfamethaxazoles' target enzyme, dihydropteroate synthase (DHPS).47 The results of studies that have evaluated the clinical significance of such mutations are conflicting. A retrospective Danish study suggested that DHPS mutations are predictive of mortality,48 whereas another did not confirm this prediction.49 Lack of improvement within 7 days of therapy generally is interpreted as a failure of treatment and therefore an indication for a trial of the alternative agent. A change in antimicrobial also would be warranted if severe adverse reactions develop despite the use of adjunctive corticosteroids. There is no evidence of increased efficacy, but there is increased toxicity when combining TMP-SMX with pentamidine. However, when switching from TMP-SMX to pentamidine, it may be advisable to administer both drugs for a few days until therapeutic levels of pentamidine can be expected in lung tissue.
Untreated, PCP is universally fatal. With the use of appropriate antimicrobials, overall mortality of AIDS-related PCP is below 10%. However, the mortality clearly increases with the severity of the episode.21,23,44 The expected mortality of a mild first episode of PCP, therefore, usually is negligible. In addition, young age and early diagnosis have been correlated with better outcome.21,23,50 The mortality of ARF secondary to AIDS-related PCP appears to be changing. In the early days of the epidemic, mortality was greater than 80% in most series.51,52 Mortality has been reduced to less than 50% with the addition of systemic corticosteroids.23,43,44 However, if PCP-related ARF develops despite early intervention with maximal therapy, including corticosteroids and appropriate antimicrobial agents, the prognosis appears to be dismal, with a mortality greater than 90% in some series.53
Mycobacterium Tuberculosis (MTb)
Tuberculosis occurs with varying degrees of frequency among HIV-infected individuals, reaching 20% in some series. Because the risk of developing tuberculosis is proportional to the risk of developing it prior to the acquisition of HIV, its incidence in North America is greatest among intravenous drug users, blacks, and Latin Americans. Tuberculosis usually develops within the year prior to the diagnosis of other AIDS-defining conditions. Either pulmonary or disseminated tuberculosis in an HIV-infected individual is diagnostic of AIDS according to the CDC classification of HIV disease.
The symptoms of tuberculosis in the context of HIV generally are nonspecific. This is particularly the case because “classic” tuberculosis symptoms such as fatigue, malaise, weight loss, fever, and night sweats are extremely common, even in moderately advanced stages of HIV disease. In contrast to the immunocompetent host, in the context of HIV disease, reactivating tuberculosis usually has radiologic features similar to those of primary tuberculosis, including hilar and/or mediastinal adenopathy, middle and lower lung infiltrates, pleural effusions, or a miliary pattern. Apical infiltrates or cavities are seen only in a minority of patients. As many as 9% of patients with CD4 counts of less than 200 cells/μL have a normal chest x-ray with a positive sputum culture for MTb.54 Furthermore, PCP is diagnosed simultaneously in as many as 25% of the cases of tuberculosis. Prospective tuberculin skin testing (PPD) is useful among HIV-infected individuals because tuberculosis develops more frequently in patients known to have a previously positive test; however, at the time of diagnosis of AIDS, at least 30% of patients are anergic. MTb usually can be diagnosed with smear and culture of sputum or BAL. Of particular note is the diagnostic yield of blood culture (2% to 12%) in some patients. Rapid diagnostic tests have been approved for the detection of M. tuberculosis RNA or DNA in respiratory tract specimens within 24 hours. Such tests are particularly useful in the management of selected patients who are positive or negative for an acid-fast bacilli smear, particularly for those with an intermediate pretest probability of having tuberculosis.55 Treatment guidelines for tuberculosis have been revised recently by the American Thoracic Society (ATS) and the CDC. Tuberculosis (i.e., first-line antituberculous drug–susceptible) in HIV-infected adults should be treated with isoniazid (plus pyridoxine), rifampin, pyrazinamide, and ethambutol for the initial 2 months (initial phase) of therapy. Ethambutol and pyrazinamide are then discontinued. The continuation phase of treatment consists of isoniazid (plus pyridoxine) and rifampin for 4 more months (total 6 months). Patients who respond slowly to treatment should have the continuation phase of treatment increased to 7 months (total 9 months, or 6 months after documented culture conversion). During the continuation phase, treatment may be administered either on a daily basis or three times weekly. However, twice-weekly therapy is not recommended, particularly for those with CD4 counts of less than 100 cells/μL.56 Numerous significant drug interactions have been identified between rifamycins and many antiretrovirals, except for NRTIs and NtRTIs. Patients with CD4 counts of less than 300 cells/μL likely will require concurrent antituberculous and antiretroviral therapy. Those with CD4 counts between 200 and 300 cells/μL should be considered for antiretroviral therapy. Rifabutin may be substituted for rifampin and has the advantage of being associated with fewer and less profound antiretroviral drug interactions.56,57
A high proportion of patients with multi-drug-resistant tuberculosis (MDR-TB) have been HIV-infected. MDR-TB should be suspected in patients with persistent fevers after 14 days of therapy, particularly in areas of high prevalence.58 Persistent fevers also have been associated with extensive pulmonary or miliary disease in cases of non-MDR-TB. In contrast to previous reports, HIV-infected patients with MDR-TB had survival rates similar to those with non-MDR-TB when an early diagnosis was established and treatment was initiated with a regimen containing at least two drugs to which the isolate was susceptible in vitro.58 Expert consultation is recommended for the management of patients with suspected or proven drug-resistant TB. Principles of therapy include the use of at least three previously unused drugs, not limiting regimens to three drugs if other active unused drugs are available (since four- to six-drug regimens appear to be more effective), using directly observed therapy (DOT), and avoiding intermittent therapy except possibly for injectable drugs after the first 2 to 3 months.56 MTb IRS is important to consider in the differential diagnosis of any HIV+ patient who appears to worsen during the course of therapy for MTB.
M. Tuberculosis Immune Reconstitution Syndrome
M. tuberculosis immune reconstitution syndrome (MTb-IRS) is a paradoxical worsening of the signs and symptoms of tuberculosis during the course of antituberculous therapy. This phenomenon was reported occasionally in the pre-AIDS era and considered to be a consequence of resolution of mycobacterial-induced suppression of cell-mediated immunity. MTb-IRS has been reported to occur in up to 36% of HIV-infected patients who initiate HAART.59 MTb-IRS is important to consider in the differential diagnosis of any HIV+ patient who appears to worsen during the course of therapy for MTb infection. The manifestations may include fever, worsening pulmonary infiltrates, lymphadenopathy, and CNS granulomas. Case reports suggest a possible benefit of systemic corticosteroids for the management of moderate to severe IRS related to MTb and IRS related to other organisms. The diagnosis of MTb-IRS is one of exclusion, including consideration of coexisting opportunistic infections and also multi-drug-resistant MTb.
Among tuberculosis patients with advanced HIV disease (CD4 count <200 cells/μL), HAART recipients have improved 12-month survival compared with historic controls in the pre-HAART era (95% versus 85%).60 However, problems related to polypharmacy and overlapping drug toxicities argue against the simultaneous initiation of antituberculous and antiretroviral therapy. Consequently, a more appropriate time to begin HAART may be after 4 to 8 weeks of antituberculous therapy56; furthermore MTb-IRS may be less likely to occur then.61