HIV infection and pulmonary disease

Chest 陳宏杰

Outline

• HIV infection and Bacterial pulmonary infection

• HIV infection and Pneumocystic carinii pneumonia

• HIV infection and Tuberculosis

AIDS and bacterial pulmonary infection

• Bacterial pneumonia occurs more frequently in HIV seropositive patients, with an annual incidence ranging from 5.5 to 29 per 100 compared with 0.9 to 10 per 100 in HIV seronegative patients. ~Pulmonary Complications of HIV Infection Study Group.

Hirschtick RE; Glassroth J; Jordan MC; et al.N Engl J Med 1995 Sep 28;333(13):845-51.

• Bacteria have been reported to account for 3 to 45 percent of all respiratory infections in HIV–infected hosts. ~Bacterial infections in adult patients with the acquired immune

deficiency syndrome (AIDS) and AIDS-related complex. Witt DJ; Craven DE; McCabe WR. Am J Med 1987 May;82(5):900-6.

• Among HIV–infected patients, injection drug users (IDU), inner city inhabitants, smokers, and persons from developing countries are at highest risk for bacterial pneumonias. ~Bacterial pneumonia

in persons infected with the human immunodeficiency virus. Pulmonary Complications of HIV Infection Study Group. Hirschtick RE; Glassroth J; Jordan MC; et al.N Engl J Med 1995 Sep 28;333(13):845-51. ~Bacterial infections in adult patients with the acquired immune deficiency syndrome (AIDS) and AIDS-related complex. Witt DJ; Craven DE; McCabe WR. Am J Med 1987 May;82(5):900-6.

• The incidence of bacterial pneumonia decreased progressively from 1993 to 1996 and 1997 (22.7 versus 12.3 and 9.1 episodes/100 person-years, respectively).

• In a multivariate model, use of HAART was associated with a 45 percent reduction in the risk for bacterial pneumonia.

• Depressed CD4 counts, a prior episode of Pneumocystis carinii pneumonia (PCP), and injection drug use remained significant risk factors for pneumonia regardless of antiretroviral therapy. ~ Effect of antiretroviral therapy on the incidence of bacterial pneumonia in patients with advanced HIV infection. Sullivan JH; Moore RD; Keruly JC; Chaisson RE. Am J Respir Crit Care Med 2000 Jul;162(1):64-7.

Major causes of bacterial pneumonia in HIV infected patients

Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus are the most commonly isolated bacteria, with S. pneumoniae accounting for the majority of cases in which a bacterial pathogen is isolated.~ Bacterial pneumonia in patients with the acquired immunodeficiency syndrome. Polsky B; Gold JW; Whimbey E; et al. Ann Intern Med 1986 Jan;104(1):38-41. ~ Prospective study of etiologic agents of community-acquired pneumonia in patients with HIV infection. Rimland D; Navin TR; Lennox JL; et al. AIDS 2002 Jan 4;16(1):85-95.

• Factors associated with Pseudomonas pneumonia include prior hospitalization, antibiotic exposure, neutropenia, and advanced immunosuppression. ~ Pulmonary complications of HIV infection: autopsy findings. Afessa B; Green W; Chiao J; Frederick W. Chest 1998 May;113(5):1225-9. ~ Incidence and determinants of Pseudomonas aeruginosa infection among persons with HIV: association with hospital exposure. Sorvillo F; Beall G; Turner PA; Beer VL; Kovacs AA; Kerndt PR. Am J Infect Control 2001 Apr;29(2):79-84. ~

• Pseudomonal infection in AIDS patients is associated with a 33 percent in-hospital mortality rate, poor one-year survival rates, and relapse of infection. ~ Serious Pseudomonas aeruginosa infections in patients infected with human immunodeficiency virus: a case-control study. Fichtenbaum CJ; Woeltje KF; Powderly WG. Clin Infect Dis 1994 Sep;19(3):417-22. ~ Pseudomonas aeruginosa bacteremia in patients infected with human immunodeficiency virus type 1. Vidal F; Mensa J; Martinez JA; et al. Eur J Clin Microbiol Infect Dis 1999 Jul;18(7):473-7.

Pathophysiologic mechanisms underlie the susceptibility to infection with encapsulated, pyogenic organisms

• Deficiencies in humoral immunity, including HIV–related B lymphocyte dysfunction with impaired antibody responses to S. pneumoniae and P. aeruginosa, and depressed IgA and IgG2 subclass antibody levels.

• Decreased serum opsonic activity against pneumococcal capsular polysaccharides

• Alveolar macrophage and neutrophil dysfunction.

• Smoking, which is associated with a five-fold increase in the risk of invasive pneumococcal disease in HIV-infected individuals, remains an important, modifiable risk factor in the HAART era. ~ Epidemiologic changes in bacteremic pneumococcal disease in patients with human immunodeficiency virus in the era of

highly active antiretroviral therapy. Grau I; Pallares R; Tubau F; et al. Arch Intern Med 2005 Jul 11;165(13):1533-40.

• HIV-infected smokers experience decreases in the percentage and absolute numbers of pulmonary CD4+ lymphocytes and suppression of IL-1 beta and TNF-alpha production within the lung, which may contribute to risk of infection.

• Nosocomial pneumonia in HIV–infected patients is most commonly caused by S. aureus and gram-negative organisms, including P. aeruginosa, K. pneumoniae, and Enterobacter species.

• These infections almost always occur late in the course of HIV infection and in patients with additional host factors predisposing to bacterial infections, such as neutropenia. ~ Murray, JF, Felton, CP, Garay, SM, et al. Pulmonary complications of the acquired immunodeficiency syndrome. Report of a National Heart, Lung, and Blood Institute workshop. N Engl J Med 1984; 310:1682. ~ Bacterial infections in adult patients with the acquired immune deficiency syndrome (AIDS) and AIDS-related complex. Witt DJ; Craven DE; McCabe WR Am J Med 1987 May;82(5):900-6.

• Clinical symptoms• The clinical presentation of bacterial

pneumonia in the HIV (+) patient is similar to that in patients not infected with HIV.

• Most patients have an abrupt onset of fever, chills, cough with sputum production, dyspnea, and pleuritic chest pain.

• Leukocytosis (+), excepts severe immunosuppression.

• Bacteremia is frequently associated with pneumonia, with rates as high as 75 % reported with S. pneumoniae infection.

• Pretreatment blood cultures yielded positive results for a probable pathogen in 5%–14% in large series of nonselected patients hospitalized with CAP. ~from ATS CAP guideline 2007

• Radiologic findings• The most common chest roentgenographic

manifestation of bacterial pneumonia in the HIV–infected patient is segmental or lobar consolidation, although diffuse reticulonodular infiltrates and patchy lobar infiltrates may also be seen.

Pneumococcal pneumonia (left 2)Staphylococcal pneumonia (up)H.Influenza pneumonia (R’t up)K.P pneumonia (Right lower)

• Diagnosis• Sputum culture• Blood culture• S. pneumonia can be isolated in blood cultures

in up to 60 percent of HIV-infected patients with pneumococcal pneumonia. ~Janoff, EN, Breiman, RF, Daley, CL,

Hopewell, PC. Pneumococcal disease during HIV infection: Epidemiologic, clinical. and immunologic perspectives. Ann Intern Med 1992; 117:314.

• Treatment• Outpatients• Inpatients• -- General ward admissions• -- ICU admissions

• Prevention• Pneumococcal vaccine• H. influenzae vaccine• -- HIB vaccine is not recommended for adults

infected with HIV• Prophylactic antibiotics• -- Trimethoprim–sulfamethoxazole has been

shown to decrease the risk for bacterial infections. ~Hirschtick, R, Glassroth, J, Jordan, M, et al. Bacterial pneumonia in persons infected with the human immunodeficiency virus. N Engl J Med 1995; 333:845.

• Macrolide antibiotics are also effective in preventing bacterial infections in patients who are receiving these agents as prophylaxis for Mycobacterium avium complex disease. ~Havlir, DV,

Dube, MP, Sattler, FR, et al. Prophylaxis against disseminated Mycobacterium avium complex with weekly azithromycin, daily rifabutin, or both. Califronia Collaborative Treatment Group. N Engl J Med 1996; 335:392.

HIV infection and Pneumocystis carinii infection

• Pneumocystis jiroveci (formally carinii) pneumonia (PCP), is the most common opportunistic respiratory infection in patients infected with HIV. ~ Pneumocystis pneumonia. Thomas CF Jr; Limper AH N Engl J Med 2004

Jun 10;350(24):2487-98.

• PCP remained the leading cause of death, which was associated with not receiving or failing to comply with HAART or PCP prophylaxis. ~Pulvirenti, J, Herrera, P, Venkataraman, P, Ahmed, N. Pneumocystis carinii pneumonia

in HIV-infected patients in the HAART era. AIDS Patient Care STDS 2003; 17:261.

• Epidemiology• Transmission (?)• Incidence• -- 95% of patients who developed PCP had a

CD4 count below 200 cells/mm3. ~Stansell, JD, Osmond, DH,

Charlebois, E, et al. Predictors of pneumocystis carinii pneumonia in HIV-infected persons. Am J Respir Crit Care Med 1997; 155:60.

• -- HIV transmission category, age, smoking history, and use of antiretroviral therapy did not predict development of PCP.

• changes in the incidence of PCP• -- primary prophylaxis against the infection in

patients with CD4 cell counts <200/microL• -- widespread adoption of highly active

antiretroviral therapy (HAART).• ~Hoover, DR, Saah, AJ, Bacellar, H, et al. Clinical manifestations of AIDS in the era of pneumocystis prophylaxis. Multicenter

AIDS Cohort Study. N Engl J Med 1993; 329:1922.• ~ Wolff, AJ, O'Donnell, AE. Pulmonary manifestations of HIV infection in the era of highly active antiretroviral therapy. Chest

2001; 120:1888.• ~San-Andres, FJ, Rubio, R, Castilla, J, et al. Incidence of acquired immunodeficiency syndrome-associated opportunistic

diseases and the effect of treatment on a cohort of 1115 patients infected with human immunodeficiency virus, 1989-1997. Clin Infect Dis 2003; 36:1177.

• Clinical manifestations:• In HIV-infected patients, PCP is generally

gradual in onset and characterized by fever (79 to 100 %), cough (95 %), and progressive dyspnea (95 %). ~Early predictors of in-hospital mortality for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. Kales CP; Murren JR; Torres RA; Crocco JA. Arch Intern Med 1987 Aug;147(8):1413-7.

• Although fewer patients are receiving aerosolized pentamidine as PCP prophylaxis, atypical manifestations and extrapulmonary PCP are considerations in those receiving this agent.

• Radiologic findings• The most common radiographic abnormalities

are diffuse, bilateral interstitial or alveolar infiltrates. ~DeLorenzo, LJ, Huang, CT, Maguire, GP, Stone, DJ. Roentgenographic patterns of Pneumocystis carinii pneumonia in 104 patients with AIDS. Chest 1987; 91:323.

• HRCT: 51 patients with suspected PCP and normal, equivocal, or nonspecific chest x-ray findings; HRCT had a sensitivity of 100 percent and a specificity of 89 percent when the presence of patchy or nodular ground-glass attenuation was used to indicate possible PCP. ~Hartman, TE, Primack, SL, Muller, NL, Staples, CA. Diagnosis of thoracic complications in AIDS: accuracy of CT. AJR Am J Roentgenol 1994; 162:547.

• Other lab studies:• Gallium-67 citrate scanning: high sensitivity

but low specificity, high cost, delay diagnosis• Diffusing capacity for carbon monoxide

(DLCO)• Assessment of oxygenation at rest and with

exercise• CD4: <200 cells/mm3• LDH: the mean LDH of PCP survivors was 340

IU, while the mean level of non-survivors was 447 IU. ~Zaman, MK, White, DA. Serum lactate dehydrogenase levels and Pneumocystis carinii pneumonia: Diagnostic and prognostic significance. Am Rev Respir Dis 1988; 137:796.

• Diagnosis of PCP infection• Sputum: sensivity: 55-92%; specificity: ~100%

~Zaman, MK, Wooten, OJ, Suprahmanya, B, et al. Rapid non-invasive diagnosis of Pneumocystis carinii

from induced liquified sputum. Ann Intern Med 1988; 109:7. ~ Cruciani, M, Marcati, P, Malena, M, et al. Meta-analysis of diagnostic procedures for Pneumocystis carinii pneumonia in HIV-1-infected patients. Eur Respir J 2002; 20:982.

• Bronchoalveolar lavage: BAL alone has a diagnostic yield of 97 to 100 percent in HIV-infected patients. ~Jules-Elysee, K, Stover, DE, Zaman, MB, et al. Aerosolized pentamidine:

Effect on diagnosis and presentation of Pneumocystis carinii pneumonia. Ann Intern Med 1990; 112:750.

• Transbronchial lung biopsy• Fine needle aspiration• PCR: under investigation

Treatment

• Oral regiments: TMP-SMX, TMP-dapsone, or clindamycin-primaquine for 21 days.

• Intravenous regiment: TMP-SMX, Pentamidine, clindamycin-primaquine, trimetraxate.

• TMP-SMX is considered the regimen of choice for intravenous therapy of PCP.

• Isolation — There is evidence that person to person transmission of PCP is more common than was previously thought. ~Kovacs, JA, Masur, H. Prophylaxis against opportunistic infections in patients with human immunodeficiency virus infection. N Engl J Med 2000; 342:1416.

• Pregnancy — As in other patients, TMP-SMX is the preferred therapy in pregnant women; other therapies such as TMP-dapsone may also be used. ~Benson, C, Kaplan, J, Masur, H, et. al. Treating opportunistic infections among HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America. Clin Infect Dis 2005; 40:S131.

• Use of corticosteroids• Patients with PCP typically worsen after two

to three days of therapy, presumably due to increased inflammation in response to dying organisms.

• Corticosteroids given in conjunction with anti-Pneumocystis therapy decrease the incidence of mortality and respiratory failure associated with severe PCP. ~Adjunctive corticosteroids for Pneumocystis jiroveci pneumonia in patients with HIV-infection. Briel M; Bucher H; Boscacci R; Furrer H. Cochrane Database Syst Rev. 2006 Jul 19;3:CD006150.

• Those recommendations that patients should receive corticosteroid therapy if, while breathing room air, an arterial blood gas measurement shows either:

• -- A partial pressure of oxygen of 70 mmHg or less

• -- An alveolar-arterial (A-a) oxygen gradient of 35 mmHg or more

• ~Consensus statement on the use of corticosteroids as adjunctive therapy for pneumocystis pneumonia in the acquired immunodeficiency syndrome. The National Institutes of Health-University of California Expert Panel for Corticosteroids as Adjunctive Therapy for Pneumocystis Pneumonia. N Engl J Med 1990; 323:1500.

• Treatment failure • Patients who show initial worsening with

therapy should start to show clinical improvement around the fifth day of therapy.

• Patients who are not showing any improvement after five to seven days of therapy are considered to have treatment failure.

• Patients with HIV and severe immunosuppression can have more than one opportunistic infection (OI).

• Prognosis• The degree of hypoxemia at presentation is

strongly related to the prognosis of PCP. ~Prognostic factors influencing the outcome in pneumocystis carinii pneumonia in patients with AIDS. Fernandez P; Torres A; Miro JM; Vieigas C; Mallolas J; Zamora L; Gatell JM; Valls ME; Riquelme R; Rodriguez-Roisin R . Thorax. 1995 Jun;50(6):668-71.

• Other correlates with worse outcome include increasing age, prior episodes of PCP, an elevated serum lactate dehydrogenase concentration, low CD4 cell count, and the presence of cytomegalovirus in bronchoalveolar lavage fluid. ~Dworkin, MS, Hanson, DL, Navin, TR. Survival of patients with AIDS, after diagnosis of Pneumocystis carinii pneumonia, in the United States. J Infect Dis 2001; 183:1409. ~Benfield, TL, Helweg-Larsen, J, Bang, D, et al. Prognostic markers of short-term mortality in AIDS-associated Pneumocystis carinii pneumonia. Chest 2001; 119:844.

HIV infection and mycobacteria infection

• Interaction between HIV and tuberculosis• HIV-infected patients are at increased risk of

developing active TB from both reactivated latent and exogenous infection. ~Barnes, PF, Bloch, AB, Davidson, PT, Snider, DE. Tuberculosis in patients with human immunodeficiency virus infection. N Engl J Med 1991; 324:1644.

• An HIV seropositive status is also a risk factor for accelerated progression of TB, particularly in the setting of extensively drug-resistant (XDR) tuberculosis. ~Shuchman, M. Improving global health--Margaret Chan at the WHO. N

Engl J Med 2007; 356:653.

• TB infection is associated with significant increases in plasma HIV viremia: ~Toossi, Z, Mayanja-Kizza, H, Hirsch, CS, et al. Impact of tuberculosis (TB) on HIV-1 activity in dually infected patients. Clin Exp Immunol 2001; 123:233.

• -- Generalized immune activation, which increases the proportion of CD4 cells that are preferential targets for HIV. ~Vanham, G, Edmonds, K, Qing, L, et al.

Generalized immune activation in pulmonary tuberculosis: co-activation with HIV infection. Clin Exp Immunol 1996; 103:30.

• -- Increased expression of the HIV coreceptors CCR5 and CXCR4. ~Wolday, D, Tegbaru, B, Kassu, A, et al. Expression of chemokine receptors CCR5 and CXCR4 on CD4+ T cells and plasma chemokine levels during treatment of active tuberculosis in HIV-1-coinfected patients. J Acquir Immune Defic Syndr 2005; 39:265.

• Impact of HAART:• HAART reduces the risk of developing TB. ~Lawn, SD,

Bekker, LG, Wood, R. How effectively does HAART restore immune responses tonMycobacterium tuberculosis? Implications for tuberculosis control. AIDS 2005; 19:1113.

• The greatest risk factor for the development of TB on HAART is the pretreatment level of immunodeficiency, as reflected by the baseline CD4 cell count; the CD4 cell count at six months after initiation of HAART is also associated with an increased risk of TB. ~Girardi, E, Sabin, CA, d'Arminio Monforte, A, et al. Incidence of Tuberculosis among HIV-infected patients receiving highly active antiretroviral therapy in Europe and North America. Clin Infect Dis 2005; 41:1772.

• Clinical manifestation:• Extrapulmonary tuberculosis: about 30%• The most common sites of extrapulmonary

involvement are blood and extrathoracic lymph nodes, followed by bone marrow, genitourinary tract, and the central nervous system. ~Barnes, PF, Bloch, AB, Davidson, PT, Snider, DE. Tuberculosis in patients with human

immunodeficiency virus infection. N Engl J Med 1991; 324:1644. ~Jones, BA, Young, SMM, Antoniskis, D, et al. Relationship of the manifestations of tuberculosis to CD4 cell counts in patients with human immunodeficiency virus infection. Am Rev Respir Dis 1993; 148:1292.

• Radiographic findings:• Patterns typical for primary TB — 36 percent.• Patterns compatible with post-primary

(reactivation) TB — 29 percent.• A miliary pattern — 4 percent.• Abnormalities atypical for TB, such as diffuse

infiltrates suggestive of PCP — 13 percent.• Minimal changes — 5 percent.• Normal chest radiographs — 14 percent.• ~Greenberg, SD, Frager, D, Suster, B, et al. Active pulmonary tuberculosis in patients with AIDS: Spectrum

of radiographic findings (including a normal appearance). Radiology 1994; 193:115.

• Most of the patients with CD4 counts greater than 200 cells/mm3 showed post-primary patterns (55 percent).

• Patients with fewer than 200 CD4 cells/mm3 were nearly as likely to have normal chest radiographs (21 percent) as they were to have post-primary patterns (23 percent).

Active pulmonary tuberculosis in

patients with AIDS: Spectrum of radiographic

findings (including a normal

appearance). Radiology 1994;

193:115.

Clinical and radiographic correlates of primary andreactivation

tuberculosis: a molecular

epidemiology study. Geng, E, Kreiswirth, B, Burzynski, J, Schluger, NW.

JAMA 2005; 293:2740.

Radiographic findings on HIV-infected patients with pulmonary tuberculosis

• Diagnosis:• Tuberculin skin test: CD4 count• Sputum smear and culture for TB• Urine cultures• Stool cultures: helpful to diagnose MAC

infection• Invasive tests• Nucleic acid-based amplification assays

• Effecacy of TB treatment• Therapy for susceptible TB is typically as effective

in the HIV-infected patient as it is in the general population.

• Although most HIV-infected patients can be successfully treated with standard six-month treatment regimens, longer courses of treatment are indicated for some patients.

• These include patients with cavitary disease who remain smear-positive after two months of induction therapy, as well as patients with CNS or skeletal involvement

• Relapse rates after short-course (6-month) treatment of tuberculosis in HIV-infected and uninfected persons. ~AIDS:Volume 13(14)1 October 1999pp 1899-1904

• Virological Response to Highly Active Antiretroviral Therapy Is Unaffected by Antituberculosis Therapy. ~J Infect Dis 2006; 193:1437

• No difference in virological response was seen between the patients with HIV and tuberculosis and the control group.

• Fourteen (13%) of 111 patients with HIV infection and tuberculosis failed to achieve a virus load of < 400 copies/mL within 6 months of starting HAART, compared with 13 (12%) of 111 persons without tuberculosis (P=.84)

• We prefer a rifabutin-based regimen for six months as first-line therapy in HIV-infected patients who are also treated with PIs because of the extensive interactions between rifampin and many antiretroviral drugs.