HIV infection and pulmonary disease

							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 and
    reactivation
  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.