Pulmonary complication of HIV infection

1
Pulmonary complication of HIV infection

• Josip Begovac
• University Hospital of Infectous Diseases, Zagreb
  Croatia
• HIV/AIDS Curriculum for the Training of
  Infectious Disease Specialists from the Western
  Balkans
• Zagreb, Croatia
• November 3-5, 2006

2
Pulmonary complications of HIV infection- Outline

• Epidemiology and pathogenesis
• Aproach to the patient
• Bacterial pneumonia
• Pneumocystis jiroveci pneumonia (PCP)
• Tuberculosis
• Noninfectious complications of HIV/AIDS
• Pulmonary diseases in the HAART era

3
Rates of opportunistic infections
amongHIV-infected patients with CD4 lt 100
20
CMV MAC PCP
15
Number of opportunistic infections per 100
person-years
10
5
0
1994
1995
1996
1997
Palella et al., New Engl J Med 1998338853-60
4
Effects of HIV in the lung

• Direct infection of pulmonary macrophages and
  lymphocytes
• Progression of HIV infection decreases lung CD4
  T cells
• Intense infiltration of CD8 T cells may occur
  within the lung
• with up-regulation of cytokines
• Defects in humoral immunity lead to impaired
  antigen-specific
• responses
• Viral compartmentalization may occur in lung

Am J Resp Crit Care Med 20011642120
5
Infectious lung complications in patientswith
HIV/AIDS
Curr Opin Pulm Med 200511202
6
Assessment of risk factors forspecific pulmonary
diseases

• Severity of immunosuppression
• Patient demographic characteristics
• Place of current or prior residence
• Use of prophylaxis medications

7
Important history from patient with respiratory
symptoms

• Duration of illness
• Previous illnesses
• COPD/asthma
• Cardiac risk factors

8
Presenting signs and symptoms

• Fever, night sweats
• Weight loss
• Cough present
• Sputum production
• Shortness of breath, dyspnea
• Chest pain
• Orthopnea
• Hypoxemia
• Associated non-pulmonary symptoms

9
CD4 cell count and respiratory tract infections

• Any CD4 cell count
• Upper respiratory tract illness             Upper
  respiratory tract infection (URI)             Si
  nusitis             Pharyngitis
•        Acute bronchitis       Obstructive airway
  disease       Bacterial pneumonia       Tubercul
  osis       Non-Hodgkin's lymphoma       Pulmonar
  y embolus       Bronchogenic carcinoma

10
CD4 cell count and respiratory tract infections

• CD4 cell count lt500 cells/µl
• Bacterial pneumonia (recurrent)
• Pulmonary mycobacterial pneumonia
  (nontuberculous)
• Tuberculosis

11
CD4 cell count and respiratory tract infections

• CD4 cell count lt200 cells/µl
• Pneumocystis jiroveci pneumonia
• Cryptococcus neoformans pneumonia/pneumonitis
• Bacterial pneumonia (associated with
  bacteremia/sepsis)
• Disseminated or extrapulmonary tuberculosis

12
CD4 cell count and respiratory tract infections

• CD4 cell count lt100 cells/µl
• Pulmonary Kaposi's Sarcoma             Bacterial
  pneumonia (Gram-negative bacilli
  and             Staphylococcus aureus
  increased)             Toxoplasma pneumonitis
•       CD4 cell count lt50 cells/µl            Dis
  seminated Histoplasma capsulatum            Disse
  minated Coccidioides immitis            Cytomegal
  ovirus pneumonitis            Disseminated
  Mycobacterium avium complex            Disseminat
  ed mycobacterium (nontuberculous)            Aspe
  rgillus species pneumonia            Candida
  species pneumonia
• Tuberculosis

13
Respiratory tract diseases according to CD4 cell
count
Sinuitis, pharyngitis, bronchitisBacterial
pneumoniaTuberculosis Non-Hodgkin lymphom
Bacterial pneumonia (recurrent)
500
PCPCryptococcus pneumonia Bakterial pneumonia
(bacteremia)Diseminated/extrapulmonary
tuberculosis
CD4 cells
Pulmonary KSToxoplasma pneumonitis
200
MAC, CMV pneumonitisAspergillus i Candida
pneumonia
100
50
10 years
14
Characteristic Chest Radiographic Findings in
Selected HIV-Related Opportunistic Infections and
Neoplasms

• Diffuse or multifocal infiltrates
• Pneumocystis jiroveci     Bacteria     Myc
  obacterium tuberculosis     Fungi     Kaposi's
  sarcoma     Non-Hodgkin's lymphoma     Cytomegal
  ovirus

HIV InSite Knowledge Base
15
Characteristic Chest Radiographic Findings in
Selected HIV-Related Opportunistic Infections and
Neoplasms
HIV InSite Knowledge Base
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Characteristic Chest Radiographic Findings in
Selected HIV-Related Opportunistic Infections and
Neoplasms
HIV InSite Knowledge Base
17
Characteristic Chest Radiographic Findings in
Selected HIV-Related Opportunistic Infections and
Neoplasms
HIV InSite Knowledge Base
18
Characteristic Chest Radiographic Findings in
Selected HIV-Related Opportunistic Infections and
Neoplasms
HIV InSite Knowledge Base
19
Every picture tells a story(look at it yourself
and review with radiologist)
20
Pulmonary complications

• Bacterial pneumonia

21
Case 1
The Medical Management of AIDS, 6th edition, 1999
22
Features of bacterial pneumoniain HIV-infected
patients

• Rate of development is inversely related to CD4
  count
• Risk is significantly increased in injection drug
  users
• Two major differences compared with HIV-negative
  controls
• higher frequency of bacteremia
• higher recurrence rate ? relapse, recrudescence,
  re-infection
• Most common etiologic agents are S. pneumoniae
• and Gram-negative organisms

23
Bacterial pathogens isolated in 111 episodes
ofpneumonia in hospitalized patients with HIV
Community-acquired (n80)
Nosocomial (n31)
Pathogen
Gram-negative Pseudomonas aeruginosa
Haemophilus influenza Klebsiella pneumoniae
Escherichia coli Gram-positive Streptococcus
pneumoniae Staphylococcus aureus
Streptococcus viridans
17 12 1 0 2 12 2 8 1
40 20 10 3 1 31 20 8 2
Chest 20001171017-1022
24
Independent risk factors associated with 585
episodes of pneumococcal disease among
HIV-infected persons
RR (95 CIs)
Characteristic
P value
Injection drug use Black race/ethnicity History
of AIDS-related OI CD4 count lt200
cells/mm3 200-499 cells/mm3 Antiretroviral
therapy (3 drug) Vaccination (CD4 count gt500
cells/mm3)
lt.01 lt.01 lt.01 lt.01 lt.01 .01 .02
1.5 (1.2, 1.9) 1.5 (1.2, 1.9) 2.1 (1.7, 2.5) 3.7
(2.2, 6.3) 2.5 (1.5, 4.2) 0.5 (0.3, 0.9) 2.6
(0.3, 0.9)
CID 200132794-800
25
Annual invasive pneumococcal disease ratesper
100,000 persons age 18-64 years of age
J Infect Dis 20051912038
26
Case 2
The Medical Management of AIDS, 6th edition, 1999
27
Pneumocystis jiroveci pneumonia
JAMA 20012862450-60
28
Gomori methenamine silver stain at high
magnification demonstrates cysts of Pneumocystis
jiroveci in lung
29
Low magnification of Pneumocystis jiroveci in
lung with exudate
30
P. jiroveci pneumonia with reticular infiltrates
and pneumatoceles
The Medical Management of AIDS 6th edition, 1999
31
PCP, age 32.y. CD4 15/mikroL the patient did
not take prophylaxis nor ART
32
P. jiroveci pneumonia with predominatelyupper
lobe reticular infiltrates
The Medical Management of AIDS, 6th edition, 1999
33
PCP, age 42.y. CD4 30/microL newly diagnosed
HIV infection
34
Epidemiology and transmission of Pneumocystis
jiroveci

• Serologic studies demonstrate that infection
  occurs early in life
• Dormancy with reactivation of infection is
  unlikely
• Asymptomatic colonization may occur in
  immunocompetent
• and some immunocompromised individuals
• Person-to-person transmission is possible based
  on limited data
• and one clustered outbreak has now been
  identified

35
Diagnosis of Pneumocystis jiroveci pneumonia
Technique
Sensitivity ()
Specificity ()
DLCO (lt75) HRCT Gallium scanning Sputum
induction BAL Oxygen desaturation
90 100 high 74-83 high 80-100
low low low high high low
The Medical Management of AIDS 6th edition 1999
36
Utility of serum LDH in diagnosis ofPneumocystis
jiroveci pneumonia in HIV infection

• Published reports of sensitivities ranging from
  83 to 100
• Most studies done on hospitalized patients
• Lowest sensitivity reported in ambulatory
  outpatients
• Many studies done prior to use of PCP
  prophylaxis
• LDH is nonspecific for P. jiroveci pneumonia
• Patients with PCP may have a normal or mildly
  elevated LDH
• Strong correlation between serum LDH level and
  prognosis

37
Algorithm for evaluation of patients with
suspected PCP
JAMA 20012862450-60
38
Criteria for empiric Pneumocystis jiroveci
pneumonia therapy

• At risk for P. jiroveci pneumonia
• Not receiving PCP prophylaxis
• Clinical presentation suggestive of PCP
• Mild disease
• Reliable, adherent, tolerate PO intake
• Sputum induction unavailable or low yield

The Medical Management of AIDS 5th edition
1997275-300
39
Treatment of Pneumocystis Pneumonia
Thomas C and Limper A. N Engl J Med
20043502487-2498
40
Use of adjuvant corticosteroid therapy in
treatment of P. jiroveci pneumonia

• Worsening often occurs 3-5 days after start of
  anti-PCP therapy
• Corticosteroids significantly improve gas
  exchange
• Use if PO2 lt 70 mm Hg or alveolar-arterial
  gradient gt 35 mm Hg
• Start early
• Establish diagnosis

41
Drugs for Prophylaxis against Pneumocystis
Pneumonia
Thomas C and Limper A. N Engl J Med
20043502487-2498
42
Mutations at the DHPS active siteof Pneumocystis
jiroveci
JAMA 20012862450-60
43
Approach to clinical failure of PCP therapy

• Review diagnosis
• How was initial dx established?
• Was there concurrent process initially?
• Has another process supervened?
• Review treatment
• Is pt receiving the best PCP treatment?
• Is sulfa resistance possible?
• Is pt receiving adjuvant steroids?
• Is dosing of medication correct?
• Does pt have thrush, nausea, emesis, diarrhea?
• Adequate time for therapy to work?
• Consider further evaluation with bronchoscopy

44
Association of mutation frequency in the DHPS
gene of Pneumocystis jiroveciwith prior sulfa
prophylaxis
JAMA 20012862450-60
45
Association of DHPS gene mutation of Pneumocystis
jiroveci with all-cause mortality
AIDS 200519801
46
ICU admission, mechanical ventilation, and
mortalityin episodes of HIV-related PCP
Number of PCP episodes
Period of study
Mortality ()
Admitted to ICU ()
Mechanical ventilation ()
348 2174 110 257 1660
60 62-46 79 50 62
1985-89 1987-90 1989-94 1990-95 1995-97
6.3 18 100 8.2 14
5.7 31 4.7 9
Thorax 200358721
47
Pneumothorax in HIV infection

• Majority are due to PCP, independently increases
  risk
• of mortality
• 2-7 per 1,000 person-years in AIDS patients
• 1-2 of hospitalized patients with HIV develop
  spontaneous pneumothorax, increases to 4-12 if
• PCP present
• Risk factors include previous and current
  history
• of PCP, use of aerosolized pentamidine, smoking,
• and pneumatoceles

Curr Opin Pulm Med 2001202
48
P. jiroveci pneumonia and pneumothorax
The Medical Management of AIDS 6th edition, 1999
49
PCP Subcutaneus emphysema
50
An algorithm for treatment of pneumothoraxin
patients with HIV
Curr Opin Pulm Med 2001202
51
Tuberculosis- epidemiology in Europe

• In the WHO European Region, where according to
  the most recent WHO estimates, almost 445 000 new
  cases and more than 69 000 related deaths
  occurred in 2004.
• The highest rates of TB are reported in the
  countries of eastern Europe
• The European Region has the highest prevalence
  rates in the world for multi-drug resistant (MDR)
  TB 7 of the 9 countries in the world with gt6.5
  prevalence of MDR-TB in new cases are in the
  Region (Estonia, Israel, Kazakhstan, Latvia,
  Lithuania, the Russian Federation and Uzbekistan)
  
• More frequently found among prisoners than in the
  outside population

52
Epidemiology of TB-HIV coinfection

• In eastern Europe there are independent epidemics
  of TB and HIV/AIDS and a large majority of TB
  patients developed their disease without
  HIV-related immunodepression.
• Prisoners are more vulnerable to becoming
  infected with TB and HIV
• HIV promotes the progression of infection with
  Mycobacterium tuberculosis to active TB (risk of
  developing active TB reaches 510 annually)

53
TB-HIV coinfection

• TB is one of the most common opportunistic
  infections (OI) in HIV-infected people.
• Pulmonary TB (PTB) remains, especially in adults,
  the commonest form of TB,
• The presentation depends on the degree of
  immunosuppression.
• The clinical presentation of TB cases in early
  HIV infection is similar to that of individuals
  without HIV infection, resembling post-primary
  PTB, that is, with positive sputum smears (two or
  more initial smear examinations positive for
  acid-fast bacilli (AFB) or only one plus
  consistent radiographic abnormalities) and often
  with cavities in the chest x-ray.
• The clinical presentation in late cases resembles
  primary PTB the sputum smear is often negative
  and radiological infiltrates are present instead
  of cavities.
• In case of severe immunodeficiency, the rate of
  extrapulmonary TB (EPTB) increases in both adults
  and children. Because of difficulties in
  diagnosis, disseminated TB may account for a high
  proportion of deaths in hospitals.

54
TB risk assessment and diagnosis in PLWHA

• Particular attention should be paid to
• people with respiratory symptoms
• household contacts of anyone with an active case
  of pulmonary TB
• co-existing risk and vulnerability -increasing
  factors (injecting drug use, alcohol abuse,
  incarceration).
• The initial assessment for TB should include
• a history of TB exposure (own and household)
• a history of possibly-related symptoms
  (especially a cough of more than 2 weeks duration
  without any clear explanation).

55
TB risk assessment and diagnosis in PLWHA

• If an HIV-infected person does not have an
  obvious risk of TB (recent exposure or clinical
  symptoms), a tuberculin skin test should be
  performed.
• A positive tuberculin skin test is indicative of
  past or recent TB infection, which is a condition
  for starting TB preventive treatment (TPT). A
  negative tuberculin skin test usually means no
  risk of TB in PLWHA (except those with severe
  immunosuppression).
• The test is usually considered positive in
  HIV-infected people when induration exceeds 5 mm.
  The reaction only shows that the person has at
  some time been infected with M. tuberculosis.

56
Clinical management of TB/HIV in adults and
adolescents

• HIV-infected patients coinfected with TB have a
  higher risk of developing active TB, therefore,
  tuberculosis preventive treatment (TPT) should be
  initiated with Isoniazid, 5mg/kg (300 mg maximum)
  OD for 6 months.

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Active TB, requiring or not requiring ART

• TB treatment in HIV-infected patients is a
  priority and should be started as soon as active
  TB has been diagnosed. Treating TB promptly will
  reduce TB-related mortality and the risk of
  transmission.
• TB treatment regimens consist of two phases
• an initial phase and a continuation phase.
• the duration of the initial phase is two to three
  months
• the duration of the continuation phase is four to
  five months.

60

• Streptomycin instead of ethambutol should be used
  for meningeal TB
• Meningeal and osteoarticular TB might need longer
  than 6 months treatment

61
CD4 cells 113 per microL., 35.y.
62
Mediastinal lymphadenopathy. M. tbc cultured from
sputum, CD4 cells 56 u microL
63
Mycobacterium tuberculosis

• Extrapulmonary
• lymophadenitis, disseminated disease, meningitis

64
Noninfectious complications of HIV/AIDS

• HIV-related lung cancer
• Kaposi sarcoma
• AIDS-related lymphoma
• HIV-related pulmonary hypertension
• Thromboembolic disorders
• More frequent in recent years (except KS)

65
Kaposi sarcoma

• Most frequent tumor associated with HIV
• MSM
• Skin and mucous membrane lesions
• Fever, cough dyspnea chest pain, hemoptysis
• X-ray bilateral central or perihilar chest
  infiltrates, pleural effusions
• Bronchoscopy red or purple endobronchal nodes
• treatment-chemotherapy

66
Human herpesvirus type 8
67
Kaposis sarcoma with several pulmonary
nodulesand subsequent hemorrhage
A
B
The Medical Management of AIDS 6th edition, 1999
68
Pulmonary complications in the HAART era
69
AIDS, 2006201095
70
AIDS, 2006201095
71
Pulmonary complications in the HAART era

• Antiretrovirals
• IRIS (Immune reconstitution syndrome)
• Tumors
• Non-Hodgkin lymphoma
• Primary effusion lymphoma
• Lung cancer
• Pulmonary hypertension

72
Antiretroviral therapy as a cause of respiratory
disease

• First, patients may present with unexplained
  tachypnea and dyspnea in the absence of pulmonary
  pathology. Clinicians must recognize that the
  tachypnea and dyspnea may be caused by
  nucleoside-induced lactic acidosis
• enfuvirtide, or T-20, has been associated with an
  increased incidence of bacterial pneumonias
• abacavir can produce a hypersensitivity reaction,
  with fever, rash, and myalgias. Patients can
  manifest dyspnea (13), cough (27), and
  pharyngitis (13). In approximately 20 of
  patients, pulmonary infiltrates are seen
• antiretroviral agents can produce intense
  immunological reactions (immune reconstitution
  syndromes

73
Immune reconstitution syndrome

• It appears that the patients most likely to
  develop this syndrome are
• patients with low CD4 T-cell counts (e.g. lt 50
  cells/µl)
• high viral loads (gt 100 000 copies/µl)
• good virological response to ART.
• Latent opportunistic infection
• The syndrome may manifest in the first few days
  after the initiation of ART when the viral load
  has fallen but before the CD4 T-cell count has
  increased
• Result of an improvement in qualitative T-cell
  function as CD4 T cells become less activated.
  This improved qualitative T-cell function leads
  to a more robust response against organisms or
  antigens

74

• Immune reconstitution syndrome

75
IRIS- Mycobacterium tuberculosis

• 36 of HIV-infected patients treated with ART
  versus 7 of HIV-infected patients not taking ART
  
• 2-40 days after HAART-a
• particularly likely in patients
• who had a substantial fall in HIV viral load (2.4
  log drop)
• a larger median increase in CD4 T-lymphocyte
  counts
• The timing of ART initiation
• lt6 w 7/13
• gt6 w 1/15

76
IRIS- Mycobacterium tuberculosis

• Clinical
• fever
• Worsening or new lymphadenopathy
• Worsening of CNS lesion
• Worsening of pulmonary infiltrates
• Worsening of pleural effusion

77
IRIS- M. tubeculosis- case report
M. tuberculosis cultured from sputum, CD4 T
cells 10 microL, 144 000 copies/ml. Antituberculou
s drugs started 30.06.2002. HAART
22.07.2002. CD4 T cells (20.08.2002) 187 per
microL, VL 320 copies/ml
Clinical new lymph node after 2 months of
HAART-a
Ches x-ray 30.06.02
78
IRIS- P. jiroveci

• three patients presented with PCP (median CD4
  T-lymphocyte count of 26 cells/µl),
• improved on conventional anti-PCP therapy,
• started ART therapy within 15-18 days of PCP
  diagnosis
• All three developed acute respiratory failure
  within a median of 5 days (range 3-17 days)
• Histopathological findings of alveolar
  inflammatory infiltrate with a few persistent
  Pneumocystis cysts were thought to be consistent
  with an immune reconstitution syndrome
• frequency?

79
IRIS- P. jiroveci case report

• Age 43.g., newly diagnosed HIV infection, CD4 T
  cells 43 u microL, 4 960 000 copies/ml
  (13.01.2005)

PCP cotrimoxsazole steroides
80
IRIS- P. jiroveci prikaz bolesnika

• 5 day of PCP treatment (18.01.2005) HAART
• After 8 days of anti-PCP therapy a good response
  on chest x-ray (21.01.2005)

81
IRIS- P. jiroveci case report

• After 11. days of HAART respiratory distress (16.
  day of PCP therapy)
• CD4 T cells 19 per microL, 76 100 copies/ml
  drop 1.8 log)

82
IRIS- Mycobacterium avium complex

• Lymphadenopathy and fever
• Pulmonary infiltrates
• low CD4 cell count

83
IRIS- Mycobacterium avium complex-case report)

• Age 45.y., CD4 cell 8 per microL, 62 500
  copies/ml (29. 08. 2002), HAART and
  PCP-prophylaxis given
• Fever 1.10.02 (39 C)

84
IRIS- Mycobacterium avium complex (case report)
CD4 cels after 6 w of HAART 105 per microL, lt50
copies/ml
Chest x-ray after 6-w of HAART
85
IRIS- Mycobacterium avium complex (case report)

• After 1 monts bronchoscopy was performed M.
  avium complex resistant to streptomycin,
  isoniazid, piyazinamide, ethambutol and
  ciprofloxacin.
• Treated with 12 azithromycin (625 mg/dan) and
  rifampin for 12 months

Chest X-ray after 1 months
86
Non-Hodgkins lymphoma
The Medical Management of AIDS 6th edition, 1999
87
Non-Hodgkins lymphoma and the lung

• Typically high-grade of B-cell origin
• Approximately one-third of patients have thoracic
  involvement
• Pleural effusions most common thoracic
  manifestation,
• usually with parenchymal involvement
• Pleural fluid cytology may have better diagnostic
  yield in
• HIV-infected patients

88
Non-Hodgkins lymphoma

• second most common HIV-associated malignancy
• HL occurs in patients at all CD4 T-lymphocyte
  counts, although the relative risk of NHL is
  higher at lower CD4 T-lymphocyte counts
• present with cough (71) and dyspnea (63)
• The chest radiographs usually demonstrate
  isolated or multiple peripheral nodules. In a
  case series of 38 patients pleural effusions
  occurred in 68 and thoracic lymphadenopathy in
  54 of the cases
• Diagnosis pleural cytological study,
  transbronchial biopsy, percutaneous transthoracic
  needle biopsy or open-lung biopsy
• aggressive chemotherapy possible in the HAART era

89
Primary effusion lymphoma

• Associated with HHV 8
• Pleural effusions are the most common
  manifestations peritoneal and pericardial
  effusions also occur.
• CD4 T-lymphocyte cell counts are usually less
  than 150 cells/µl, but can range from 2 to 291
  cells/µl.
• Diagnosed by cytology or biopsy. The detection of
  HHV-8 by in-situ hybridization or in-situ
  polymerase chain reaction provides supportive
  evidenc.
• Very poor prognosis

90
Clumps of round to ovoid malignant lymphatic
cells with abundant basophilic
cytoplasm in pleural sediment (MGG stain, x100)
Highly irregular nuclei with multiple, prominent
nucleoli (MGG stain, x1000
Vince A., et al Acta Cytol 200145420
91
Lung cancer in persons with HIV infection

• Increased incidence of lung cancer in persons
  with HIV
• (2- to 10-fold)
• Majority have smoking as risk factor
• Disease occurs at younger age
• More aggressive locally and metastatic disease
• Poor response to therapy

92
Pulmonary arterial hypertension related to
HIV(PAHRH)

• Incidence of PAHRH is approximately 0.5, which
  is 2,500 times greater than that of PPH in
  general population
• Pathogenesis unclear
• no HIV within pulmonary artery endothelial cells
• chronic immune stimulation causes release of
  proinflammatory cytokines and growth factors
• underlying individual susceptibility likely

93
Benefit of HAART in survival of patientswith
pulmonary hypertension related to HIV
Clin Infect Dis 2004381178