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Pulmonary Infections/Complications in HIV patients Module
Created by Peggy Beeley, MD
Objectives:
1. Name the most common pulmonary infections and complications in the setting of
HIV.
2. Learn strategies for diagnosing common pulmonary conditions in HIV.
3. Learn generalities for empiric treatments for the most common pulmonary infections in
this patient population.
References:
1. NHLBI Workshop summary, NIH Bethesda, Maryland
Pulmonary Complications of HIV Infection
Am J Respir Crit Care Med Vol 164. pp 2120-2126, 2001
2. Wolff, A, et al. HIV-related pulmonary infections: a review of the recent literature
Current Opinion in Pulmonary Medicine 2003, 9:210-214
3. Turner, D, et al. Induced sputum for diagnosing Pneumocystis carinii pneumonia in
HIV patients: new data, new issues. Eur Respir J 2003;21: 204-206
4. Mandell, Douglas and Bennett’s Principles and Practice of Infectious Diseases, Sixth
Edition
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Pulmonary Complications of HIV Infection
I.
II.
III.
IV.
Incidence of opportunistic infections have drastically dropped since HAART
therapy has improved survival and helped maintain good health in persons
living with HIV.
Pulmonary Disease in HIV continues to be the leading cause of morbidity and
mortality in this group.
Pathogenesis of Pulmonary Disease in HIV
a. HIV infects, destroys and depletes T-cells, leading to impaired cellular
immunity. This occurs throughout the body but seems to have a particular
impact on the lung and protection against infections of the lung.
b. HIV infection leads to defects in humoral immunity.
i. Ability to generate antigen-specific responses is impaired.
ii. May be due to impaired ability of HIV-infected T cells to activate
B Cells.
iii. Accounts for increased number of bacterial pneumonias.
c. Immunological Reconstitution
i. Occurs when Highly Active Anti-retroviral Therapy (HAART)
leads to an increase in population of memory and naïve T cells.
ii. Some patients develop a granulomatous disorder that resembles
sarcoidosis.
iii. Others with latent or active mycobacterial infections may develop
fever, lymphadenopathy and opacities on chest x-ray.
Differential Diagnosis
a. This is not an all inclusive list but rather lists the more common etiologies
of infection and lung disease in HIV positive patients.
b. Pneumocystis jirovecii
i. Often still abbreviated as PCP, but will now use PJP.
ii. Will be discussed separately.
c. Community Acquired Bacterial Pneumonia
i. HIV positive patient have 100 fold higher risk of bacterial
pneumonia than persons not infected with HIV.
ii. Most common:
1. Streptococcus pneumoniae
2. Staphylococcus aureus
3. H influenzae
iii. Less Common: Enterobacteriaceae, Pseudomonas aeruginosa,
Moraxella catarrhalis, Group A streptococcus, Nocardia species,
Legionella species, Rhodococcus equi, and Chlamydia
pneumoniae.
d. Mycobacterial Pathogens
i. M. tuberculosis (major player in HIV in the developing world)
ii. M. kansasii (most common of the non-tuberculous mycobacterium)
iii. M. avium complex (more commonly causes disseminated; and
other mycobacterium are less common causes of pneumonia.
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e. Viral Pneumonia
i. Most Common: Influenza virus
ii. Less Common: Cytomegalovirus, Herpes simplex virus,
Adenovirus, Respiratory syncytial virus, Parainfluenza virus
f. Fungal Infections include (in relative order of frequency): Cryptococcus
neoformans, Histoplasma capsulatum, Coccidioides immitis, Aspergillus
species, Blastomyces dermatitidis, Penicillium marfeneffei
g. Parasitic Diseases: Toxoplasma gondii, Strongyloides stercoralis
h. Neoplasms: Kaposi’s sarcoma, Lymphoma, Lung Cancer
i. Other pulmonary processes seen in normal persons, PE, CHF, COPD, etc.
V.
Relative Importance of the most common pathogens.
a. Prospective Study designed to identify etiologic agents in HIV infected
patients by Rimland, et al. in Atlanta studied 230 patients.
i. Causative organism was identified in 67%.
1. PJP in 36% of these.
2. 35% due to Streptococcus pneumoniae.
3. 28% due to Haemophilus influenzae.
4. Only 3.7% were “atypical” organisms and were in the
presence of a second pathogen.
5. Mycobacterium tuberculosis accounted for 6.2%.
ii. 95% of those without a causative organism were deemed as
probable bacterial processes.
VI.
Initial Clues to the Diagnosis.
a. General Rules:
i. Rule 1: Clinical or laboratory findings are not reliable features to
make a diagnosis with the exception of microbiologic evidence.
ii. Rule 2: Finding one pathogen does not exclude a second pathogen.
iii. Rule 3: Early respiratory isolation of HIV patients with respiratory
symptoms or pulmonary findings is important in reduction of
hospital acquired tuberculosis.
b. HIV staging
i. PJP is much more likely if CD4 is < 200.
ii. If CD4 count is unknown, thrush, hairy leukoplakia (this finding is
how HIV infection is recognized in some African countries that
can not afford serology) and weight loss may act as clinical
markers of a poor immune system.
iii. Some infections, i.e. bacterial pneumonia and tuberculosis may
occur with relatively preserved CD4 counts.
iv. All infections and complications occur with more frequency in
advanced HIV disease.
c. Acute versus Sub-acute presentation
i. Bacterial or viral pneumonias seem to display an abrupt onset and
present within days of onset of symptoms. Bacterial pneumonia
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d.
e.
f.
g.
VII.
may have more prominent sputum production or pleuritic chest
pain.
ii. PJP and TB tend to have a gradual progression of symptoms and
often present after weeks of symptoms. But either can present with
a more fulminate course, including ARDS-like picture.
Local epidemiology or past residence
i. Coming from or living in an area of high prevalence leads to
higher suspicion of infection, i.e. Tuberculosis.
ii. Past residence or travel are important clues to determine risk for
fungi, i.e. Coccidioides or Histoplasma.
IVDU increases the risk for bacterial pneumonias including Staph aureus.
Receipt of PJP prophylaxis, especially Bactrim dramatically reduces risk
for PJP.
Generalizations of radiographic findings.
i. Diffuse interstitial infiltrates
1. More likely to be PJP
2. May also be seen in many other processes including TB
and occasionally H influenzae.
ii. Consolidation
1. More likely to be bacterial or TB.
2. M also be an atypical presentation of PJP.
iii. Cavitary Lesions
1. Tuberculosis, although often HIV patients have primary
disease or atypical presentations of TB reactivation.
2. Fungi, nocardia, PJP, MAC and even bacterial pneumonia
may present with cavities.
iv. Normal Chest X-Ray
1. Seen in 10% of PJP and TB infections in HIV positive
patients.
Pneumocystis jirovecii, formerly P. carinii (a special pathogen)
a. Microbiology and Epidemiology.
i. In vitro culture is not reliable, thus scientific investigation is
limited in the laboratory.
ii. Unicellular fungi.
1. Unusual because it lacks ergosterol in its plasma
membranes (antifungals do not work).
iii. Remains the most common AIDS-defining indicator condition.
iv. First described in malnourished and premature infants in central
and Eastern Europe after World War II.
v. Pneumocystis is host species specific.
1. First recognized in rats by Dr. Carini, P. carinii was
initially presumed to be the causative agent of human
infection by an indistinguishable microscopic appearance.
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vi.
vii.
viii.
ix.
VIII.
2. Correction of the taxonomy to reflect the human infecting
species occurred in 2002, thus P. jirovecii
Person-to-person transmission is assumed but unproven.
Studies of recurrent PJP by genotyping have shown that 50% of
cases were infected with strains of a different genotype, suggesting
that patients are often infected with new strains rather that
reactivating latent infections.
CD4 T cell are required to clear P.jirovecii and alveolar
macrophages participate in defense against P. jirovecii.
Surfactant proteins have been implicated in the pathogenesis,
leading to microatelectasis, decreased lung compliance.
Work-up of pulmonary findings in HIV patients.
a. CBC with differential – toxic granulocytes and left shift suggestive of
bacterial process.
b. Blood cultures
c. Chest x-ray – PA and lateral instead of portable if at all possible.
d. Oxygen saturation at rest and with exercise. PJP patients may have normal
resting saturation but a significant drop after exercise. Often used
clinically but not specific.
e. Arterial Blood Gas
i. A-a gradient is may be very elevated and if > 30 mm Hg is a
predictor of poor outcome.
ii. Use of A-a gradient provides perimeters for adjunctive
corticosteroids.
f. Sputum for gram stain, acid fast stains and cultures; requires an adequate
specimen.
g. LDH – tends to be elevated in most PJP infections.
h. Induced Sputum for PJP and TB.
i. Uses aerosolized isotonic saline to “induce” cough and sputum.
ii. This procedure is a common practice in most institutions for
diagnosis of PJP.
iii. Sensitivity varies widely depending on the experience of the
respiratory therapist and center. Overall sensitivity from all studies
is 55%.
iv. Since this is a non-invasive test, it would seem that it would it
would be cost effective. A cost-analysis study on PCR technique
showed that induced sputum was actually more costly than BAL in
a low prevalence population.
i. CD4 counts and HIV viral loads are not very helpful in acute illness.
i. CD4 counts may be only transiently low and viral loads transiently
high in this setting.
ii. The values may not reflect the true status of the immune system.
j. Tuberculin Skin Testing (TST, PPD)
i. Only helpful if positive.
ii. A negative test is not uncommon in disseminated disease.
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k. Bronchoscopy and BAL
i. Used less frequently than in the past.
1. Many centers have high induced sputum yield for PJP.
2. Observed improvement with empiric treatment leads to
presumptive PJP diagnosis.
ii. Remains the highest yield procedure to isolate causative
pathogens. Most sensitive test for PJP.
iii. Needed for visualization and confirmation of suspected Kaposi
sarcoma.
l. Biopsy: Trans-bronchial, Trans-thoracic and Open Lung.
i. Reserved for cases in which initial diagnostic steps have failed to
find cause or the patient is failing empiric therapy.
ii. Biopsy is required to establish invasive infection of
cytomegalovirus and aspergillus (both of these may be respiratory
tract colonizers)
m. High Resolution CT of the Chest
i. Shows subtle findings not evident on chest x-ray
ii. If normal, PJP is very unlikely
n. Gallium Scan: Negative study helps rule out PJP, not often used.
o. Serum Cryptococcal antigen and urine Histoplasmosis antigen may be
helpful in disseminated disease.
IX.
Empiric Treatment
a. This is an only an overview. Please see other sources, i.e. Sanford’s guide
for details of dosing and alternative treatments.
b. Community Acquired Pneumonia
i. Coverage of Streptococcus pneumoniae and Haemophilus
influenza is of the utmost importance.
ii. Cefotaxime or Ceftriaxone is generally the preferred empiric
choice.
iii. Or a flouroquinolone with extended S. pneumococcus coverage,
i.e. Levaquin. (caution: failures have been reported in patients with
persistent bacteremias/endocarditis)
iv. If illness is severe, both a 3rd generation cephalosporin and a
macrolide or flouroquinolone are warranted.
v. If your community has a high rate of resistant S. pneumococcus,
Vancomycin may need to be added.
vi. If the patient has a prior history of bronchiectasis or pseudomonas
infections, use anti-pseudomonal B-lactam, i.e. Zosyn or Cefepime
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Empiric Treatment, continued
c. Pneumocystis jirovecii
i. Trimethoprim-sulfamethoxazole (15-20mg TMP plus 75-100mg
SMX) kg/day IV given q 6 or 8 hours
ii. Or for less severe disease TMP/SMX 2 double strength tablet po
TID.
iii. Duration of treatment should be 21 days.
iv. Alternatives include Pentamidine 4mg/kg IV q day or other multidrug regimens.
v. Prednisone should be started if PaO2 < 70 mm Hg or A-a gradient
> 35 mm Hg.
d. Other suspected organisms - firm diagnosis is preferred.
Case Presentation
CHIEF COMPLAINT:
Shortness of breath.
HISTORY OF PRESENT ILLNESS:
Mr. X is a forty-three-year-old male with a history of advanced acquired immune deficiency syndrome
and noncompliance with HAART and prophylactic treatments who presents with a complaint of cough
and shortness of breath. He has recently had a progressive decline in his health. His last CD4 count of 7
was noted one month ago.
The patient comes to the Emergency Department complaining of worsening shortness of breath for the
past few weeks, He has an associated cough productive of reddish yellow sputum. The patient denies
chest pain, fever, weakness or numbness, headaches, vision changes, sick contacts. He has not found
anything to relieve his symptoms other than partial relief with no activity.
The patient denies incarceration, past tuberculosis diagnosis, past PPD positivity or contacts of persons
known to have tuberculosis.
PAST MEDICAL HISTORY:
1.
Advanced acquired immune deficiency syndrome diagnosed 7 years ago, multiple resistant
viral profile on genotype and phenotype testing.
2.
Chronic noncompliance with HAART and prophylaxis.
3.
Depression
4.
Oral thrush with possible candidal esophagitis.
5.
History of PJP.
6.
Herpes zoster.
7.
Hypotension with an admission workup of adrenal insufficiency last year. Cortsyn stim test was
normal.
ALLERGIES: No known drug allergies
CURRENT MEDICATIONS – OUTPATIENT:
The patient has been noncompliant with his medications, specifically stopping some medications “weeks
ago”. The barriers to his taking medications have been explored but remain unclear as the patient is not
forthcoming with his reasoning.
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Not taking Dapsone 100 mg by mouth every day, fluconazole 400 mg by mouth every day, or azithromycin
1200 mg by mouth every week.
Intermittent use of the following:
Fosamprenavir 700 mg by mouth twice a day, Tenofovir 300 mg by mouth every day, abacavir 300 mg by
mouth twice a day and Ritonavir 100 mg by mouth twice a day. Oxycodone 500 mg by mouth as needed
for pain and Boost for malnutrition are intermittently used.
FAMILY HISTORY:
The patient does not know family history.
SOCIAL HISTORY:
Ten-pack-year history for tobacco. In the past, he drank “a lot” of alcohol but currently denies drinking.
Denies history intravenous drug use or other illicit drugs.
The patient is intermittently homeless but currently lives alone in a motel and works at the front desk for a
few hours a week for his room and board.
REVIEW OF SYSTEMS:
GENERAL: Negative for any vision changes or headaches. He has night sweats but no fever.
Head and Neck: Reports difficulty with swallowing. The patient denies any nasal discharge or ear pain.
CHEST: See HPI
CV: Denies palpitations or exertional chest pain.
GASTROINTESTINAL: Denies abdominal pain, black tarry stools, bright red blood per rectum or
diarrhea.
GENITOURINARY: Denies painful urination, increased urinary frequency or urgency.
EXTREMITIES: negative for edema.
PHYSICAL EXAMINATION:
VITAL SIGNS: T currently 36.3, T-max 36.3, blood pressure 85/56, heart rate 117, respiratory rate 32,
oxygen saturation 95% on 5 liters NC.
GENERAL: The patient appears malnourished, alert and oriented x two. Does not know the date.
HEENT: Negative for nasal discharge. Positive for copius white-colored coalesced patches of tongue,
palate and oral mucosa.
NECK: negative for lymphadenopathy, negative for thyromegaly.
CARDIOVASCULAR: Normal-sinus tachycardia. No murmurs, rubs or gallops.
LUNGS: Decreased breath sounds bilaterally with no wheezing, rhonchi or rales appreciated. No
retractions.
ABDOMEN: Normal bowel sounds. He has no hepatosplenomegaly and has a nontender and nondistended
abdomen.
EXTREMITIES: No edema, no erythema.
SKIN: No rashes are appreciated.
LABORATORY:
On admission: WBC count 7.3 with left shift and toxic neutrophils, hemoglobin 10.7, hematocrit 31,
platelet 185. Sodium 142, potassium 4.0, chloride 107, bicarb 21, BUN 29, creatinine 1.1, glucose 88.
MCV 105, Total proteins 8.5, albumin 3.1, AST 27, ALT 9, alkaline phosphatase 240, total bilirubin 2.3,
indirect bilirubin 0.7, direct bilirubin 1.5, lipase 347, LDH 456. ABG showed pH of 7.41, CO2 of 35, O2
of 93 and bicarb 22.
Chest x-ray showed a right upper lobe density and a bilateral diffuse infiltrates.
CD4 count of 9 when checked about 4 months ago. Although ordered several times, he has not had his
blood drawn recently.
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Past workup for hepatitis B, hepatitis C, hepatitis A, RPR, toxoplasmosis, toxoplasmosis IgG, cryptococcus
antigen, histoplasmosis and CMV antigenemia were all within normal limits. Mycobacterium Avian
Complex blood culture negative about 3 months ago.
Based on the patient presentation, what are your thoughts as to the most likely diagnoses?
Given his low CD4 count you would be concerned about both common infections and other opportunistic
infections. The slow onset of his symptoms and gradual worsening of his dyspnea suggest PJP. However,
community acquired pneumonia, mycobacterial infections (tuberculosis and non-tuberculous
mycobacteria), fungal infections and neoplasms i.e. Kaposi’s must be considered. In favor of CAP is the
sputum production, left shift and toxic neutrophils. His homelessness and upper lobe density would make
you think about TB.
What medications were being prescribed to prevent infections and how effective are they?
Dapsone is the agent that was to be used for prophylaxis against Pneumocystis jirovecii; He was not taking
this medication putting him at high risk for PJP infection. Although some studies have shown similar
efficacy to trimethoprim-sulfamethoxazole (Bactrim double strength), dapsone is still considered a second
line agent. Bactrim has the added benefit of protection from reactivation Toxoplasmosis. Azithromycin has
been found to be effective at preventing disseminated MAC infection by several studies. It is used in
patients with CD4 < 50 who are at highest risk for developing disseminated MAC.
What would you do to pursue the diagnosis?
Respiratory isolation is important to initiate while working up this patients condition. Blood cultures and
sputum for bacteria and AFB studies would be important. TST might be useful if positive. Although,
induced sputum for PJP could be attempted, lack of finding this organism would not be reassuring or
exclude the diagnosis. A chest CT could give additional information that would provide more clues to the
possible diagnosis. Bronchoscopy with BAL would be the study to most likely reveal the cause of his
illness.
What treatment, if any, would you begin now?
Treatment for community acquired pneumonia and even empiric therapy for PJP would be reasonable. If
bronchoscopy guided BAL is being considered, PJP can usually be recovered from secretions up to three
days after therapy is begun.
Description of initial workup, treatment and eventual findings.
1.
Acquired immune deficiency syndrome infectious workup included: UA and urine culture, urine
histoplasmosis antigen, serum cocci antibody, sputum culture, blood cultures before antibiotics,
sputum cultures before antibiotics, sputum AFB x three, and PPD.
2.
Placed on respiratory isolation.
3.
Empiric therapy for possible Pneumocystis jirovecii pneumonia and community-acquired
pneumonia was started and included IV Bactrim, prednisone, ceftriaxone and doxycycline.
4.
Despite a brief ICU admission, he improved and was prescribed bactrim and prednisone to
complete a 21 day course as an out-patient for presumptive PJP.
5.
He returned to clinic 2 weeks later and no longer had respiratory symptoms but remained noncompliant with his HIV medications.
6.
One month later 2 AFB cultures from sputum grew MAC. These were believed to be due to MAC
colonization as he was asymptomatic.
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Question 1
A 25 yo female with known HIV and a low CD4 count of 50 is admitted for hypoxia, cough and fever that
has gradually worsened over the past 3 weeks.
Which of the following is true regarding the workup for Pneumocystis jirovecii?
1. The normal appearing chest x-ray is inconsistent with Pneumocystis jirovecii infection.
2. Induced sputum is a reliable means of diagnosing PJP and has a sensitivity of greater the 90% for
detecting PJP.
3. A CD4 of 300 essentially excludes the diagnosis of PJP.
4. None of the above.
Correct answer is #4, none of the above.
Explanation:
Answer 1 is false because the Chest X-Ray can appear entirely normal (in 10%) or classically as a “batwing” or “CHF-like” diffuse process or as a number of more atypical patterns.
Answer 2 is false. Although some studies show that the sensitivity of induced sputum for PJP can be as
high as 95% in the hands of a highly experienced respiratory therapist in a high prevalence population the
yield is lower in most institutions. Often empiric therapy or bronchoscopy targeted BAL is required for
diagnosis. In one prospective study by Miller et al, (Journal of Infectious Diseases 1991) the sensitivity of
induced sputum for the diagnosis of P. [carinii] was 13% and of BAL was 77%.
Answer 3 is false. Although the vast majority of cases of PJP do occur at CD4 counts less than 200
cells/mm3, there are plenty of confirmed cases up to 400 cells/mm3 and rare cases to 500 cells/mm3.
Question 2
37 yo male with known HIV, but no medical care, presents with weight loss, fever and cough. A CXR
reveals a right upper lobe cavitary or cystic appearing lesion.
Which of the following statements is false?
1. Travel history and social history is important to determine risk factors for potential diagnoses.
2. Patient should be placed in respiratory isolation as soon as possible.
3. CXR findings are not consistent with Pneumocystis jirovecii.
4. Mycobacterium avium and other non-tubercular mycobacterium can present with the described x-ray
findings.
Correct answer is #3
Explanation:
Answer 3 is correct because there are numerous atypical patterns of PJP on x-ray, including localized
infiltrates, notably of the upper lobes, in patients who fail to respond to aerosolized pentamidine
prophylaxis. It may also present as cavitary lesions, solitary lung nodules, spontaneous pneumothoraces
and pleural effusions. Lymphadenopathies causing hilar or mediastinal enlargement are very rare and are
usually linked to lymphoma and concomitant infections including mycobacterium.
Answer 1 is true. Obviously travel history and social history are very important in determining risk for
individual infections in HIV patients. TB is an infection that should be recognized as soon as possible.
Travel or residency of endemic areas of multi-drug resistant TB should be noted to establish the best
treatment regimens. Burkholderia pseudomallei (melioidosis) is seen primarily in the south pacific and
resembles tuberculosis. Rhodococcus equi and Nocardia may occur with soil and animal exposure and may
have similar appearance.
Answer 2 is true. All patients with upper lobe processes should be placed in respiratory isolation. Some
experts argue that all HIV patients with pulmonary infiltrates or respiratory symptoms should be placed in
respiratory isolation until TB is ruled out.
Answer 4 is true because mycobacterial infections, other than TB, can present in a similar fashion.
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Post Module Evaluation
Please place completed evaluation in an interdepartmental mail envelope and address to
Dr. Wendy Gerstein, Department of Medicine, VAMC (111).
1) Topic of module:__________________________
2) On a scale of 1-5, how effective was this module for learning this topic? _________
(1= not effective at all, 5 = extremely effective)
3) Were there any obvious errors, confusing data, or omissions? Please list/comment
below:
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
4) Was the attending involved in the teaching of this module? Yes/no (please circle).
5) Please provide any further comments/feedback about this module, or the inpatient
curriculum in general:
6) Please circle one:
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