A HIV-infected patient has cough, fever, and sputum production for 4 days. A chest x-ray shows a left lower lobe infiltrate, the WBC is 4,200/mm3 and a CD4 count is 150/mm3. He takes no medication. The most likely

microbial pathogen is :

a. S. pneumoniae b. Mycobacterium tuberculosis c. Rhodococcus equii d. P. carinii e. Cryptococcosis

Approach to HIV-infected patient with respiratory symptoms

The most common AIDS defining complications are:1 -Bacterial pneumonia

Risk factors: Prior PCP Low CD 4

IDUPIs use is associated with decreased incidence of

bacterial pneumonia2 -pneumocystis jirovecii pneumonia

Non infectious causes MalignancyKaposi`s sarcoma, lung cancer, NHL, primary effusion lymphomaPulmonary diseaseCOPD, organizing pneumoniacardiac

CHF, primary pulmonary hypertensionothersSarcodosis, drug hypersensitivity ( Abacavir), Lymphocytic interstitial pneumonitisIRIS

Clinical assessment

*History -the duration of symptoms

-smoking (bacterial pneumonia)-IDU(bacterial pneumonia and TB) -clues to B cell dysfunction increased risk of

encapsulated organisms such as S.pneumniae and H.influenzae

-PCP prophylaxis -use of ART

-local epidemiology and past residency TB and endemic fungi

-Exposure to potential sources of TB-

Physical examinationDiagnostic clues include

*fundoscopy : viral , fungal and TB *skin lesions : cryptococcus

*lymphadenopathy : TB vs lymphoma

Diagnostic workup

Laboratory tests*CBC :neutropeniapseudomonus

*LDH: PCP, TB, toxoplasmosis and lymphoma*blood culture and urinary Ag for S.pneumoniae

The rate of pneumococcal bacteremia is 60%*sputum studies

*cryptococcal antigen *urine and blood testing for histoplasma

polysaccharide capsule*PPD

Physiologic studies*ABG or pulse oximetry before and after exercise

*Diffusing capacity for carbon monoxide PCP low DLCO before the development of chest

infiltrate and resting hypoxemiaDLCO <80% of predicted in symptomatic patient+/-

abnormal CXR further testing

CD4 count*any CD4: sinusitis, bronchitis

*CD4 >500 : TB and bacterial pneumonia and HHV-8 related Kaposi's sarcoma

*CD4 <200 :PCP, CMV and disseminated fungal infections

*MSM : progressive Kaposi`s sarcoma in late stage of HIV

Radiologic tets

Chest X RayPCPTypical: bilateral airspace infiltrates

 other findings: nodular densities, lobar consolidation, cystic lesions, upper lobe opacities, and pneumothorax or normal CXRTBCD4>200 typical TB patternCD4<200 normal CXR or primary pattern

Bacterial pneumoniaLobar or segmental opacities +air brocnhogram in patient with CD4>200

PCPTB

CT scan of the chest-more sensitive than CXR in detecting

lymphadenopathy, interstitial infiltrate & nodulesNuclear scan

*gallium citrate lung scanning : highly sensitive for PCP but not specific.

*Kaposi's sarcoma is positive on Thallium-201 scans but negative on Gallium citrate scansPET scanFalse positive results in patient with high HIV RNA level

Endemic fungi

(and MAC)

Normal CXRTB

PCP

Invasive testingFiberoptic bronchoscopy

-The procedure of choice for diagnosing pulmonary disease in HIV patients (PCP, TB , fungal and viral)

-It also used to obtain transbronchial lung or mediastinal lymph node biopsy

-in bacterial infection* protected BAL is recommended

* semi-quantitative culture of collected specimen

CT guided TTNA-it has high yield in diagnosing the cause of peripheral

nodules and localized infiltrate-not widely used

* small size of the samples limits the number of studies that can be performed

* lower diagnostic yield than FOB in interstitial diseases*higher complication than FOB

Surgical lung biopsy-it has the greatest sensitivity in patient with parenchymal

lung disease-indications

* nondiagnostic bronchoscopy* failed medical therapy after a diagnostic bronchscopy

*Failed empiric therapy after nondiagnostic bronchoscopy

*occurs at any CD4 count*recurrent pneumonia is considered as AIDS defining condition

*TMP/SMX and pneumococcal vaccine *risk factors

- smoking- IDU

- lower CD4 count - lack of ART

- chronic viral hepatitis*mortality increased with

- advanced immunodeficiency- shock

-radiographic progression on therapy

Most frequently identified organisms-typical

Pneumococcal H.Influenzae (subacute illness with interstitial infiltrate that mimic PCP)

-atypical organismsOther organisms

-pseudomonus aeroginosa* neutropenia

* prior use of chephalosporins* CD4<50

-staph aureus (including MRSA)

NocardiaRelatively rare??

Subacute or chronic infection with cavitaionDisseminated disease with +ve blood c/s in advanced HIV

Rhodococcus equiGram positive coccobacilli, weakly acid fast

-fever , cough , fatigue and weight loss-other site of involvement

-chest X ray: unilobar nodularr infiltrate or consolidation with cavityOr pleural effusion

-diagnosis: blood culture histopathology

•treatnment

Indication of hospitalization-CD4<200

-high PSI in those with CD4>200Empiric Outpatient Therapy (Oral) Preferred Therapy :

1-oral B-lactam + a macrolide Preferred B-lactams: high-dose amoxicillin or amoxi/clav

Alternative B-lactams: cefpodoxime or cefuroxime2-fluroquinolones

Alternative therapy:doxcycyclin+beta lactam

**duration of therapy

Empiric Therapy for Non-ICU Hospitalized Patients Preferred Therapy :

1 -IV B-lactam + a macrolide Preferred beta-lactams: ceftriaxone, cefotaxime, or ampicillin-sulbactam

2 -IV fluoroquinolone

Alternative Therapy : IV beta-lactam + doxycycline

IV penicillin may be used for confirmed pneumococcal pneumonia

Empiric Therapy for ICU Patients Preferred Therapy :

IV B-lactam + IV azithromycin IV B-lactam + (levofloxacin or moxifloxacin)

Preferred B-lactams: ceftriaxone, cefotaxime, or ampicillin-sulbactam Alternative Therapy :

For Penicillin-Allergic Patients: Aztreonam (IV) + an IV respiratory FQ

Empiric Therapy for Patients at Risk of Pseudomonas Pneumonia Preferred Therapy :

IV antipneumococcal, antipseudomonal B-lactam + FQ Preferred B-lactams: pip-taz, cefepime, or carbapenem

Alternative Therapy : *IV antipneumococcal, antipseudomonal B-lactam + an

IV aminoglycoside + IV azithromycin * IV antipneumococcal, antipseudomonal beta-lactam +

an IV aminoglycoside + an IV antipneumococcal fluoroquinolone (moxifloxacin or levofloxacin)

For Penicillin-Allergic Patients :Replace the beta-lactam with aztreonam

Empiric Therapy for Patients at Risk of Staphylococcus aureus Pneumonia: Vancomycin IV or linezolid (IV or PO) should be added to the baseline regimen Although not routinely recommendedThe addition of clindamycin to vancomycin (but not to linezolid) may be considered for severe necrotizing pneumonia to minimize bacterial toxin production

•PCP

PCP

-lack ergosterol in its plasma membrane-Mode of infection

1-inhalation2 -transplacental (few reports)

3 -person-person spreadEvidence??

-enviromental sampling-HCW

*infection can lead to colonization mild upper respiratory symptoms

Risk factors for colonization-immunosuppression status

-immunosuppressive therapy(steroids or TNF inhibitors)

-COPD-pregnancy

-smokingClinical significance of colonization

-increase risk of developing pneumonia-trigger inflammation leading to COPD

-patient on prophylaxis may develop drug resistance

-risk factors for PCP in HIVCD4<200 or CD4 cell percentage<14previous episodes of PCPOral thrushRecurrent bacterial pneumoniaUnintentional weight lossHigh HIV RNA

-Mechanism of PCP development*reactivation of latent infection

* exposure to PCP

Presentation-non specific and can mimic wide variety of infections

-5-10% are asymptomatic-Typical presentation

Others: fatigue, chills, chest pain and weight loss-hemoptysis is uncommon

ExaminationHypoxia:

mild :pO2 ≥70 mm Hg or A-a gradiant <35mmHg moderate: A-a 35-45mmHg

severe: A-a >45mmHgChest exam: normal or fine end inspiratory crackles

Laboratory test-ABG hypoxia

Wide a-a gradiant-LDH: high level reflect lung damage

increasing level in patient on therapy indicate poor prognosisDD of high LDHHistoplasmosisMulticentric castleman diseaselymphoma

CXRearly : normal late: confluent alveolar shadwing with sparing of

costophrenic angels and apices classical : bilateral diffuse interstitial infiltrate extending

from perihilar regionAtypical: unilateral infiltrate

nodules or cysts mediastinal lymphnodes

effusion pneumothorax

Typically, ground glass opacity CT chest :nuclear studies :

gallium 67 citrate diffuse intense bilateral uptake

Extrapulmonary PCP

-advanced HIV with no prophylaxis or on aersolized pentamidine

-incidental finding vs rapidly progressive disease-presentaion:

*rapidly enlarging thyroid*pancytopenia 2nd to BM necrosis

*retinal cotton wool spots*multiple hypodense lesions in the spleen

Other sites: LN , liver, adrenal and kidney-histopathology: area of necrosis filled with foamy

materials

diagnosis

-Definitive diagnosis: histopathology or cytology

-clinical suspicionCompatible clinical picture + ground glass opacities on CXR BAL or induced sputum

-normal CXRHRCT, if Normal exclude PCP-normal CXR PFT

If DLCO >75% rule out PCPIf DLCO <75 % continue diagnostic work up

Specimen collectionNon invasive :

induced sputum ( 50-90 % sensitivity)Endotracheal aspirate (92% Sensitivity )Invasive

*** BAL (90% sensitivity)Transbronchial biopsy : not routinely recommendedOpen lung biopsy: if BAL is not diagnostic

to diagnose other infection or condition

to diagnose complicationVATS

*Grocott methenimine silver or its variant (toludine blue O, cresyl violet)*Calcoflour white

Stain the wall of the cyst

*Wright Giemsa or one of its more rapid varient (Diff-Quik) Stain cystic and trophic stages but not cell wall

*Papanicolaou stainDetect foamy eosinophilic material but does not stain organism

*immunofluroscence testing : using monoclonal Ab more sensitive than usual stain

*PCR: highly sensitive with moderate specificityCan be used on oropharyngeal washPCR in serum(inconsistent)

Positive PCR with negative other test??-colonization

-subclinical infection-recent use of anti PCP therapy

*RT-PCR detect RNA from viable organisms

*lab test-LDH

-CEA, HB, Alb, ACE level, thyroxin low specificity

-plasma Sadenosylmethionine concentration-serum or plasma 1-3 B-D-glucoan

false +ve in Bacterial pneumoniaHemodialysisIV IG

*prevent exposure*primary prophylaxis

Indications1-CD4<200 or CD4 cell percentage <14%

2 -CD4 200-250 in patient with difficult access to health care

3-oropharyngeal candidiasis or other AIDS defining illness* recommended drug

TMP/SMX (DS vs SS tablet) advantage

Side effects and drug discontinuation

*Aerosolized pentamidine administered by nebulization devices other than the Respirgard II nebulizer

*Intermittently administered parenteral pentamidine *Oral clindamycin plus primaquine

Indication of discontinuing

primary prophylaxis

CD4 increased > 200 for at least 3

months

CD4 100-200 with HIV < 50

Oral pyrimethamine plus sulfadoxine

response to therapy depend on -the agent used

-number of previous PCP episodes

-severity of pulmonary illness,-degree of immunodeficiency

-timing of initiation of therapy -comorbidities.

Factors that predict poor out come-patient age

-recurrent PCP-poor oxygenation

-marked CXR abnormalities-high WBC , low Hb or low Albumin

-high LDH-ICU admission with high APACHE 2 score

-extrapulmonary disease-pneumothorax

-BAL findings of Concurrent CMV or other organisms

>5% neutrophiliaBiopsy showing fibrosis and edema

Moderate to severeparenteral pentamidine or

oral primaquine + intravenous clindamycinmild disease

atovaquone

When to initiate ART

Toxoplasma pneumonia *interstitial pneumonitis, necrotizing

pneumonitis, consolidation, pleural effusion, empyema, or all.

* Tachyzoites may be found in alveolocytes, alveolar macrophages,

pleural fluid, or extracellularly within alveolar exudate .

*T.gondii DNA may be demonstrated in bronchoalveolar lavage (BAL)fluid by the PCR.

- occurs mainly in patients with advanced AIDS (mean CD4 count, 40 cells/mm3)

- presents as a prolonged febrile illness with cough anddyspnea which may resemble PCP

- it is usually accompanied with sepsis like syndrome. Mortality, even when treated appropriately, may

be as high as 35% .Extrapulmonary disease may be present in about

50% of cases with toxoplasmic pneumonitis.pulmonary toxoplasmosis is not associated with TE.