Pneumocystis carinii Pneumonia

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Pneumocystis carinii Pneumonia

• Eric D. Anderson, MD
• Assistant Professor of MedicineDivision of
  Pulmonary, Critical Care Sleep Medicine

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Case 1

• DH was a 39 year old African American male with a
  history of HIV diagnosed one year prior. He
  presented to the pulmonary clinic with a
  complaint of gradually worsening dyspnea on
  exertion. He had an occasional cough productive
  of scant white phlegm and a 20 lb. weight loss
  over the past several months. He denied fevers,
  shakes, chills, chest pain, or hemoptysis.

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Case 1

• PMH
• HIV. CD4 count and viral load unknown
• Pneumonia 1 year prior to admission.
• Oral thrush.
• Current Medications
• Mycelex troches 5x daily
• Ibuprofen PRN

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Case 1

• Social History
• No tobacco, etoh, IVDA
• No blood transfusions
• Homosexual

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Case 1

• Physical Exam
• 65 tall 152 lbs.
• Temp 97.3 HR 80 RR 24 BP 120/78
• Mild tachypnea, but not in distress.
• Oral thrush coating posterior pharynx.
• Regular rhythm S1, S2. No S3. No murmur.
• Lungs clear to auscultation and percussion.
• No clubbing, cyanosis, or edema.

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Case 1

• Labs
• WBC 4.6 Poly 87, lymph 8, mono 5
• Hgb/Hct 8.4/26.0
• LDH 474
• Pulse oximetry
• 90 on room air
• ABG 7.46/32/62

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Case 1

• HIV status
• CD4 17
• Viral Load 750,000

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Case 1

• Video flexible bronchoscopy was performed.
• Bronchoalveolar lavage was positive for PCP.
• Patient was treated with Bactrim and prednisone.
• 5 days into therapy he developed sudden onset of
  severe dyspnea.

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Case 1

• A chest tube was inserted for the tension
  pneumothorax.

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Case 1

• Patient underwent Video Assisted Thoracic Surgery
  (VATS) with removal of ruptured cysts and
  pleurodesis.
• Postoperatively, had persistent air leak and
  worsening oxygenation.

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Case 1

• Additional left chest tube was inserted to
  attempt to reexpand the lung.

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Case 1

• Despite supportive measures, patient had
  worsening oxygenation and eventually expired.

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Lecture Objectives

• 1. To describe the history and life cycle of
  pneumocystis carinii.
• 2. To discuss the mode of transmission and
  clinical features of infection with pneumocystis
  carinii.
• 3. To describe useful diagnostic studies.
• 4. To become familiar with the common CXR
  appearance of pneumocystis carinii.
• 5. To review histologic features of
  pneumocystis carinii infection.
• 6. To discuss treatment and prophylactic
  regimens and associated toxicities of treatment.

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PCP Historical Features

• 1909 - First recognized in lungs of Guinea pigs
  by Chagas.
• Similar to Trypanosoma cruzi, yet different.
• These observations were confirmed by Carini soon
  after.
• 1912 - Delanoes named it after its discoverer and
  to reflect its tendency to infect the lungs.

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PCP Historical Features

• Not initially believed to affect humans.
• 1951 - Vanek described an interstitial pneumonia
  with Pneumocystis carinii organisms in a human.
• 1955 - First reported in immunodeficiency.
• 1957 - First associated with chemotherapy.
• 1982 - AIDS and Pneumocystis carinii association.

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PCP Incidence on the Rise

• Less than 500 cases reported in U.S. 1967-1970.
• Late 1980s numbers increased to 20-60,000 new
  cases

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PCP Incidence

• Cause of the increase is multifactorial.
• Corresponds to the AIDS epidemic.
• Also due to increased numbers of patients
  receiving immunosuppression for transplantation.
• More toxic chemotherapy to patients.

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PCP Incidence in HIV

• Pneumocystis carinii is the most common
  opportunistic infection in AIDS in the U.S..
• 65 of these cases are the AIDS-defining illness.
  (1991 - down to 25)
• 80-90 of patients with HIV will develop PCP if
  not given prophylaxis.
• Only 15 of patients compliant with prophylaxis
  will develop disease.

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PCP ClassificationFungus or Protozoan?

• Shares both fungal and protozoan nucleic acids
  and structural features of each.
• Does not grow in fungal cultures, and antifungal
  therapy is ineffective.
• Found to respond to anti-parasitic therapy.
• Initially, thought to be a Protozoan.
• Now believed to be a fungus, probably related to
  Saccharomyces.

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PCP A Unicellular Organism

• Two forms
• Trophozoites - may be able to reproduce without
  cyst formation.
• Cysts - fill with up to eight sporozoites and
  rupture, releasing the sporozoites.
• Sporozoites mature into trophozoites and form
  cysts.

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PCP Hosts

• Humans.
• Rats, mice, and rabbits.

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PCP Transmission

• Airborne via human-to-human transmission or
  environmental.
• Possibly, exposed almost universally as children
  and then have reactivation later as immunity
  decreases.

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PCP Transmission

• Site of Infection
• Primarily in the lungs within the alveoli.
• Attaches to and damages type I pneumocytes.
• Results in interstitial inflammation with
  lymphocytes and macrophages.

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PCP Extrapulmonary Infection

• Once rare, more common with AIDS.
• Extrapulmonary sites of infection
• Reticuloendothelial system (liver, spleen, bone
  marrow)
• Sinuses, middle ear, eye, and dermis around head.

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Patients at Risk

• AIDS at CD4
• Congenital and acquired defects in cellular
  immunity.
• Organ transplantation recipients.
• Chemotherapy.
• Corticosteroids.
• Malnutrition.
• Premature birth.

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PCP Clinical Features

• Cough - 60-91
• Usually nonproductive, occasionally whitish
  sputum.
• Only productive in 23-30 of patients.
• Dyspnea - 29-95
• May be present only on exertion at first.
• Fever - 79-100
• May be accompanied by night sweats, but not
  rigors.

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PCP Clinical Features (contd)

• Chest pain - 14-23
• If a pneumothorax accompanies the infection.
• Tachypnea and tachycardia
• Occasionally, severe respiratory distress.
• Rales
• May be present, but are often absent.

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PCP Pearls

• Similar to atypical pneumonias.
• Physical examination is often less severe than
  x-ray findings.
• Gradual onset, especially in HIV disease where
  often the patient is ill for 3-6 weeks before
  presentation (median 28 days)

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Diagnostic Studies ABG

• Hypoxia.
• 80-90 of patients.
• PaO2 is commonly 55-65 mm Hg.
• Respiratory Alkalosis.
• Due to Hyperventilation driven by hypoxia.
• PaCO2 is commonly 30-35 mm Hg.
• Elevated Aa gradient (average 41).

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Diagnostic Studies PFTs

• DLCO.
• 90 of AIDS patients with PCP have a diminished
  DLCO.
• Nonspecific.
• Decreased VC and increased residual volumes.

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Other Diagnostic Studies

• LDH.
• Elevated in 90 of patients with PCP.
• Sensitive, but nonspecific. (A normal LDH makes
  PCP less likely).
• Gallium scan.
• Also nonspecific, but positive in 90 of AIDS
  patients with PCP.

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Other Diagnostic Studies

• Exercise studies.
• Also nonspecific.
• However, a normal exercise tolerance may exclude
  the diagnosis of PCP and
• An abnormal exercise tolerance may help
  demonstrate an early infection.

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PCP CXR Findings

• 90-95 have pulmonary infiltrates.
• Combined interstitial alveolar infiltrates.
• Predominantly at bases and centrally.
• Air bronchograms present occasionally.
• Lobar infiltrates are rare and pleural effusions
  are unusual with PCP.
• Pneumothorax can be present.

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Histologic Diagnosis

• Sputum (induced if necessary)
• Diagnostic in 60-80 of AIDS, but a negative
  predictive value of 54.
• Only 5-10 of non-HIV patients are diagnostic.
• Flexible Bronchoscopy with Bronchoalveolar
  lavage
• 80-90 diagnostic. Safe.

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Histologic Diagnosis

• Transbronchial biopsy
• 85-95 diagnostic.
• 1-5 morbidity.
• Percutaneous Lung aspiration
• 91 diagnostic.
• 44 complications.
• Open lung biopsy
• Only in rapidly deteriorating patients with a
  negative bronchoscopy.

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Histologic Diagnosis

• Future techniques Serum PCR?
• Stains
• Gram and Giemsa stain both cyst and trophozoites.
• Gomoris silver and Toluidine stains for cysts.

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PCP Treatment Goals of Therapy

• Treating the Acute Infection.
• Antipneumocystis chemotherapy.
• Decreasing the inflammatory response.
• Improving the immunologic status of the patient.
• Supportive care with oxygen, nutrition, chest
  tubes etc.
• Preventing Infection.

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PCP Treatment
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Antipneumocystis ChemotherapyFolate Antagonists

• Effectively inhibit dihydrofolate reductase with
  a greater affinity towards pneumocystis than
  mammalian enzyme.

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Trimethoprim-Sulfamethoxazole

• Preferred treatment if tolerated.
• 80-95 effective in HIV
• 60-80 in non-HIV.
• Inexpensive, effective, oral/IV, usually well
  tolerated.
• PO for mild to moderate infection, IV for acute
  or impending respiratory failure.
• Treat for 21 days or longer.

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Trimethoprim-Sulfamethoxazole

• Toxicity fever, rash, pruritus, HA, nausea,
  vomiting, leukopenia, nephritis, stomatitis,
  thrombocytopenia, increased aminotranferases.
• Rarely, anaphylaxis and Stevens-Johnson.
• Toxicities due to the hydroxylamine portion of
  the sulfamethoxazole component.

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Trimethoprim - Dapsone

• May be as effective as Trimethoprim-sulfamethoxazo
  le.
• Toxicity
• Hemolysis
• Rash
• Methemoglobinemia
• Nausea.

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Trimetrexate

• Alternative therapy for acutely ill patients who
  can not tolerate TMSX or IV pentamadine.
• IV dosing.
• High efficacy, but less than TMSX.
• High recurrence rate if not given with a sulfa
  drug.

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Trimetrexate

• Toxicity Fever, rash, cytopenias, elevated
  transaminases.
• Leukovorin used to avoid granulocytopenia.

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Other Antipneumocystis Medicines

• Pentamadine, Atovaquone, and Clindamycin -
  primaquine
• Mechanism unclear

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Pentamadine

• First used to treat PCP in 1958.
• Second most widely used medication.
• Equal efficacy to TMSX, but used less 2' to
  adverse toxicities.
• 60-90 cure rate.
• IV therapy.

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Pentamadine

• More toxicity
• Nephrotoxic
• Pancreatitis
• Arrythymias
• Leukopenia
• Hypo/hyperglycemia
• Hypotension (with rapid infusion).

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Clindamycin - primaquine

• Mild to moderate disease.
• Mechanism unclear.
• Oral therapy.
• Toxicity Rash, nausea, hemolysis, and
  methemoglobinemia.

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Atovaquone

• Mild to moderate disease.
• Oral therapy.
• Toxicity Fever, rash, increased
  aminotransferases.

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Antiinflammation TherapyPrednisone

• First used in 1987.
• Adjunctive therapy to decrease inflammatory
  response to PCP.
• Hypothesis - Pneumocystis death exacerbates the
  inflammatory response.
• Should be initiated within 72 hours of anti-PCP
  therapy.

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Antiinflammation TherapyPrednisone

• Shown to improve survival in patients with paO2 70 or Aa gradient 35 mm Hg.
• Decreases the risk of respiratory failure and
  death by 50.
• Tapered dose (40 mg BID x 7, 40mg QD x 7, 20 mg
  QD x 7).
• Longer steroid tapers not studied.
• Watch for flare of other infections (TB, fungus
  ...).

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PCP Prophylaxis

• Shown to decrease infection rates and
  recurrences.
• HIV and one of the following
• Previous PCP infection (Risk of recurrence 50).
• CD4
• Oral thrush.
• Persistent fevers 2 weeks.

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PCP Prophylaxis

• Immunocompromised hosts
• Allogeneic organ or bone marrow transplant
  recipient.
• Children with severe combined immunodeficiency.
• Children with ALL.
• Patients on chronic steroids

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PCP Prophylactic Regimens Trimethoprim-Sulfameth
oxazole

• Daily or three times per week.
• patient.
• Have also noted a significant decrease in rates
  of CNS Toxoplasmosis
• Believed to be a result of use of Sulfa as a
  prophylaxis.

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PCP Prophylactic Regimens Aerosolized
Pentamadine

• Not as effective . Up to 16 recurrence.
• Apical recurrences due to administration.
• Does not prevent extrapulmonary infection.
• Costly due to administration.
• Use monthly with albuterol to prevent
  bronchoconstriction.

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PCP Prophylactic Regimens Dapsone

• Another effective prophylactic agent
• Now used as the second choice in most
  institutions.
• Daily dosing.
• 10 - 15 breakthrough rate.

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PCP Prophylactic Regimens Atovaquone

• When intolerant to other regimens.
• May be less toxic than dapsone.

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Restoration of T-Cells with HAART Therapy

• If CD4 cells increase to greater than 200, does
  prophylaxis need to be continued?
• April 1999, NEJM reported 262 patients with
  restored CD4 200 and CD4 14
• Over an 11 month period
• No cases of PCP breakthrough.

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Restoration of T-Cells with HAART Therapy

• 474 patients with CD4 200 and HIV RNA level 5,000
• No PCP in 19 month follow up
• NEJM January 18, 2001 344(3)159-67.
• 325 patients with prior PCP (Secondary
  Prophylaxis)
• Average CD4-50 and improved to 350
• No recurrence in 13 month follow up
• NEJM January 18, 2001 344(3)168-74.

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PCP Survival

• Mortality
• 6-12 of HIV
• 39 of non-HIV
• Nearly 100 fatal if untreated in HIV.
• Some patients may develop resistance lowering
  chance of survival.
• 50-60 mortality if require mechanical
  ventilation.

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PCP Recurrence

• 50 - 75 of patients with AIDS and PCP will
  relapse in a year if no prophylaxis is offered.
• 10-20 relapse in other immunocompromised
  patients.

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PCP and Low CD4

• Patients without HIV who develop PCP have lower
  CD4 count than control patients with other types
  of pneumonia
• CD4 counts might be helpful as a screening tool
  when immunocompromised patients present with lung
  infection
• Mansharamani NG et al., Chest 2000 118(3)712-20.
• Idiopathic Low CD4 syndrome is also associated
  with PCP

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PCP Recent Data

• Incidence of PCP is declining.
• However, recent cases seem to be more severe.
• Number of patients with respiratory failure has
  decreased to
• 5-10 of HIV
• 66 of non-HIV
• But, mortality of patients with respiratory
  failure has increased to 59-89.
• Mansharani NG et al., Chest 2000118(3)704-11.

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PCP Recent Data

• If patients worsen despite 5 days of therapy, or
  do not improve in 7-10 days,
• ---- 75-100 mortality.