Pneumocystis Carinii PneumoniaElizabeth Wozniak, MS4Diagnostic RadiologyDecember 16, 2005

BackgroundFirst identified in the early 1900s by researchers working with guinea pigs and ratsInitially classified as a protozoan based on morphologic appearanceExists in two forms: trophozoites 1-4 m and cysts 8 m in diameterReclassified in 1988 as a fungus based on genomic analysis

BackgroundPneumocystis species have been identified in most mammals and are species specificHuman form was recently renamed P. jiroveciiThere is still little known about Pneumocystis because it cannot be cultured

Epidemiology

Serologic studies show universal seropositive status by age twoRoute of transmission is currently unknownLikely airborne transmission from person to personPossible environmental transmission as well

Risk FactorsImpairment in Cellular ImmunityHIV:CD4 count < 200Chronic corticosteroid therapyPrednisone 16 mg qd for longer than eight weeksOthers including: transplant patients, chemotherapy recipients, congenital immune system defects, premature infants, and malnutrition

PathophysiologyPneumocystis infection is specific to the lungTrophozoites bind tightly to alveolar epithelium, but do not invade cellsCD4 T cells recognize pathogen and recruit macrophagesMacrophages release TNF- which propagates immune response through further recruitment and cytokine release

Pathophysiology continued

Results in a large inflammatory response which can lead to diffuse alveolar damage, impaired gas exchange, and respiratory failureRespiratory involvement and death is more closely correlated with degree of lung inflammation than with organism burden

HIV vs. non-HIVHIVHigh fungal loadLittle inflammationSpared oxygenationNon-HIVLow fungal loadLarge inflammationPoor oxygenation

Signs and SymptomsProgressive dyspnea, DOENon-productive coughLow grade feverHypoxemiaTachypneaTachycardiaOften normal pulmonary exam vs. mild cracklesTime courseHIV: gradual onset in 2-6 weeksNon-HIV: abrupt onset in 4-10 days, can correlate with taper or increased dose of corticosteroids

DiagnosisRequires microscopic evidence of PneumocystisSputum induction: diagnostic yield of 50-90% in HIVBronchoalveolar lavage: diagnostic yield of >90% in HIVRarely requires transbronchial or surgical lung biopsyDiagnostic yield much lower in non-HIV cases (given low fungal burden). Consider empiric treatment if negative sputum/BAL but high suspicion Histologic evidenceTrophozoites stain with modified Papanicolaou, Wright Giemsa, or Gram-Weigert stainsCysts stain with Gomori methenamine silver, cresyl echt violet, toluidine blue O, or calcofluor white stainsMonoclonal antibodies bind both formsPCR is not currently available but a future consideration

Diagnosis continuedGomori methenamine silver (GMS) stain from BAL specimen showing crushed ping-pong ball appearance of cyst wall

Diagnosis continuedWright-Giemsa stain showing trophozoites within foamy exudates (at arrows) from BAL

Diagnosis continuedCalcofluor white stains the fungal cyst wall for rapid diagnosis

Diagnosis continuedImmunofluorescence showing trophozoites (arrowheads) and cysts (arrows)

Radiographic FindingsTypically see bilateral, ground glass opacities that progress over time to become homogenous and diffuse10% of HIV patients will show upper lobe cystsLess common to see solitary or multiple nodules, upper lobe predominance, or pneumothoraxRare to see pleural effusion or lymphadenopathy (search for another cause)HRCT is more sensitive during early stages when CXR will likely appear normal

PA Chest Radiograph68 y/o on longterm corticosteroids.Demonstratesbilateral, perihilar,R > L, ground glassopacities

PA Chest Radiograph

Progressivedisease showingextensive groundglass opacificationwith consolidation

PA Chest Radiograph

Diffuse groundglass opacity withreticular patternindicating cystformation

PA Chest RadiographDiffuse, groundglass opacities with large left sided pneumothoraxCysts predisposepatients to pneumo-thorax

PA Chest Radiograph

Patchy, groundglass opacities in theapices in anAIDS patient on pentamidine prophylaxis

CT Chest

Patchy, bilateralground glass opacities in a 9month-old HIVpositive child

Radiographic Differential DiagnosisNon-cardiogenic edemaDiffuse pulmonary hemorrhageWegeners, Goodpastures, etc.CMV pneumonitisHypersensitivity pneumonitisPulmonary alveolar proteinosis

TreatmentTrimethoprim-Sulfamethoxazole 15-20 and 75-100 mg/kg respectively given daily divided into BID dosingSome strains with emerging mutations in dihydropteroate synthase gene, sulfa drug targetNot yet clinically significantFor sulfa allergy: primaquine + clindamycin, atovaquone, or pentamidineCorticosteroids decrease morbidity and mortality in severe disease. Indicated if:PaO2 < 70 mm HgP[A-a]O2 > 35 mm HgPrednisone 40 mg bid x five days with taper

PrognosisBased on severity of inflammationWhich patients have a better prognosis?HIV10-20% mortality with primary infection. Increased with mechanical ventilationNon-HIV30-60% depending on cause of immunosuppressionLDH level has been linked to prognosisLDH represents degree of underlying inflammatory damage to lungPoorer outcomes when it is elevated at diagnosis or continues to rise despite treatment

ProphylaxisPrimary prophylaxisHIV patients with CD4 count < 200 or with a history of oral candidiasisPatients taking corticosteroids > 16 mg for > 8 weeksSecondary prophylaxisLifelong after developing PCP infectionMedications:TMP-SMXAlternatives: dapsone, pentamidine, atovaquoneCan prophylaxis ever be discontinued?Yes, if CD4 count > 200 for > 3 months

ReferencesThomas, C.F and Limper, A.H. Pneumocystis Pneumonia. New England Journal of Medicine: 350;24. June 10, 2004.Gosselin, M.V. Diffuse Lung Disease in the Immunocompromised Non-HIV Patient. Seminars in Roentgenology: 37;1. January, 2002.Gosselin, M.V. Pneumocystis Carinii Pneumonia. Book chapter.Chamberlain, J.J. and Ries, K. Pneumocystis carinii. Current Diagnosis and Treatment in Infectious Diseases, 2001.PCP treatment guidelines in HIV at www.idsociety.orgRadiographic images obtained from UCSF Department of Pathology websitePathology images obtained from NEJM article

**Cysts predispose to pneumothorax.Nuclear medicine scan uses gallium and shows widespread lung activity. This is a somewhat outdated form of diagnosis.*Corticosteroids decrease mortality in severe disease ~50% and decrease need for mechanical ventilation*IL-8 has been used in the research setting to determine prognosis as a representation of the degree of inflammation although this is not currently clinically relevant.

*Can use TMP-SMX in patients on methotrexate which has been a contraindication in the past. Be sure to supplement folate.