Pneumocystis Carinii Pneumonia :Percutaneous Lung Biopsyand Review of Literature *Michael L . Cohen, M.D.," and Earle B . Weiss, M.D .,F.C .C .P.t

In patients with impaired immune defenses, unusualorganisms such as Pneumocystis carinii may be respon-sible for fatal diffuse interstitial pneumonia. Inasmuchas relatively specific therapy is available, a precise diag-

"From the Lung Station (Tufts), Tufts Medical Service,Boston City Hospital, Boston, Massachusetts .

"Research Fellow, Lung Station (Tufts), Present addressPulmonary Division, Salem Hospital, Salem, Massachusetts .

)'Associate Professor of Medicine, Tufts University School ofMedicine ; Physician-in-Charge, Pulmonary Physiology Sec-tion, Lung Station (Tufts), Boston City Hospital ; ResearchAssociate, Lung Station (Tufts), Boston City Hospital .

Reprinted from CHEST

Vol . 60, p . 195-199

August 1971 Issue

PNEUMOCYSTIS CARINII PNEUMONIA

195

mocystis Carinii Pneumonia :Percutaneous Lung Biopsyand Review of Literature *Michael L, Cohen, M .D.,°° and Earle B . Weiss, M.D .,F.C .C .P.t

CHEST, VOL . 60, NO. 2, AUGUST 1971

In patients with impaired immune defenses, unusual

organisms such as Pneumocystis carinii may be respon-sible for fatal diffuse interstitial pneumonia . Inasmuch

as relatively specific therapy is available, a precise diag-

"From the Lung Station (Tufts), Tufts Medical Service,Boston City Hospital, Boston, Massachusetts .

"Research Fellow, Lung Station (Tufts), Present addressPulmonary Division, Salem Hospital, Salem, Massachusetts .

tAssociate Professor of Medicine, Tufts University School ofMedicine ; Physician-in-Charge, Pulmonary Physiology Sec-tion, Lung Station (Tufts), Boston City Hospital ; ResearchAssociate, Lung Station (Tufts), Boston City Hospital .

196

nosis must be established in all instances . The presentcase supports the role of percutaneous lung biopsy forthis purpose. The toxicity of pentamidine isethionate anda review of the current literature is presented .

Pneumocystis carinii appears to be a disease of in-creasing incidence . Previously described in prema-

ture and debilitated infants, or children with hypogam-maglobulinemia, P carinii pneumonia has since beendiscovered in transplant patients receiving immuno-suppressive therapy,'- ;; patients with heinatopoieticand lymphoreticular malignancies receiving adrenal cor-

ticosteroids or cytotoxic agents, 4-s and patients withimmunoglobulin deficiencies . 7 ' 8 Untreated, this diseaseis usually fatal . Recent reports of successful treatment ofP carinii pneumonia with pentamidine isethionate, indi-cate that a specific diagnosis is mandatory . In the appro-priate clinical setting and where the usual diagnosticmodalities are unrevealing, the percutaneous needle bi-opsy of the lung may play a significant role .

CASE REPORT

A 34-year-old woman underwent cadaveric renal trans-plantation on November 24, 1968, because of end-stagechronic glomerulonephritis. Bilateral nephrectomy and splee-nectomy had been performed on October 29, 1968 . Immuno-suppressive therapy consisted of azathioprine (Imuran),prednisone, antilymphocyte serum and local irradiation . Thedevelopment of hypertension required admission two monthslater. The recumbent blood pressure was poorly controlled de-spite methyldopa, hydralazine, spironolactone, and guanethi-dine; renal function, however, was not impaired (creatinine0.8 mg percent) . A spiking fever to 105° F developed on the109th posttransplant day (March 15, 1969) ; however physicalexamination and numerous laboratory studies failed to revealits source . A few days later the patient became dyspneic, therespiratory rate was 52/minute, rales were audible over theleft-lower lobe, and a chest x-ray picture showed bilateralpulmonary congestion suggestive of pulmonary edema . ThePao, was 38 mm Hg, Paco ., 20 mm Hg, and pH 7 .46. Two(lays later the chest x-ray film revealed progressive opacifica-tion (Fig 1) .

A needle biopsy (Franklin modification of the Vim-Silver-

Freusc 1 . Chest roentgeno^ram on day of percutaneous lungbiopsy revealing bilateral intra-alveolar infiltration pattern .

Frcuu s 2 . Tolnidinc blue stain of tissue imprint obtained frompercutaneous lung biopsy . P carinii cysts appear as darkround bodies 1 to 5 micron size . An internal structure can beseen within some cysts. X 1000 .

man) of the right lung was performed on March 20, 1969with transient hemoptysis (5 to 10 ml) as the sole complica-tion. Tissue imprints and fixed sections, when stained withmethenamine silver and Graw's modified toluidcne blue,revealed P carinii cysts (Fig 2) . Pentamidine, 4 mg/kg wasadministered for four days, then increased to 8 mg/kg forfour additional days .

On March 30, 1969 the patient developed oliguria ; aninfusion IVP and a renal arteriogram suggested renal rejec-tion. Peritoneal dialysis was instituted, pentamidine and Im-uran were discontinued, and prednisone, which had beentapered to a maintenance dosage of 20 mg, was now in-creased. Although she continued a spiking febrile course, thechest x-ray improved significantly with reduction in dyspneaand tachypnea . Nine days later she suffered a cerebrovascu-lar accident, remaining comatose until her death .At postmortem examination, the lungs revealed acute

bronchopneumonia ; however, there was no evidence of inter-stitial pneumonitis, nor were P carinii identified . There wasinfarction of the transplanted kidney, with diffuse thrombosisof small arterioles and venules consistent with a hyperacuterejection of the type seen in patients with preformed anti-white cell antibody . Although this patient had preformedantibody to over 90 percent of randomly selected donors, shedid not have antibody to the donor used for transplantation .

DISCUSSION

Pneumocystis carinii was described in the Europeanliterature in the 1940's, as occurring primarily in prema-

ture and debilitated infants,) but is now recognized as apathogen causing diffuse interstitial pneumonia in pa-tients with altered immune mechanisms . Goodell and co-workers 10 estimated that P carinii comprised a mini-mum of 44 percent of cases with diffuse interstitialpneumonias in patients with neoplastic disease who were

receiving immunosuppressive therapy . Rifkind and col-leagues and hill and co-workers:s called attention tothis organism as a factor in the death of renal transplantpatients, and LeClair r recently described three cases ofP carinii pneumonia among cardiac transplant recip-ients .

We have encountered three cases of P carinii pneu-

CHEST, VOL. 60, NO . 2, AUGUST 1971

COHEN AND WEISS

PNEUMOCYSTIS CARINII PNEUMONIA

Table 1-Summary of Literature-Cases of P . Carinii Proved by Lung Biopsy and Successfully Treated .

*Age in years .**Acute lymphocytic leukemia .tChronie lymphocytic leukemia ./Chronic myelogenous leukemia .

CHEST, VOL. 60, NO . 2, AUGUST 1971

197

Reference Age*

Disease MedicationsBiopsy +Complications Treatment Complications Follow-up

28 7.5

Hypogammaglobulinemia Open- Pentamidine Not stated

X-raymonths Not stated unchanged

8

Open (5 moslater)---TensionpneumothoraxI wk afterbiopsyOpen Pentamidine+

p 3 months

Not stated

2 years2 Hypogammaglobulinemia

16 8 HypogammaglobulinemiaNot statedOpen

GammaglobulinHydroxystil- Megaloblas- 3 years

25 10 ALL** Methotrexate

Not stated

Open-

bamidine,PentamidineHydroxystil-

tic marrow

Not stated

16 monthsVincristinePrednisone

Not stated bamidine, D/CMethotrexate

7 14 ALL** Methotrexate Open Pentamidine Not stated

10 months

14 ALL** X-ray, Pred-Not statedNeedle- Pentamidine Hypoglycemia Not stated

20 ALL**

nisone, 6-M-P,MethotrexateVincristine

Hemothorax,mildNeedle Pentamidine Transient

Clear

26 46 CLLt

Prednisone

Chlorambucil

Not stated

Open Pentamidine,

oliguria

x-ray at13 days

Not stated

8 months .

4 50 Malignant

Prednisone

Cyclophos-

Extremedyspnea

Needle-

Steroids

Pentamidine,

Autopsyshowed nopneumocystis

papules with Clear

5 50

lvmphohistiocytoma

CML$

phamideVinblastinePrednisoneBusulfan

Not stated

Open

D/CPrednisone

Pentamidine

slough

x-rayRenal tubular at 1dysfunction

monthHypoglycemia 1 year

27 53 CLLt Chlorambucil

Not stated

Open Amphotericin,

Painful,weepinginjection siteNot stated

Clear

16 57 CLLtPrednisonePrednisone

Not statedOpen

SteroidsPentamidine

x-rayNot stated

"ImprovedChlorambucil "Respiratory discharged"

23 8 ALL** 6-MPdistress"Needle-- Pentamidine Not stated

"Improved''

20 58 Mycosis fungoides

AmphotericinVincristinePrednisoneAmphotericin

Not stated

Needle--- Pentamidine

x-rayresolution

None

Complete

12 49 Renal transplant Azathioprine

Not stated

Needle- Pentamidine

clearing at2 months

None

Well after

Present 34 Renal transplant

Prednisone

Azathioprine

Hemoptysis(5 to 10 ml)Needle- Pentamidine

14 months

None

Died aftercase Prednisone Hemoptysis I month

(5 to 10 ml) No evidenceof p carinaat postmortemexam

198

monia in renal transplant patients on immunosuppres-sive therapy, antilymphocytic serum, prednisone andImuran in a one-year period. One case was diagnosed atpostmortem, the other two by percutaneous needle lungbiopsy and were treated with pentamidine . The presentcase was successfully treated for P carinii pneumoniabased upon clinical and radiographic criteria . Althoughshe died one month after treatment, there was no evi-dence of pulmonary P carinii by detailed postmortemexamination . Our third casel 2 is alive and well 16months after therapy ; his chest x-ray remains clear, andthe transplanted kidney functions adequately .

In the English literature, 14 other biopsy proved casesof P carinii pneumonia have been successfully treated(Table 1) ; five of these were established by needle biop-sy of the lung, and 12 were treated with pentamidineisethionate .

Pentamidine isethionate, a diamidine with trypan-asomacidal activity and utilized since 1941 in the treat-ment of African sleeping sickness and leishmaniasis, ispotentially nephrotoxic . Western and Schultz 13 statethat hundreds of thousands of patients have been treatedwith this drug without a recorded instance of permanentrenal damage . In the French literature,r 4 four cases oftransient azotemia were reported in patients treated forAfrican sleeping sickness ; however, it was suggested thatthis was due to a protein catabolic effect rather thanrenal injury . DeVita and associates,4 reported a case oftransient renal impairment possibly related to a doublingof the dose of pentamidine for four days ; and a secondcase that experienced one day of oliguria with fullrecovery; nephrotoxic antibiotics, however, may havebeen added factors .

Because of the precarious function of transplantedkidneys, potentially nephrotoxic drugs should be limited .Our previously reported case 12 received 4 mg/kg ofpentamidine for 14 days, without any renal damage asmeasured by conventional renal function tests . The pres-ent patient received 4 mg/kg for four days, then 8mg/kg for an additional four days . Although she becameoliguric after completion of her treatment, postmortemexamination implicated the oliguria to a hyperacuterejection phenomenon rather than to pentamidine tox-icity . 15

Pentamidine is usually administered intramuscularlyat a dose of 4 mg/kg for ten days . It occasionally causespain at the injection site, and sterile abscesses and tissueslough have been reported . 5 Other complications in-clude vomiting, dizziness, hypotension, tachycardia, hy-poglycemia, and one possible case of a megaloblasticbone marrow by an antifolate effect

.' In patients with altered or with suppressed immunedefense mechanisms it is mandatory to establish thespecific etiology of any pneumonia to provide specifictherapy, and thereby to avoid complications of toxicityof empirical therapy . P carinii may, at times, be recover-able from the sputum, blood, or pleural fluid ; however, asignificant number of cases remain undetected by theseconventional means. Ivady and co-workers, 17 basedupon a vast pediatric experience, advocated aspiration of

COHEN AND WEISS

tracheal mucus through a laryngoscope . Since the orga-nisms rarely appear in the sputum," lung biopsy isanother approach available to establish this diagnosis .These patients are frequently critically ill, with severehypoxemia, and therefore may be poor surgical candi-dates. Following open lung biopsy, assisted ventilationmay be required because of severe postoperative respira-tory distress . 16 Although Robbins mentions a death dueto a non decompress able pneumothorax following needleaspiration of a lung infected with P carinii, others havesuccessfully employed needle biopsy with only minorcomplications, providing there are no contraindicationsto the procedure (ie bleeding diathesis) . 5,19, Y 0

Rifkind and colleagues 6 reported the arterial bloodgas data in five patients . Oxyhemoglobin saturation val-ues ranged from 90.5 percent to 44 .5 percent while thepartial pressures of CO2 were normal or low . As demon-strated in the present case, clinical progression is asso-ciated with increasingly severe hypoxemia . Whileunclarified at present, the mechanism of hypoxemiaappears to be due to a diffusion defect and/or veno-arterial shunting.

For needle lung biopsy the most densely involved areais selected from conventional chest roentgenograms .Since diffuse disease is frequently present, the biopsy isperformed in the right lower lobe to avoid cardiactrauma . Oxygen is routinely provided . After 0.5 to 1 .0mg atropine IV, local anesthesia (1 percent lidocaine,[1 percent Xylocaine]) to the parietal pleura is fol-lowed by a 0 .5 cm skin incision through which thebiopsy is conducted employing a Franklin modificationof the Vim-Silverman needle . Vital signs and chest x-rayare monitored over the next 24 hours .

Processing of the biopsy specimen is of utmost impor-tance. The resulting tissue is divided as follows : one-third in 10 percent formalin for sections, one-thirdhomogenized with sterile saline for culture, and one-third touched to several glass slides for touch imprintwhich may then be treated with Gram's, acid fast, orWright's stains . We routinely make touch imprints of thebiopsy material in addition to fixed sections since it isnot infrequent that such tissue imprints reveal manymore pneumocystis organisms . 5 'a,9 .21 The 4-micron sizespherical, intra-alveolar cysts stain readily with Gomori'smethenamine silver or Grawe's modification of the tolui-dene blue stain . 22

We have successfully utilized the Franklin-Silvermanneedle in two renal transplant patients, with transienthemoptysis (5 to 10 ml) as the sole complication . Addi-tionally, in some 40 cases with a variety of diffuse andlocal pulmonary diseases, it is well demonstrated thatneedle biopsy is a rapid diagnostic modality with limitedmorbidity and mortality for resolving difficult causes ofdiffuse pneumonopathies, particularly in critically ill pa-tien ts .23, 24

REFERENCES

1 Hill RB Jr, Rowlands DT Jr, Rifkind D : Infectious pul-

monary disease in patients receiving immunosuppressivetherapy for organ transplantation . New Eng J Med 271 :1021, 1964

CHEST, VOL. 60, NO . 2, AUGUST 1971

PNEUMOCYSTIS CARINII PNEUMONIA

2 Rifkind D, Marchioro TL, Schneck SA, et al : Systemicfungal infections complicating renal transplantation andimmunosuppressive therapy. Amer J Med 43 :28, 1967

3 Hill RB Jr, Dahrling BE, Starz] TE, et al : Death aftertransplantation (editorial) Amer J 'Vied 42 :327, 1967

4 DeVita VT, Emmer M, Levine A, et al : Pneumocystiscarinii pneumonia. New Eng J Med 280 :287, 1969

5 Lillehei JP, Funke JL, Drage CW, et al : Pneumocystiscarinii pneumonia. JAMA 206 :596, 1968

6 Rifkind D, Faris TD, Hilt RB Jr : Pneumocystis cariniipneumonia . Ann Intern Med 65:943, 1966

7 Einzig S, Hong R, Sharp HL : Successful treatment ofpneumocystis carinii in an immunologically deficientacute lymphatic leukemia patient . Cancer 23 :658, 1969

8 Marshall WC, Weston HJ, Bodian M : Pneumocystis car-inii pneumonia and congenital hypogammaglobulinemia .Arch Dis Child 39 :18, 1964

9 Gajdusek DC : Pneumocystis carinii-etiologic agent ofinterstitial plasma cell pneumonia of premature andyoung infants . Pediatrics 19 :543, 1957

10 Goodell B, Jacobs JB, Powell RD, et al : Pneumocystiscarinii : The spectrum of diffuse interstitial pneumonia inpatients with neoplastic disease . Ann Intern Med 72 :337,1970

11 LeClair RE : Transplantation pneumonia, associated withpneumocystis carinii, among recipients of cardiac trans-plants . Amer Rev Resp Dis 100 :874, 1969

12 Cohen ML, Weiss EB, Monaco AP : Successful treatmentof pneumocystis carinii and nocardia asteroides in a renaltransplant patient. Amer J Med 50 :269, 1971

13 Western KA, Schultz MG : Pentamidine nontoxicity . AnnIntern Med 70 :234, 1969

14 Payet M, Sankale M : Transitory hyperazotemia duringthe treatment of human African trypanosomiasis by dia-midines. Bull See Path Exot 53:690, 1960

15 Williams GM, Hume DM, Hudson RP Jr, et al : "Hyper-acute" renal-homograft rejection in man . New Eng J Med279:611,1968

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16 Robbins JB : Pneumocystis ca nii pneumonitis-a review .Pediat Res 1 :131, 1967

17 Ivady G, Paldy L, Koltay M, et al : Pneumocystis cariniipneumonia (letter to the editor) . Lancet 1 :616-617, 1967

18 Erchul JW, Williams LP, Meighan PP : Pneumocystiscarinii in hypopharyngeal material . New Eng J Med267:926,1962

19 Mulligan WJ, Krause FD, Morningstar W, et al : Pneumo-cystis carinii infestation. Ohio State Med J 64 :1017, 1968

20 Jacobs JB, Vogel C, Powell RD, et al : Needle biopsy inPneumocystis carinii pneumonia . Radiology 93 :525, 1969

21 Burke BA, Korvetz LJ, Good RA : Occurrence of Pneumo-cystis carinii in children with agammoglobulinemia . Pe-diatrics 28 :196, 1961

22 Chalvardjian AM, Grawe LA : A new procedure for theidentification of Pneumocystis carinii cysts in tissue sec-tions and smears . J Clin Path 16 :383, 1963

23 Krumholz RA, Manfredi F, Weg JG, et al : Needle biopsyof the lung . Ann Intern Med 65:293, 1966

24 Youmans CR Jr, Middleton JM, Derrick JR, et al : Percu-taneous needle biopsy of the lung for diffuse parenchymaldisease . Dis Chest 54 :25, 1968

25 Moore, DL, Carnahan CE, Mills SD, et al : Pneumocystiscarinii pneumonitis complicating leukemia . Mayo ClinProc 44:162, 1969

26 Smith E, Gaspar IA : Pentamidine treatment of Pneumo-cystis carinii pneumonia in an adult with lymphatic leu-kemia. Amer J Med 44 :626, 1968

27 Schultz JC, Ross SW, Abernathy BS : Diagnosis of Pneu-mocystis carinii pneumonia in an adult with survival .Amer Rev Resp Dis 93 :943, 1966

28 Patterson JH, Lindsey IL, Edwards ES : Pneumocystiscarinii pneumonia and altered host resistance : Treatmentof one patient with pentamidine isethionate . Pediatrics38 :388, 1966

Reprint requests : Dr. Weiss, Lung Station (Tufts), BostonCity Hospital, Boston 02118