Treatment of cytomegalovirus pneumonia with high-dose acyclovir

Treatment of Cytomegalovirus Pneumonia with

High-Dose Acyclovir

JAMES C. WADE, M.D.

Seattle, Washington

MARIE HINTZ, Ph.D.

La Jolla, California

ROBERT W. McGUFFIN, M.D.

STEVEN C. SPRINGMEYER, M.D.

Seattle, Washington

JAMES D. CONNOR, M.D.

La Jolla, California

JOEL D. MEYERS, M.D.

Seattle, Washington

From the Divisions of Infectious Diseases, On- cology, and Respiratory Diseases, Department of Medicine, University of Washington School of Medicine; The Fred Hutchinson Cancer Research Center, Seattle, Washington; and the Department of Pediatrics, School of Medicine, University of California at San Diego, La Jolla, California. This investigation was supported by &ant CA 18029 and CA 26966 awarded by the National Cancer Institute, DHHS. Dr. Wade is a recipient of NIH Training &ant Al 07044. Dr. f&G&fin is supported in part by a Clinical Fellowship from the American Cancer Society. Dr. Meyers is the recipient of Young Investigator Award Al 15689 from the Na- tional Institute of Allergy and infectious Diseases. Requests for reprints should be addressed to Dr. Joel D. Meyers, Division of Infectious Diseases, Fred Hutchinson Cancer Research Center, 1124 Columbia Street, Seattle, Washington 98104.

Cytomegalovirus pneumonia is a serious complicatlor of marrow transplantation, with a 90 percent fatality rate. Acyclovir, a. new antiviral agent with variable in vitro activity against cytoMegalovirus, was administered to eight marrow transplant patients With biopsy- proven cytomegalovirus pneumonia; one patient survived. Doses were between 400 and 1200 mg/m* and peak plasm& levels between 47 .and 316 PM were attained. Possible marfow toxicity occurred in three patients, and mild neurotoxlcity occjlrred in one. High-dose acyclovir had mild toxicity but was not (mectlvd as treatment for cytomegalovirus pneumonia after marro* transplantation.

Marrow transplantation is complicated by the frequent occurrence and usually fatal outcome of cytomegalovirus pneumonia [ 11. Previous trials using adenine arabinoside as prophylaxis against cytomegalovirus infection [2] and adenine arabinoside and leukocyte interferon alone or in combination as treatment of cytomegalovirus pneumonia have been uniformly unsuccessful [3,4].

Acyclovir, a new antiviral agent, has recently been shown to be effective both prophylactically [5] and therapeutically [6-$1 for herpes simplex virus infections occurring after organ transplantation. An uncontrolled study suggests that acyclovir treatment may also be beneficial for varicella zoster virus infections occurring, in immunocompromised patients [9]. The activity of acyclovir against cytomegalovirus in vitro has been variable [ lo- 131. Crumpacker et al. tested six clinical cytomegalovirus isolates for sensitivity to acyclovir. Two of these six were inhibited by acyclovir concentrations of 100 and 160 y M, respectively, while the other four were resistant at concentrations as high as 200 ~1 M [ 111. Despite this variable sensitivity, Cupps et al. reported the successful treatment of a patient with biopsy-proven cytomegalovirus pneumonia as well as concomitant disseminated herpes zoster and localized herpes simplex virus type-2 infection with acyclovir 5 mg/kg (N 200 rng/m*) [ 141.

Acyclovir dosages presently used (250 to 500 mg/m*) produce peak plasma levels up to 100 PM. This is approximately 25 percent of the concentration that suppresses granulocyte-monocyte colony-forming activity in cell culture [ 151, suggesting that higher dosages; of acyclovir to achieve plasma levels in the range previously shown to suppress some cytomegalovirus isolates in vitro would be possible without producing significant marrow toxicity. We therefore studied the efficacy and toxicity of high-dose acyclovir as therapy for cytamegalovirus pneumonia after marrow transplantation.

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ACYCLOVIR IN THE IMMUNOCOMPROMISED HOST-WADE ET AL.

PATIENTS AND METHODS

Patient Selection. All patients in this trial had received an allogeneic marrow transplant from a human leukocyte antigen-identical sibling. Marrow transplantation was performed at the Fred Hutchinson Cancer Research Center using previously published procedures [ 161. Methotrexate (Patients 1, 2, 4, 6, 7, and 8) or cyclosporin A (Patients 3 and 5) was given to each patient after transplant as prophylaxis against graft versus host disease. All patients underwent open-lung biopsy for hypoxemia and diffuse pneumonia, and all had lung tissue showing an interstitial pneumonia containing characteristic intranuclear and intracytoplasmic inclusions. Informed consent was obtained from all patients, and this protocol was approved by the Institutional Review Committee at the Fred Hutchinson Cancer Research Center. Treatment Protocol. Acyclovir (provided by Burroughs Wellcome Co., Research Triangle Park, North Carolina) was diluted in 5 percent dextrose in water at a concentration of less than 10 mg/ml and was administered intravenously over one hour for doses less than 800 mg/m2 or over two hours for doses of 800 mg/m2 or greater. Acyclovir was given every

eight hours to patients with a serum creatinine of 12 mg/dl. Patients with a serum creatinine greater than 2 mg/dl had their dosing interval adjusted according to the formula: dosing interval in hours = serum creatinine X 8. Acyclovir was continued at the initial dosage for at least four days or until toxicity was observed. If no toxicity was observed, the dosage was increased. “Marrow” toxicity was the primary determi- nant of toxicity and was defined as a decrease in the circulating neutrophil count to less than 50 percent of the pre- therapy value (mean neutrophil level for the five days before treatment) for two successive days. Treatment of successive patients was begun at the highest nontoxic dosage reached for the previous patient.

Patients were evaluated daily with complete blood counts, serum creatinine, arterial blood gases, and chest radiograph. Tests of serum electrolytes, chemistry, liver function, and urinalysis with microscopic examination were repeated three times weekly. Patients were also monitored by serial assay of granulocyte-monocyte colony-forming units (CFU-C) in cells from both peripheral blood and marrow. A semisolid agar tissue culture system was used with a modification of a previously described technique [ 171. Marrow mononuclear cells separated on Ficoll-Hypaque were plated in 0.3 percent agar at 1 X lo5 cells/ml. Granulocyte colonies of 40 cells or more were counted after 14 days of incubation. Virology and Serology. Throat, urine, sputum, or endotracheal aspirate, and blood (buffy coat) specimens were cultured two to three times a week. Specimens were inoculated onto a human foreskin fibroblast cell line and observed for six weeks before being considered negative. Cytomegalo- virus was identified by characteristic cytopathic effect. Lung tissue obtained at biopsy or autopsy was inoculated onto human fibroblast tissue culture (fetal tonsil) for primary virus isolation (Diagnostic Virology Laboratory, Childrens Ortho- pedic Hospital and Medical Center, Seattle, Washington). The initial lung cultures were not performed quantitatively; however, quantitative cultures were done simultaneously on both lung biopsy and autopsy specimens frozen at -70%. Lung tissue was homogenized and a 10 percent (weight/volume)

suspension was made in tissue culture medium. Serial lo-fold dilutions beginning at 10m2 were inoculated onto monolayers of human foreskin fibroblasts. Cultures were observed for six weeks. Cultures negative at that time were trypsinized, reinoculated, and incubated for an additional five weeks. The titer of virus was expressed at TCID 50 percent/g lung tissue

[181. Serum was collected before transplant from both the pa-

tient and marrow donor and weekly after transplant from patients to determine antibody to cytomegalovirus by mi- crotiter complement fixation [ 191 using glycine-extracted AD-169 antigen. A fourfold rise in titer was considered a significant seroconversion. Acyclovir Plasma and Tissue Levels. Whole blood was obtained immediately before and after acyclovir infusion at least twice a week during therapy. Selected fresh tissue specimens and heart blood were obtained when possible at autopsy from patients who died of pneumonia. The plasma and tissue were frozen at -20% until drug levels were de- termined by radioimmunoassay [20,21]. Lymphocyte Transformation Assay. Lymphocyte transformation assays using the mitogen phytohemagglutinin (PHA) and cytomegalovirus antigen were performed as previously described [22]. Lymphocytes were harvested after three-day exposure to mitogen and a fiveday exposure to viral antigen. Results were expressed as a stimulation index, calculated as the mean response in counts/min of stimulated cells di- vided by the response in counts/min of unstimulated control cells, using media as the control for mitogen stimulation, and uninfected tissue culture antigen as control for viral antigen stimulation.

RESULTS

Patients. Eight patients were treated with acyclovir for cytomegalovirus pneumonia (Table I). All had received

a marrow transplant for leukemia, and six were in hematologic remission before receiving transplant. Six of the eight were seropositive for cytomegalovirus before transplant; three of eight received marrow from seropositive donors. All patients received random donor platelet and red blood cell transfusions. Granulocytes from seropositive donors were also given to three patients, only one of whom was seronegative for cytomegalovirus before transplant.

Pneumonia occurred a median of 59 days (range 18 to 88) after transplantation. The last seven patients underwent open lung biopsy within three days (median, one day) of the onset of pneumonia, and acyclovir treatment was started within three days (median one day) of biopsy in all patients. Diagnosis was delayed in the first patient due to pulmonary infiltrates interpreted initially as localized pulmonary edema. The onset of fever led to a cytologic examination of endotracheal secretions. Cells containing cytoplasmic and intranuclear inclusions suggestive of cytomegalovirus infection were found. The diagnosis was confirmed by open lung biopsy the next day.

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ACYCLOVIR IN THE IMMUNOCOMPROMISED HOST--WADE ET AL.

TABLE I Characteristics of Patients Treated with High-Dose Acyclovir for Cytomegalovirus Pneumonia

Reciprocal Antibody liter

Number Underlying

lllnaaa

Age WarsV

Sex

1 ANLL remission 15/F 2 ANLL remission 15/M 3 ANLL remission 33/M 4 ANLL remission 43/M 5 ANLL remission 39/M 6 ANLL remission 30/M 7 ANLL relapse 10/F 8 CML chronic 42/M

16 Cytamqalovirus Patient

Before Alter Transplant Transplant Donor

<8 32 <8 64 <8

128 - 256 <8 2512 64

128 - <8 128 - <8

2512 - 64 1512 <8

Granu- locyte Donor

<8 32

None 64

None <8

128

Onset o!

28 18 72 63 88 54 63 54

Days Alter Transplant

Lang Acyclovir Biopsy Treatment

36 36 21 23 73 74 64 64 89 92 56 57 65 65 55 56

Death

47 51 85 74

111 93

Survived 60

ANLL = acute nonlymphocytic leukemia. CML = chronic myelogenous leukemia. l No CMV titer greater than that measured pretransplant.

Acyclovir Dosages and Plasma and Tissue Levels.

The first patient undergoing daily hemodialysis for renal failure associated with hepatic veno-occlusive disease received acyclovir 400 mg/m2 administered once daily. Treatment of the seven subsequent patients was started at 500 mg/m2 or greater (Table II). Acyclovir 500 to 700 mg/m2, given as one-hour infusions, produced a mean peak plasma level immediately after drug infusion of 154 p M (range 47 to 3 16 pMj. The mean trough level at these dosages was 10 p M (range 1 to 36 p M). Doses of 800 mg/m2 or greater were infused over two hours. With this change in infusion time, the mean peak plasma level at 800 and 900 mg/m2 was 142 p M (range 98 to 217) while at 1000 to 1200 mg/m2 the peak plasma levels averaged 222 p M (range 121 to 310). Mean trough levels at these dosages were 32 CL M and 65 p M,

respectively.

Simultaneous samples of lung, heart, liver, kidney, brain, spinal cord, and plasma were obtained at autopsy from five of the study patients (Table Ill). The average acyclovir concentration in lung tissue was 13 1 percent of the simultaneous plasma level. Acyclovir was still detectable in lung tissue of Patient 6 six days after discontinuation of the treatment. Levels in heart and liver were similar to those in the lung. Acyclovir levels measured in the kidney were approximately 10 times higher than the plasma level without a significant dif- ference in levels between the renal medulla and cortex. The acyclovir levels in brain and spinal cord were somewhat more variable, ranging from 25 to 70 percent of the simultaneous plasma level. Efficacy. Seven of the eight patients died of cytomegalovirus pneumonia. Despite an intense interstitial pneumonia with characteristic histologic inclusions, the

TABLE II Acyclovir Plasma Levels and Dosages for the Treatment of Cytomegalovirus Pneumonia

Patient Number

Acyciovir Dose (mg/m*)

Days of Therapy

Mean Peak

Acyclovir Plasma Levels (PM) Mean

Range Trough Range

1 400 10 2 500 21

700 5 3 600 7

700 1 4 600 5

700 5 5 700 12

800’ 7 6 800 4

1000 8 1100 6 1200 14

7 900 5 1000 3

8 1200 4

l Doses of 800 mg/m2 or greater were infused over two hours.

163 134-192 26 20-29 110 47-280 7 0.8-39 122 79-154 9 2-9 162 142-182 25 20-33 185 178-191 19 12-26 111 99- 124 6 3-8 118 95-141 5 4-6 243 202-316 16 1 O-36 217 7 152 91-193 34 16-64 238 219-264 46 36-63 251 221-271 46 13-65 250 216-310 91 666105 119 97-160 5 3-7 - -

224 186-266 23 12-55

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TABLE Ill Acyclovir Tissue Levels and Dosages For the Treatment of Cytomegalovirus Pneumonia

Patient Number

Last Acyclovir

Dose (mg/m2) Plasma’ Lung Heart

Acyclovir Levels (@f) Renal

Liver Medulla Renal Cortex Brain

Spinal Cord

1 400 18 2 700 29 3 600 19.2 6+ 1200 0.5 8 1200 200.4

* Obtained from heart blood at autopsy. 7 Received no therapy for six days before death. NA = not available.

23.1 26.8 21.8 160 130 NA 6.3 36.4 37.7 38.4 320 360 NA 7.6 23.0 NA NA NA NA NA NA

0.7 0.5 0.4 3.1 7.3 0 NA 280 250 310 2680 2620 142 118

TABLE IV Efficacy of High-Dose Acyclovir for the Treatment of Cytomegalovirus Pneumonia

Cytomegatovirus Titer in Patient Days of Lung Tissue Number Survival’ Biopsy Autopsy

1 19 1 x lo’+ 1 x 105+ 2 33 1 x 10s 1 x 108 3 13 2x 108 3x 107 4 11 3x 107 NA 5 22 3x 107 NA 6 39 3x 107 1 x 102 7 Survived Not grown Survived 8 6 1 x 10s 3x 10s

Meanf 1.4 x 105 1.6 X lo5

* From the onset of pneumonia. + Tissue culture infectious dose 50 percent. x Paired specimens only. NA = not available.

lung biopsy specimen from the only survivor did not grow cytomegalovirus. The median survival from onset for those with a fatal pneumonia was 19 days (range 6 to 39) (Table I). Six patients received acyclovir up to the time of death while acyclovir was discontinued in the seventh (Patient 6) before death because of apparent marrow toxicity.

Five patients had autopsy lung tissue cultured for cytomegalovirus, and all five still had virus present

(Table IV). The loglo mean virus titer was unchanged when paired lung biopsy specimen and autopsy cultures were compared. However, the paired specimens from Patients 6 and 8, both of whom received acyclovir 1200 mg/m2, had a decrease in virus titer of five and three logslo, respectively.

All eight patients had cytomegalovirus recovered

from sites other than the lung (Table V). Seven of the eight had virus recovered from cultures of the throat, urine, or blood before the onset of pneumonia. Five of the patients (1 to 4 and 7) had persistently positive cultures from extrapulmonary sites during treatment, while Patients 5, 6, and 8 had negative cultures for one or more weeks before death. Acyclovir was discontinued in Patient 6 because of apparent marrow toxicity; five days later his blood culture was again positive for cytomegalovirus. Patient 7, who survived, was never viremic but had serial throat cultures which remained positive for cytomegalovirus during therapy and for 10 days after. Immune Function. Seroconversion occurred in two patients (Table I). Both had antibody titers which increased the week of their open-lung biopsy. Despite the rise in antibody, both patients died.

The lymphocyte transformation response to phytohemagglutinin and cytomegalovirus antigen is shown in Table ul. Response to phytohemagglutinin was

TABLE V Recovery of Cytomegalovirus from Extrapulmonary Sites

Patient Before 1 Week of Treatment Positive

2 3 4 5 After Sites*

+ + + + + + - t+ Dead ++ + + ++ + + ++ + -

+ + + ++ - Dead

Dead +

Dead

-

+

Dead -

Dead

+Dead’ i-Survived

Th, E-T Th. U, E-T E-T, BC Th, E-T, BC Th, U, BC l-h, E-T, BC Th. U BC

l Site cultured: Th = throat: U = urine; E-T = endotracheal aspirate; BC = blood culture 7 Positive blood culture. t Positive blood culture after discontinuation of acyclovir.

252 Acyctovtr Symposium The American Journal of Medicine


TABLE VI Lymphocyte Transformation Response of Patients Treated with Acyclovir for Cytomegalovirus Pneumonia l

Phytohemagglutinin Survivor Fatal pneumonia

Cytomegalovirus antigen Survivor Fatal pneumonia

Before Afier Therapy Week 1 Week 2 Week 3 Therapy

18.7 (1) 14.9 (1) 30.9 (1) 41.9 (1) 81.2 (5) 101.3 (4) 42.5 (3) 92.2 (2)

6.7 (1) 3.8 (1) 9.9 (1) 11.2(l) 2.5 (5) 2.4 (4) 1.3 (3) 3.2 (2)

l Data expressed as logarithmic mean stimulation index (number of patients tested)

positive for all patients before the onset of pneumonia and remained unchanged during highdosage acyclovir therapy. The mean lymphocyte transformation response to cytomegalovirus antigen was negative before the onset of pneumonia for the five patients with fatal pneumonia and remained negative throughout therapy. Patient 7, who survived, had a positive lymphocyte response to cytomegalovirus antigen before the onset of the pneumonia. The lymphocyte response decreased during the first week of therapy but subsequently increased to a stimulation index of 11.2 measured three weeks after completion of acyclovir treatment. Toxicity. Apparent marrow toxicity with a fall in circulating neutrophil count to less than 50‘ percent of baseline occurred during therapy in three patients (Table VII): Patient 2 experienced renal insufficiency related to aminoglycoside and amphotericin B use early in the treatment course with a rise in serum creatinine from 0.9 to 3.1 mg/dl. He was receiving acyclovir 500 mg/m2 every eight hours. The dosing interval was adjusted based on the serum creatinine during the next

four days, until the creatinine returned to less than 1.5 mg/dl. Despite the change in dosing interval, the circulating neutrophil count fell to zero and remained at this level for three days. Over the next five days, without discontinuation of acyclovir, the neutrophil count returned to normal. Peak and trough plasma acyclovir levels of 280 ,uM and 39 PM, respectively, were reached during the period of renal insufficiency.

Patient 3 began therapy at a dosage of 600 mg/m2. By the seventh day of therapy, the neutrophll count had decreased from a baseline of 4595 to 1296/mm3. Be- cause the patient’s pneumonia was progressing, the acyclovir dosage was increased to 700 mg/m3. The following day the neutrophil count had decreased further (549/mm3) and the acyclovir dosage was decreased to 600 mg/m2. The neutrophil count continued to decline, and the patient died two days later. Peak plasma acyclovir levels in this patient never exceeded 191 pM.

Patient 6 was treated with acyclovir 800 to 1200 mg/m2. While the patient was receiving 1200 mg/m2 the neutrophil count dropped to 1080 mg/mm3. Acy-

TABLE VII Hematologic Results from Patients with Apparent Marrow Toxicity During High-Dose Acyclovir Treatment

Acyciovir Peak Palient Dosage Day of Neutrophil Marrow Marrow Blood Acyciovir

Number (m9/m2) Therapy Count (/mm3) Ceiiuiarity’ CFU-Ct CFU-Ct Level (PM)

2 Baseiinet 464 20 60.5 f 9.2 NA 500 8 0 5 2.3 f 0.5 NA 280 500 22 9405 25 2.5 f 0.6 NA 700 27 2090 30 0.0 NA 134

3 Baseline 4595 30 3.3 f 1.2 0.0 600 7 1290 0 0.0 0.0 191

6 Baseline 4700 35 33 f 5.6 7.5 f 1.7 800 4 6340 NA 13 f 2.4 11.8 f 2.4 160

1000 13 2850 40 27.8 f 3.8 13 f 1.7 264 1100 17 5880 NA 11 f 1.6 9 f 2.5 274 1200 31 1080 5-10 0.0 3.3 f 1.3 310

6 days after 2540 67 2.3 f 0.6 NA

discontinuation

* Percentage of normal marrow ceiiuarity estimated from samples obtained by iliac crest aspirations. t CFU-C = granulocyte-monocyte colony forming units in cell culture. Data expressed as: Mean f,SD per 1 X lo5 cells plated for marrow cells. Mean f SD per 5 X lo5 ceils plated for peripheral blood cells. t Baseline neutrophil count represents mean value of the neutrophil count for the five days before treatment. NA = not available.

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TABLE VIII Hematologic Results from Patients without Marrow Toxicity During High-Dose Acyclovir Treatment

Patient Number

Acyclovir

Dosage

(m91m2)

Day of Therapy

Neutrophil Count (/mm3)

Marrow Cellularity’

Marrow CFU-C’

Blood CFU-C+

Peak Acyclovir

Level (@f)

1

400 4

600

700

5

700

800

7

900

1000

8

Baselinex

10

Baseline

5

10

Baseline

12

19

Baseline

5 8

3407 40 NA NA

2355 NA NA NA

990 50 10.3 f 0.95 3.1 f 1.3

670 25 10 * 1.4 0.0

706 20 10 NA

2240 20 12.8 f 1.3 10 f 2.0

1990 10 30 f 4.4 16.3 f 3.3

1220 5 11.5 f 1.7 18 f 2.8

5040 25 7.5 f 1 1 f 0.8

3384 20 32 f 4.1 1 f 0.7

3350 NA NA NA

3285 70 9.8 f 2.1 4.5 f 1.3

1886 50 3.7 f 1.1 NA

192

125

140

316

224

160

NA

270

Abbreviations and notes as in Table VII.

clovir was discontinued and the neutrophil count

reached its nadir of 583/mm3 three days later. Six days

after drug discontinuation the neutrophil count increased

to 2540/mm3. Peak plasma levels of 3 10 p M and trough

levels as high as 105 p M were achieved at this dosage.

The hematologic variables for the five patients without

marrow toxicity are shown in Table VIII. Marrow cellularity was evaluated in all patients by

marrow aspiration before acyclovir therapy and aver-

aged 30 percent of normal (range 20 to 70 percent)

(Tables VII, VIII). Marrow cellularity at the time of au-

topsy for those patients still receiving acyclovir was 25

percent (range 0 to 50 percent). However, the three

patients who experienced “marrow” toxicity had an

average cellularity of less than 5 percent of normal at

the time the neutrophil count reached its nadir (Table

VII). Marrow cellularity in Patient 6 rose from 5 to 67

percent of normal six days after acyclovir discontin-

uation.

Serial measurements of marrow and peripheral blood granulocyte-monocyte CFU-C were carried out for

seven patients (Tables VII, VIII). The CFU-C paralleled

the decline in neutrophil count during therapy for the

three patients with possible marrow toxicity (Table VII).

Three of the remaining four patients had marrow CFU-C

determinations that remained stable or rose during

therapy, while the fourth, Patient 8, was observed to

have a drop in marrow CFU-C from 9.8 f 2.1 to 3.7 f 1.1 during his four days of therapy (Table VIII).

Possible neurotoxicity was observed in Patient 7. This patient had 60 lymphocytes,found in the cerebral spinal

fluid during a routine intrathecal injection of metho-

trexate three days before the onset of pneumonia. Tests

of spinal fluid chemistry, cytology, and cultures were

normal or negative. Acyclovir treatment was begun at 900 mg/m* five days later, Peak plasma levels during the next five days averaged 119 /_I Mand did not exceed

160 pM. After five days the acyclovir dosage was increased to 1000 mg/m*, and within 48 hours the patient

became lethargic and tremulous. Except for the tremor,

results of the neurologic exam were normal. Cerebral

spinal fluid contained four lymphocytes/mm3, an in-

creased myelin basic protein to 13 ng/ml (normal 0 to

five), but normal glucose and protein and negative cytology. Electroencephalogram was abnormal, showing

increased slow-frequency activity with generalized

polyspike and wave seizure activity. Computerized axial

tomogram of the head was normal. Acyclovir was dis-

continued, and over the next seven days the tremor and

lethargy slowly resolved. A repeat electroencephalo-

gram 14 days later showed improved results, despite

occasional polyspike and wave seizure activity.

COMMENTS

Treatment with high-dose acyclovir, similar to our

previous experience with adenine arabjnoside (un-

published data), interferon [3], or adenine arabinoside

with interferon [4], did not alter the 90 percent mortality

rate among marrow transplant patients with cytome-

galovirus pneumonia. Acyclovir’s mode of action

against herpes simplex virus includes phosphorylation

to the monophosphate derivative by viral-induced thy-

midine kinase and subsequent phosphorylation by

cellular enzymes to the active triphosphorylated com-

pound which then inhibits susceptible viral DNA polymerase [ 231. Despite the fact that cytomegalovirus does not encode for a viral thymidine kinase, cytome-

galovirus-DNA polymerase is sensitive to acyclovir

[ 231, and in vitro studies have shown some strains of

cytomegalovirus to be inhibited by acyclovir at concentrations of less than 200 p M [ lo- 131. Peak plasma

concentrations above this level were reached with the acyclovir dosages used in this trial, but a clinically important antiviral effect was not achieved. In our previous



trial of adenine arabinoside with interferon [4], a con- sistent lOO-fold drop in the virus titer of paired lung specimens sampled at open-lung biopsy and autopsy was found. In this trial this degree of antiviral activity, while not important to the clinical outcome, was seen only in those patients who received acyclovir 1200 mg/m*. Three of the four patients who received acyclovir 800 mg/m* or greater had suppression of viral shedding from extrapulmonary sites. However, this effect appeared to be transient as demonstrated by Patient 6 who again had virus recovered from a blood culture five days after acyclovir was discontinued.

The only predictor of survival was the development of specific cellular immunity as measured by the lymphocyte transformation response. As in our previous trial, the only survivor had a positive lymphocyte transformation response to cytomegalovirus at the time of diagnosis [4]. The lack of specific antiviral immunity among marrow transplant patients dying of cytomegalovirus pneumonia suggests that, for an antiviral agent to be effective, it will have to have activity independent of a host immune response.

The marrow toxicity of high-dosage acyclovir was mild despite circulating peak plasma levels of 200 to 300 /.LM and corresponding trough levels of 50 to 100 pM. In vitro study has shown that growth of marrow CFU-C was not inhibited until cells were exposed to acyclovir concentrations above 220 PM, and that to obtain a 50 percent decrease in activity levels above 440 pM were needed [ 151. The contribution of the cytomegalovirus infection to marrow suppression is difficult to measure but has been previously described [24] and may explain the marrow toxicity seen in Pa- tient 3, who did not have a peak plasma level above 191

iuM.

We have subsequently observed similar toxicity in a second marrow transplant patient who was receiving acyclovir at a dosage of 500 mg/m*. These abnormalities also resolved with discontinuation of acyclovir. These two cases and the description by Sara1 et al. [5] of delirium occurring in two marrow transplant patients who were receiving acyclovir as prophylaxis against herpes simplex virus infection suggest the possibility of acyclovir neurotoxicity among patients with concomitant central nervous system insults such as intrathecal methotrexate or craniospinal irradiation.

The ‘lack of significant toxicity and the possible antiviral activity seen at higher dosages suggests that acyclovir may be useful as one component of combination antiviral treatment. Levin and Leary [ 121 have evaluated the combination of acyclovir with leukocyte interferon in vitro against both wild and laboratory strains of cytomegalovirus. Interferon concentrations of 0.6 to 2.5 IU/ml when combined with acyclovir re- duced the IDso of acyclovir to 25 percent of the level needed when acyclovir was used alone. The acyclovir concentrations used were within the range of levels reached in our single-agent trial. Spector et al. have also shown an additive antiviral effect against cytomegalovirus with the combination of acyclovir and fibroblast interferon [ 251.

Acyclovir for the treatment of cytomegalovirus infections in other patient populations is also being evaluated [26]. Its use in patients with better preserved host defenses may be more promising than with marrow transplant patients presented here. Even at high dosages in seriously ill patients acyclovir had minimal toxicity, and its use in combination with other antiviral agents should be investigated.

The apparent neurotoxicity, which consisted of tremor and lethargy, was mild and reversible and did not ACKNOWLEDGMENT

appear directly refated to the plasma level. The cerebral We gratefully acknowledge the contribution of B. spinal fluid pleocytosis found before treatment may Newton, R.N., K. Porter, J. Anderson, L. Day, F. Shiota, suggest that neurotoxicity will occur only in patients and the nurses and physicians of the Seattle marrow

with preexisting central nervous system abnormalities. transplant team in the performance of these studies.

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Treatment of cytomegalovirus pneumonia with high-dose acyclovir

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