Download Summary of Infectious Complications Occurring

[CANCER
RESEARCH
26 Part 1, 1290-1296, June 1966]
Summary of Infectious Complications Occurring in
Patients with Hodgkin's Disease
ALBERT R. CASAZZA,
CHARLES P. DUVALL, AND PAUL P. CARBONE
Medicine Branch, National Cancer Institute,
NIH, Hethesda, Maryland
greater than 38°C,hypotension,
Summary
pulmonary symptoms,
etc.)
disease were reviewed. Thirty-five patients were found to have
significant infectious complications during their clinical course.
The majority of these problems occurred during the last quarter
of illness, when chemotherapy was ineffective. Bacterial infec
tions, especially septicemia, were most frequent although a
relatively large number of viral and fungal diseases were found.
Single episodes of toxoplasmosis and pneumocystis were also
discovered in this series.
Thirty-five of the 51 patients were infected at the time of
death ; however, infection per se could not be shown to adversely
affect survival for the entire group. However, each of the 4 docu
mented infections with cryptococcosis was primarily responsible
for the death of the affected patients. Nevertheless, all patients
had active Hodgkin's disease at autopsy. No relationship of
infection to various forms of therapy or to leukopenia was found
for bacterial infections; however, 90% of the patients with fungal
disease and 100% of the patients with cytomegalic inclusion
disease received corticosteroids.
coupled with microbiologie documentation of bacterial and fungal
disease. In only 1 instance, a response to antibiotic therapy was
used as supporting evidence. An infection was considered present
if there was appropriate histopathologic evidence regardless of
the presence or absence of cultural data. A positive heart blood
culture was interpreted in light of clinical and histopathologic
data.
The diagnosis of herpes zoster or varicella was made on find
ing typical clinical signs and symptoms alone, whereas the diag
nosis of cytomegalic inclusion disease or disseminated herpes
simplex was made usually with confirmatory histopathologic ma
terial.
Fifty-four charts were reviewed and 51 were found acceptable
for this study. Three were not included because of incompleteness.
Nineteen patients were female, and 32 were male. The median
age at the time of biopsy was 33 years. The median survival from
the time of biopsy (diagnosis) was 30 months (Table 1).
These 51 patients were classified as to the stage of disease (2)
by the authors according to the clinical data presented in the
records (Table 1).
Introduction
Results
Infections are frequently encountered during the course of
patients with neoplastic diseases (5, 6, 22). Changing patterns of
bacterial diseases and increasing frequencies of fungal diseases
have been reported, particularly in patients with acute leukemias
and malignant lymphomas (14, 16, 25). Moreover, infections due
to organisms with low pathogenicity for normal human adults
have been described (Refs. 8, 9, 16, 17, 25-27).
This report elucidates the frequency, type, and distribution of
infections occurring during the course of patients with Hodgkin's
disease and examines the role of therapy and extent of disease
predisposing to their development. Moreover, the relationship
of infection to mortality was investigated.
Thirty-eight of the 51 patients surveyed experienced episodes
of infection during the course of their neoplastic disease. Three of
these 38 patients had infections which were adequately treated
and did not recur so that the infection had no role in the ultimate
demise of these patients. The remaining 35 patients had infec
tions at autopsy. In 17 of these 35 patients the infections oc
curred prior to the terminal episode, whereas 18 became infected
only during the last 1-10 days of life (Table 2). The median sur
vival for the 2 groups of patients (i.e., those with and without
demonstrable infections at postmortem examination) was essen
tially the same (Table 2). All patients in this study population
had active Hodgkin's disease demonstrated by autopsy, and no
patient died of infection alone while the diseae was in apparent
remission. Five patients were considered to have died because of
infection (Table 3).
The charts and autopsy protocols of 51 patients with Hodgkin's
Materials
and
Methods
All charts of patients with Hodgkin's disease autopsied at the
NIH during the years 1953-64 were reviewed. The number and
type of infectious episodes and the relation of these episodes to the
course of disease, treatment, and hématologiestatus were ex
amined. The clinical and autopsy findings were evaluated to
determine the cause of death.
An infectious episode was defined as an event of clinical signs
and symptoms highly indicative of sepsis (i.e., chills, temperature
1290
T ijpes of Infection
All infectious episodes were categorized for the 35 patients with
infections at post mortem. The total number of infections was 86
and the average number of infections per infected patient was 2.3
(Table 4). Bacterial infections were most common in this
group of patient, caused the major portion of morbidity, and
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Infectious
TABLE 1
No. of patients
Ratio of females to males
Median age in years (range)
Median survival in months (range)
Clinical staging at time of biopsy
Stage I
Stage II
A
B
Stage III
Not defined
Complications
TABLE 4
51
19/32
33 (6-71)
30 (1-135)
1
25
10
15
21
infectionsBacterialBacterial
Types of
episodes497983711156171038<>1.72.3
of
aloneBacterial
otherViralViraland
onlyViral
otherFungalFungal
and
onlyFungal
otherMiscellaneousToxoplasmaPneumocystisTuberculosisTotalNo.
and
4
TABLE 2
characteristicsNo
Patient
postmortem)Clinical
infections (clinical or
postmortemClinical
infections, none at
infectionTerminal
and/or postmortem
onlyPreterminal
infection
and terminal133351817Mediansurvival(months)3230
episodes/patientNo.
of
of episodes/patient
fectionXo.
with in
TABLE 5
TABLE
Causes of death
Hodgkin's disease alone
Ilodgkin's disease and infection
Primarily Hodgkin's disease
Primarily infection
Infections alone
Bacterial infections
Xo. of patients
Septicemia
Primary site unknown
Primary site known
Pneumonias
Skin abscesses
Lung and skin
Empyema
Gastrointestinal
tract
Pneumonia
Enteritis
Urinary tract
Skin abscesses
Miscellaneous
16
35
30
5
(I
were associated most frequently with mortality. Nevertheless,
viral, fungal, and rarer types of infections were noted for 30 of
the 86 episodes. The distribution of the different types of infec
tions is listed in Table 4. Mixed infections, i.e., bacterial and
viral, bacterial and fungal, bacterial and miscellaneous, accounted
for nearly 30'o of the total number of infectious episodes.
111
21
10
5
2
3
1
Total
Bacterial Infections
Septicemia occurred with surprising frequency in these pa
tients and represented the most common manifestation of bac
terial infection. Seventy-five % of these episodes were associated
with a known primary site of infection. Table 5 depicts the fre
quencies of the different kinds of bacterial infections. Hemolytic
Staphylococcits aureus, Pseudomonas aeruginosa, and Escherichia
coli were the organisms most frequently associated with blood
stream invasion (Table 6). These same organisms were respon
sible for the majority of pneumonias. There was only 1 instance
of pneumococcal pneumonia.
Each of the 4 episodes of enteritis was associated with a strain
of salmonella organisms. The usual pathogens were encountered
in the instances of urinary tract infections and skin abscesses. All
of the 3 ca.sesof empyema and most of the cases or urinary tract
infection were associated with structural abnormalities related to
the underlying Hodgkin's disease (e.g., fistulous eommunica-
Number
n
4
4
4
I
56
TABLE 6
BACTERIALSEPTICEMIAS
organismsHemolytic Kind of
aureusPseudomonas
Slaphylococcus
sp.Escherichia
coliStreptococcus
sp.Klebsiella
sp.Proteus
sp.Paracolon
bacillusMixedGram-negativeHemolytic
Gram-negativeTotalNumber3110552111429
Staphylococcus and
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Albert R. Casazza, Charles P. Duvall, and Paul P. Carbone
TABLE 7
VIRAL INFECTIONS
Herpes zoster
Varicella
Cytomegalovirus
Herpes simplex
TABLE 9
INFECTION CORRELATEDWITH DISEASE COURSE
QUARTER1st0102nd1003rd4524th2352TERMINALPERIOD2866TOTALEPISODES5
TYPEBacterialViralFungalDISEASE
1
5
3
Total
17
Fungal Infections
TABLE 8
Infections
Number
FungalDisseminatedCryptococcusHistoplasmaNocardiaLocalPulmonary
There were 6 cases of disseminated fungal infections and 4 other
patients with localized fungal disease (Table 8). Each instance
of cryptococcal disease was felt to be the major cause of death.
Miscellaneous
Candida)Gastrointestinal
(Nocardia and
(Candida)TotalMiscellaneousMycobacteriaToxoplasmaPneumocystis
Infections
There were single cases of disseminated
tuberculosis
and
toxoplasmosis and pulmonary
pneumocystitis
encountered
in
this series of patients. These infections caused major morbidity
but were considered not to be the primary cause of death. The
case of tuberculosis was the only one in this group in which a
positive diagnosis was made before death.
Clinical Correlations
Most of the infections occurred relatively late in the disease
course. To substantiate
this hypothesis, the clinical course was
divided into quarters. The terminal period was listed separately
from the 4th quarter. The terminal period was defined as that
period (1-10 days before death) in which a sudden adverse turn
cariniiTotal4112264101113
tions). Similarly, most of the episodes of skin abscesses were
related to excoriations or the administration
of intravenous
therapy.
Of the 5 patients with Hodgkin's disease who died primarily
of infection, only 1 died of bacterial disease—staphylococcal
pneumonia.
The remaining patients
died of cryptococcal
disease.
Viral Injections
There were 8 instances of herpes zoster and 1 case of adult
varicella in this group of patients (Table 7). These occurrences
were not associated with mortality and therefore were not con
sidered in analyzing the survival data. Nevertheless, 4 of the 5
cases of cytomegalic inclusion disease and all the cases of dis
seminated herpes simplex were diagnosed only at postmortem
examination. One case of cytomegalovirus
infection (CID) was
discovered by antemortem culture of saliva. Most CID infections
were not implicated as major causes of demise; however, each
episode of herpes simplex and one of CID were considered signifi
cant contributory
factors to mortality. All of the patients with
CID had coexisting infections. Four of these 5 had inclusions
in alveolar cells of the lungs. The presence of these inclusions
was considered to be clinically insignificant in producing disease
manifestations except in 1 patient who had a hemorrhagic bronchopneumonia.
1292
of events occurred leading to the death of the patient. Table 9
shows the relative frequency of infections according to taxonomie
group that occurred during the defined intervals. The preponder
ance of episodes occurred during the 4th quarter and with the
terminal period.
Because chemotherapy
and steroid therapy have been impli
cated as predisposing factors to infection (11, 30), the amount
and type of therapy administered
was charted according to
quarters for both the infected and noninfected patients. As can
be seen in Chart 1, the proportion of patients receiving radiation
therapy and chemotherapy was relatively constant in each quar
ter for the infected group. On the other hand, the proportion of
patients receiving radiation therapy decreased and the propor
tion receiving chemotherapy increased as the disease progressed
for the noninfected group (Chart 2). The proportion of patients
receiving steroids increased significantly in the last quarter for
both groups.
Leukopenia (granulocytes less than 1000/cu mm) was not a
significant contributing factor to infection as only 4 of the 35
infected patients had this degree of leukopenia during the termi
nal episode whereas 3 of the 16 noninfected patients experienced
this degree of leukopenia within the last 10 days of life.
Although the median survival for both the noninfected group
and the infected group was similar, life-table analysis (Chart 3)
shows that the slope of the probability curve of survival for the
infected group was less than that for the noninfected groups after
the point of median survival. Because the staging and histology
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RESEARCH
VOL. 2(>
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Infectious Complications
Radiotherapy
1.0
Chemotherapy
Corticosteroidi
0.8
UJ <
H o:
<
Lu
0.6
Lu
O
0.4
tr o
O uj
0.2
ir
O.
3rd
2nd
4th
DISEASE QUARTER
CHART \. Correlation
of therapy to the course of the disease in 25 patients
with only bacterial
infections at postmortem.
Radiotherapy
1.0 -
Chemotherapy
^.>
5$
< ui
u. *~
o o
2?
O >
Corticosteroids
0.8
0.6
0.4
H UJ
ir o
o ui
è* °2
2nd
DISEASE
CHART 2. Correlation
4th
3rd
QUARTER
of therapy to the course of the disease in 16 patients without
infection.
1.0
Survival :
o infected - 35 Patients
•Unmfected - 16 Patients
0.8
cr
0.6
5 °4
OD
CO
§ 0.2
CL
10
20
30
40
50
60
70
80
90
100
DISEASE DURATION (Months)
CHART 3. Life-table analysis: probability
curves.
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Albert R. Casazza, Charles P. Duvall, and Paul P. Carbone
TABLE 10
SURVIVALANDTYPE OF INFECTIONS
Survival group infected
(months)g30>30Xonpatients1910Bacterial158Fungal02Bacterial
and fungal34Other12
patients88Infected
of both groups was similar, the difference in slope implies that
infection did not affect survival adversely.
The infected category of patients was then separated into 2
subgroups according to survival. Table 10 shows the distribution
of the various types of infection in those patients surviving up
to the median time and those living longer. Two points are ap
parent. Of those 19 patients dying with infection after a brief
course of Hodgkin's disease, 15 died with only a bacterial in
fection, whereas those dying after a relatively prolonged illness
were prone to have fungal disease as well as bacterial infections.
There was only 1 instance of disseminated fungal disease (histoplasmosis) in the 19 patients living 30 months or less, whereas
there were 5 instances of disseminated fungal disease in the 16
patients living longer than 30 months. All 4 episodes of cryptococcosis occurred in patients surviving longer than 30 months.
The mean survival of these patients so infected was 92 months
(median 102 months).
The mean survival of the 5 patients with CID was 27 months
(median 30 months). The episodes of toxoplasmosis and pneumocystis occurred in patients with longer survivals.
Discussion
Infection has been recognized as a major cause of morbidity
and mortality in patients with hématologiemalignancies (14,
25). Bacterial and fungal diseases have been frequently associated
with acute leukemia (14, 30), chronic lymphatic leukemia (4,
21), multiple myeloma (10), and lymphomas with hypogammaglobulinemia (31). Herpes zoster, tuberculosis, and fungal dis
eases, especially cryptococcosis, have been described as common
complications of patients with Hodgkin's disease (1, 5, 12, 16,
28). In the present report, 35 of 51 patients were found to have
significant clinical infections during their disease course. Bac
terial infection occurred as the only infectious complication in
15 of 19 patients surviving less than 30 months, whereas mixed
bacterial and fungal or virus was more prevalent in those pa
tients living more than 30 months. As has been reported, herpes
zoster and cryptocoeeal infections were important causes of
morbidity and/or mortality in 12 of 51 patients. Tuberculosis
was noted in only 1 patient. Eighteen patients had more than 1
infectious episode during their clinical course. Of the 86 occur
rences of infection, 25 were mixed, involving more than 1 type of
organism.
Certain features of these infections are of interest. Unlike the
secondary hypogammaglobulinemic states (10, 31), Hodgkin's
disease does not seem to be punctuated with episodes of infection
during the course of illness. The overwhelming majority of in
fections occurred during the last quarter of illness, and 33% of
patients had a single infection associated with the terminal epi
1294
sode. Moreover, 33% of patients with multiple infections con
tracted infectious disease during the last 12% of the clinical
course. Five of these 17 patients had local structural abnormali
ties which were considered significant etiologic factors.
Although I of patients were infected at autopsy, no adverse
effect of infection on survival could be demonstrated either by
comparing the median survival of infected and noninfected
groups or by analyzing the probability of survival from lifetable analysis (Chart 3). It must be emphasized that all patients
had active Hodgkin's disease at autopsy.
Several investigators have reported the high propensity of
patients with leukemia or lymphoma to develo]) staphylococcal or
Gram-negative sepsis (14, 22, 30). Hersh et al. (16) have shown
that pseudomonas septicemia is becoming more frequent and
staphylococcal septicemia less frequent as a cause of death in
acute leukemia. Our results confirm this as septicemia was the
most frequent type of bacterial infection and hemolytic Staphi/lococcus aureus, E. coli, and Pseudomonas aeruginosa were the or
ganisms most frequently responsible. However, the rising inci
dence of pseudomonas septicemia was not seen in this small group
of patients. An unusual association of salmonella infections with
Hodgkin's disease has been «'porteti by Heineman el al. (13)
and confirmed by this study, as 4 episodes of salmonella enteritis
were discovered in this group of patients.
Herpes zoster occurred with an incidence of 16%. This is higher
than the range of 3-8 c/0reported elsewhere (5, 28). There was
only 1 case of partial alopecia and facial scarring secondary to
herpes zoster. The other episodes were self-limited without serious
morbidity. One episode of mild varicella was recorded. Two pa
tients with significant herpes simplex infections had severe ul
cerative esophagitis. In 1 patient, there was extension to the
tongue, larynx, and bronchi, with an extensive herpetic bronchopneumonia. In addition there was associated candida esophagitis
and active Toxoplasma condii subacute necrotizing encephalitis
and focal myocarditis. This case has recently been reported in
greater detail (7).
Cytomegalic inclusions were fountl in 10% of cases. The lungs
were involved in 4 of the 5 cases. Although cytomegalie inclusion
pneumonia is a frequent cause of morbidity in patients under
going renal homotransplantation (15), inclusion pneumonitis was
felt to be significant in only 1 patient. A preliminary study
published elsewhere by the present authors indicates that
the salivary gland virus can be recovered from approximately
3390 of adult patients with hématologiemalignancies.1 In those
patients, as in these, the symptomotology and pathophysiology
of this infection are obscure.
In reviewing the cases of adult Pneumocystis carinii infections,
28 instances of this infection were discovered (Refs. 26, 32; C. P.
Duvall, unpublished review). Six cases were associated with
Hodgkin's disease, and 2 with other types of lymphoma. Al
though coexistent cytomegalie inclusion disease was found in 8
of the 29 instances, no patient in this present series had both
these infections. Although Pneumocystis carinii pneumonitis was
suspected clinically in the 1 case described herein, diagnosis was
not made until autopsy.
Toxoplasmosis must be recognized also as a complicating
feature of Hodgkin's disease. The clinical and pathologic findings
have been reported in greater detail (7). In this instance, the
correct diagnosis was made at postmortem examination; however,
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Infectious
Complications
in at least 1 other instance (8), a correct clinical diagnosis was
made and effective therapy was given.
Hodgkin's disease has been reported as the type of lymphoma
most frequently associated with fungal disease (16). The intrin
sic nature of Hodgkin's disease, adrenal eorticoid therapy, and
chemotherapy have been reported as factors which predispose to
and account for the increased incidence of fungal diseases in
these patients (11, 16, 17, 29). The 20% incidence noted in this
group correlates well with that reported in the literature (19).
Special mention must be made of the cryptococcal infections
encountered in this report. Although the cryptococcus organism
is a pathogenic organism under usual circumstances, it seems to
assume increased virulence when attacking patients with Hodg
kin's disease. The resulting disease is usuali}' more widely dis
its considerable nephrotoxicity, remains the agent of choice for
treating cryptococcosis, histoplasmosis, eandidiasis, and aspergillosis. Nocardia can be treated with sulfonamides (27).
Similarly, establishing the diagnosis in the rare cases of pneumocystis and toxoplasmosis is of moni than academic importance
as a new agent, pentamidine isothionate, may be effective for
the former (23, 24) and sulfonamides are useful for the latter
(8). There is no therapy available for disseminated cytomegalic
inclusion disease; however, trials of various antiviral agents in
animals are in progress, and in vitro trials utilizing tissue culture
technics are planned.
seminated (33), and this was corroborated by this study. This
infection was considered the primary cause of death in each
instance encountered during this study. Two of the 4 patients
had substantial doses of amphotericin, while 1 died shortly after
diagnosis and 1 case escaped clinical detection. Hutter and
Collins, however, have reported good results in treating 16 cases
of cryptococcus with amphotericin B (16).
Patients with Hodgkin's disease usually have normal 7-globu-
1. Aisenberg, A. C. Studies on Delayed Hypersensitivity
in
Hodgkin's Disease. J. Clin. Invest., 41: 1964-70, 1962.
2. — —. Hodgkin's Disease—Prognosis, Treatment, and Etio
lin levels. However, decreased antibody production, delayed
homograft rejection, and impaired delayed hypersensitivity
responses are manifestations of the primary immunologie defects
encountered in this disease (2, 3, 18). A retrospective report such
as this cannot evaluate such features. This study seemed to
indicate that the role of radiotherapy, chemotherapy, and
steroid therapy in predisposing these patients to infection was
relatively minor. The patients who were not infected received
relatively more radiotherapy and chemotherapy than those with
bacterial infection, whereas both groups received a similar
amount of steroids. All the patients with CID and 90';c with
fungal diseases received steroids during the course of illness.
It is to be noted that patients with structural abnormalities
due to the neoplastic disease behaved like those with localized
carcinomas and developed multiple infections (20).
Almost all infections occurred when the neoplasm was far
advanced and no longer responsive to chemotherapy. This is to
be contrasted with earlier periods of active disease during which
the patients were notably free of infection. Successful manage
ment of these infections requires effective antineoplastic chemo
therapy, accurate diagnosis, and specific therapy of the infectious
complication. If the disseminated neoplastic disease cannot be
controlled, the patient usually will either die with the initial
infection or with a subsequent episode occurring shortly there
after. Examination of the skin and lungs, detection of local
mechanical defects, and serial blood cultures should provide
valuable information for most bacterial infections. Antibiotic
therapy when administered in the absence of known etiologic
factors must be geared to combat the high incidence of staphylococcal and Gram-negative bacillar}- disease. Such a program
might include methicillin and colistin.
Unexplained clinical deterioration in the absence of proven
bacterial disease should alert the physician to the possibility of
fungal infections, particularly for those patients with disease
duration in excess of 30 months. All but 2 of the fungal infec
tions present in this series involved either the lungs, blood,
meninges or a combination of these sites. Amphotericin li despite
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CANCER
RESEARCH
VOL. 26
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Summary of Infectious Complications Occurring in Patients with
Hodgkin's Disease
Albert R. Casazza, Charles P. Duvall and Paul P. Carbone
Cancer Res 1966;26:1290-1296.
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