1354
Bacterial Infections in Patients with Visceral Leishmaniasis Thrcisio M. Andrade, Edgar M. Carvalho, and Heonir Rocha
From the Department of Medicine, University of Bahia, Salvador, Brazil
Visceral leishmaniasis is a severe protozoan disease characterized by fever, hepatosplenomegaly, anemia, leukopenia, and hyperglobulinemia and always requiring hospitalization. The disease occurs predominantly in children and is associated with many immunologic disorders, including depression of cell-mediated immunity to Leishmania antigen and other, nonrelated antigens [1-4]; the presence of serum suppressor factors capable of strongly suppressing the immune response [5, 6]; polyclonal B cell activation with autoantibody production [7, 8]; and the presence, in the serum, of high levels of immune complexes [9]. The most common complications associated with visceral leishmaniasis are bacterial infections and bleeding. Microbial infections have been reported in as many as 53 % of visceral leishmaniasis patients, and they represent the most common cause of death in this disease [10]. In addition, bacterial infection is an early finding in the clinical course ofleishmaniasis and is often documented in outpatient services in children with subclinical visceral leishmaniasis, a stage previous to the full-blown disease [11]. The knowledge of the type of infection occurring in this particular host and the more common pathogens would provide a more rational approach to patient management. In addition, it will provide a better un-
Received 7 June 1989; revised 10 May 1990. Informed consent was obtained from the patients or their parents or guardians; the study protocol was approved by the Ethical Commission of the Hospital Universitario Professor Edgard Santos. Financial support: National Institutes of Health (AI-16282). Reprints or correspondence: Prof. Heonir Rocha, Hospital Universitario Prof. Edgard Santos, 6° andar, Rua Joao das Botas, sIn Canela, 40140 Salvador, Bahia, Brasil. The Journal of Infectious Diseases 1990;162:1354-1359 © 1990 by The University of Chicago. All rights reserved. 0022-1899/90/6206-0020$01.00
derstanding ofthe susceptibility of visceral leishmaniasis patients to bacterial infections. The aim of this study was to determine prospectively the incidence and time to develop bacterial infections in hospitalized patients with visceral leishmaniasis and the most common causative agents isolated from these cases.
Materials and Methods Patients. The study considered 31 patients consecutively admitted with the diagnosis of visceral leishmaniasis from July 1983 to December 1986 in three hospitals in Salvador, Brazil (Hospital Universitario Professor Edgard Santos, Hospital Martagao Gesteira, and Hospital Santo Antonio). One patient was excluded due to the use of corticosteroids. The diagnosis of visceral leishmaniasis was made by documentation of amastigotes in bone marrow aspirates (Giemsa-stained) in 25 patients. The remaining 5, who did not have bone marrow aspiration, had positive serologic tests [11]. All patients exhibited a clinical picture compatible with visceral leishmaniasis, including fever, hepatosplenomegaly, and weight loss and at least two of the following laboratory-detennined abnormalities: anemia, leukopenia, hyperglobulinemia. Malnourishment was observed in all patients, although none had kwashiorkor or marasmus clinically. No other significant associated clinical condition was recorded in any of these cases. All 30 patients were examined twice a week by one of us. The time between admission and discharge or death was considered the admission time or hospitalization. Whenever signs of bacterial infection were detected. patients had appropriate cultures and tests to determine the causes of their infections. The time between admission and the appearance of signs of infection was called time of exposure. In patients who did not develop infection, the exposure time was the same as the admission time. Because of the great number of bacterial infections in patients with visceral leishmaniasis and to investigate the importance of variables such as age, nutritional status, and time of exposure to nosocomial infection, we decided to evaluate the frequency of infection in pa-
Downloaded from http://jid.oxfordjournals.org/ at University of Ulster on June 9, 2015
Bacterial infections are often seen in patients with visceral leishmaniasis. To determine the incidence ofsuch infection and the more common infectious agents, 30 consecutive patients with visceral leishmaniasis. were followed throughout hospitalization. There were 24 episodes of bacterial infection in 18 patients (60%). The incidence of bacterial infections in these patients was 22.2/1000 days of admission. The proportion of patients becoming infected by time was significantly greater in the visceral leishmaniasis group than in controls (P < .01). The skin, respiratory tract, and middle ear were the most common sites ofinfection, and Pseudomonas aeruginosa and Staphylococcus aureus were the most common agents. Low-grade-virulence bacteria (e.g., Serratia and Providencia species) were also isolated from some cases. Bacterial infections (mainly nosocomial) in patients with visceral leishmaniasis tend to be severe and can cause death. When bacterial infection is suspected in these patients, empiric antibiotic therapy should bestarted immediately, including coverage for R aeruginosa and S. aureus, after appropriate diagnostic procedures are taken.
JID 1990;162 (December)
Infections in Visceral Leishmaniasis
1355
Table 1. Site of bacterial infections in 18 visceral leishmaniasis patients. Site Skin Respiratory tract Middle ear Intestinal tract Oral mucosa Blood Total
No. of infections (%) 8 (33.3) 8 (33.3) 4 (16.7) 2 (8.3) 1 (4.2) 1 (4.2) 24 (100.0)
Visceral leishmaniasis
C
Q) .~
Control group
C
0
-i->'~
Itl-i->
0.
~ 0040
........ o C c
o
t o e
0.20
0.
0..
0.00 l----r-----,.....--,-----,--r-----r-.....------r-.,-----r--r------r!----,
o
5
10
15
20 25 30 35 40 45 50 55 60 65 TI~
( Days)
Figure 1. Difference between proportion of individuals with visceral leishmaniasis and control group who become infected as functionof time was statisticallysignificant (P < .01, X2 5.98, 1 df).
appropriatelydistinguishesbetweena patient who had an infection, for example, 10 days after admission (i.e., an uncensored observation) and a patient who did not havean infectionand wasdischarged 10 days after admission (i.e., a censored observation). This methodology is further described in [16]. The Kaplan-Meier curves for the controland visceral leishmaniasis groups werecomparedstatistically using the log-rank test described by Mantel [17]. All P values are two-sided.
Results
Incidence and site ofinfections. Bacterial infections were documented in 18 (60 %) of the 30 patients with visceralleishmaniasis, with a total of 24 episodes of infections (table 1). The incidence of bacterial infection in the visceral leishmaniasis patients was 22.2/1000 days. The skin, respiratory tract, middle ear, intestinal tract, and oral mucosa were the most common sites of infection. In one patient, septicemia was documented without evidence of an original site of infection. In the 16 patients with other clinical conditions, 2 (12.5 %) developed infections (pneumonia and purulent rhinitis), for an incidence of 5.5 infectionsl1000 days. Figure 1 shows as a function of time the proportion of individuals in the control and visceral leishmaniasis groups who became infected. The difference between the two groups is statistically significant (P < .01, x2 5.98, 1 df). There was no statistically significant difference (P > .05) when variables such as age, duration of illness, and time of exposure were compared between the two groups. Clinicaland laboratory features. Some clinical and laboratory features observed in the 30 visceral leishmaniasis patients are shown in table 2. Most were children. The age range was 1-29 years (mean, 9 ± 7.9). There were 19 male and 11 female patients. The duration of illness was 7 ± 6.1 months in the group with associated bacterial infection and 6 ± 5.7 months in the group without bacterial infection (P > .05).
Downloaded from http://jid.oxfordjournals.org/ at University of Ulster on June 9, 2015
tients with other clinical conditions admitted to the same hospitals where this studywasconducted.This "control" evaluation wasstarted 1 year after the beginning ofthe leishmaniasis studywhen20 visceral leishmaniasis patients had been enrolled, and involved 16 age- and sex-matched subjectswithclinical evidenceof malnourishment. The distribution of the controlpopulationin the threehospitals wassimilar to that of the visceral leishmaniasispatients. The clinicalconditions were proteincaloric malnutrition(5 cases), femurfracture (4 cases), and iron-deficiency anemiaassociated with ancylostomiasis,Hodgkin'sdisease, hypospadias, congenitalmegacolon, and idiopathic congenital myocardiopathy (1 each). These patients were followed similarlyto the visceralleishmaniasis group,andbacteriologic studies were performed whenever signs of infection were detected. Specimens for bacteriologic studies. Specimens were obtained from all sites considered infected. Cutaneous specimens were obtained with a cotton swabin a deep area of lesions after appropriate cleaning or by inoculation of 1 ml of sterile 0.9% saline into the lesion and subsequent aspiration with a syringe. All open wounds produced purulent secretion. Specimen collection was done carefully to avoidthe predominantlyisolated colonizingbacteria instead of the probable causative agent. The specimensfrom patients with respiratory tract infection were obtained as described by Sommers and Good [12]. A nebulization with warmed 0.9% sterile saline was done for 15 min, and then the induced expectorated sputum was collected for culture and Gram's stain. The specimens were considered good when there were >25 neutrophils and or , respectively) in the group with bacterial infection were compared with those in patients without bacterial infection (3375 ± 931 and 1361 ± 645 cells/ram'), no statistically significant difference was found. Granulocyte counts
Bacterial Infections in Patients with Visceral Leishmaniasis Thrcisio M. Andrade, Edgar M. Carvalho, and Heonir Rocha
From the Department of Medicine, University of Bahia, Salvador, Brazil
Visceral leishmaniasis is a severe protozoan disease characterized by fever, hepatosplenomegaly, anemia, leukopenia, and hyperglobulinemia and always requiring hospitalization. The disease occurs predominantly in children and is associated with many immunologic disorders, including depression of cell-mediated immunity to Leishmania antigen and other, nonrelated antigens [1-4]; the presence of serum suppressor factors capable of strongly suppressing the immune response [5, 6]; polyclonal B cell activation with autoantibody production [7, 8]; and the presence, in the serum, of high levels of immune complexes [9]. The most common complications associated with visceral leishmaniasis are bacterial infections and bleeding. Microbial infections have been reported in as many as 53 % of visceral leishmaniasis patients, and they represent the most common cause of death in this disease [10]. In addition, bacterial infection is an early finding in the clinical course ofleishmaniasis and is often documented in outpatient services in children with subclinical visceral leishmaniasis, a stage previous to the full-blown disease [11]. The knowledge of the type of infection occurring in this particular host and the more common pathogens would provide a more rational approach to patient management. In addition, it will provide a better un-
Received 7 June 1989; revised 10 May 1990. Informed consent was obtained from the patients or their parents or guardians; the study protocol was approved by the Ethical Commission of the Hospital Universitario Professor Edgard Santos. Financial support: National Institutes of Health (AI-16282). Reprints or correspondence: Prof. Heonir Rocha, Hospital Universitario Prof. Edgard Santos, 6° andar, Rua Joao das Botas, sIn Canela, 40140 Salvador, Bahia, Brasil. The Journal of Infectious Diseases 1990;162:1354-1359 © 1990 by The University of Chicago. All rights reserved. 0022-1899/90/6206-0020$01.00
derstanding ofthe susceptibility of visceral leishmaniasis patients to bacterial infections. The aim of this study was to determine prospectively the incidence and time to develop bacterial infections in hospitalized patients with visceral leishmaniasis and the most common causative agents isolated from these cases.
Materials and Methods Patients. The study considered 31 patients consecutively admitted with the diagnosis of visceral leishmaniasis from July 1983 to December 1986 in three hospitals in Salvador, Brazil (Hospital Universitario Professor Edgard Santos, Hospital Martagao Gesteira, and Hospital Santo Antonio). One patient was excluded due to the use of corticosteroids. The diagnosis of visceral leishmaniasis was made by documentation of amastigotes in bone marrow aspirates (Giemsa-stained) in 25 patients. The remaining 5, who did not have bone marrow aspiration, had positive serologic tests [11]. All patients exhibited a clinical picture compatible with visceral leishmaniasis, including fever, hepatosplenomegaly, and weight loss and at least two of the following laboratory-detennined abnormalities: anemia, leukopenia, hyperglobulinemia. Malnourishment was observed in all patients, although none had kwashiorkor or marasmus clinically. No other significant associated clinical condition was recorded in any of these cases. All 30 patients were examined twice a week by one of us. The time between admission and discharge or death was considered the admission time or hospitalization. Whenever signs of bacterial infection were detected. patients had appropriate cultures and tests to determine the causes of their infections. The time between admission and the appearance of signs of infection was called time of exposure. In patients who did not develop infection, the exposure time was the same as the admission time. Because of the great number of bacterial infections in patients with visceral leishmaniasis and to investigate the importance of variables such as age, nutritional status, and time of exposure to nosocomial infection, we decided to evaluate the frequency of infection in pa-
Downloaded from http://jid.oxfordjournals.org/ at University of Ulster on June 9, 2015
Bacterial infections are often seen in patients with visceral leishmaniasis. To determine the incidence ofsuch infection and the more common infectious agents, 30 consecutive patients with visceral leishmaniasis. were followed throughout hospitalization. There were 24 episodes of bacterial infection in 18 patients (60%). The incidence of bacterial infections in these patients was 22.2/1000 days of admission. The proportion of patients becoming infected by time was significantly greater in the visceral leishmaniasis group than in controls (P < .01). The skin, respiratory tract, and middle ear were the most common sites ofinfection, and Pseudomonas aeruginosa and Staphylococcus aureus were the most common agents. Low-grade-virulence bacteria (e.g., Serratia and Providencia species) were also isolated from some cases. Bacterial infections (mainly nosocomial) in patients with visceral leishmaniasis tend to be severe and can cause death. When bacterial infection is suspected in these patients, empiric antibiotic therapy should bestarted immediately, including coverage for R aeruginosa and S. aureus, after appropriate diagnostic procedures are taken.
JID 1990;162 (December)
Infections in Visceral Leishmaniasis
1355
Table 1. Site of bacterial infections in 18 visceral leishmaniasis patients. Site Skin Respiratory tract Middle ear Intestinal tract Oral mucosa Blood Total
No. of infections (%) 8 (33.3) 8 (33.3) 4 (16.7) 2 (8.3) 1 (4.2) 1 (4.2) 24 (100.0)
Visceral leishmaniasis
C
Q) .~
Control group
C
0
-i->'~
Itl-i->
0.
~ 0040
........ o C c
o
t o e
0.20
0.
0..
0.00 l----r-----,.....--,-----,--r-----r-.....------r-.,-----r--r------r!----,
o
5
10
15
20 25 30 35 40 45 50 55 60 65 TI~
( Days)
Figure 1. Difference between proportion of individuals with visceral leishmaniasis and control group who become infected as functionof time was statisticallysignificant (P < .01, X2 5.98, 1 df).
appropriatelydistinguishesbetweena patient who had an infection, for example, 10 days after admission (i.e., an uncensored observation) and a patient who did not havean infectionand wasdischarged 10 days after admission (i.e., a censored observation). This methodology is further described in [16]. The Kaplan-Meier curves for the controland visceral leishmaniasis groups werecomparedstatistically using the log-rank test described by Mantel [17]. All P values are two-sided.
Results
Incidence and site ofinfections. Bacterial infections were documented in 18 (60 %) of the 30 patients with visceralleishmaniasis, with a total of 24 episodes of infections (table 1). The incidence of bacterial infection in the visceral leishmaniasis patients was 22.2/1000 days. The skin, respiratory tract, middle ear, intestinal tract, and oral mucosa were the most common sites of infection. In one patient, septicemia was documented without evidence of an original site of infection. In the 16 patients with other clinical conditions, 2 (12.5 %) developed infections (pneumonia and purulent rhinitis), for an incidence of 5.5 infectionsl1000 days. Figure 1 shows as a function of time the proportion of individuals in the control and visceral leishmaniasis groups who became infected. The difference between the two groups is statistically significant (P < .01, x2 5.98, 1 df). There was no statistically significant difference (P > .05) when variables such as age, duration of illness, and time of exposure were compared between the two groups. Clinicaland laboratory features. Some clinical and laboratory features observed in the 30 visceral leishmaniasis patients are shown in table 2. Most were children. The age range was 1-29 years (mean, 9 ± 7.9). There were 19 male and 11 female patients. The duration of illness was 7 ± 6.1 months in the group with associated bacterial infection and 6 ± 5.7 months in the group without bacterial infection (P > .05).
Downloaded from http://jid.oxfordjournals.org/ at University of Ulster on June 9, 2015
tients with other clinical conditions admitted to the same hospitals where this studywasconducted.This "control" evaluation wasstarted 1 year after the beginning ofthe leishmaniasis studywhen20 visceral leishmaniasis patients had been enrolled, and involved 16 age- and sex-matched subjectswithclinical evidenceof malnourishment. The distribution of the controlpopulationin the threehospitals wassimilar to that of the visceral leishmaniasispatients. The clinicalconditions were proteincaloric malnutrition(5 cases), femurfracture (4 cases), and iron-deficiency anemiaassociated with ancylostomiasis,Hodgkin'sdisease, hypospadias, congenitalmegacolon, and idiopathic congenital myocardiopathy (1 each). These patients were followed similarlyto the visceralleishmaniasis group,andbacteriologic studies were performed whenever signs of infection were detected. Specimens for bacteriologic studies. Specimens were obtained from all sites considered infected. Cutaneous specimens were obtained with a cotton swabin a deep area of lesions after appropriate cleaning or by inoculation of 1 ml of sterile 0.9% saline into the lesion and subsequent aspiration with a syringe. All open wounds produced purulent secretion. Specimen collection was done carefully to avoidthe predominantlyisolated colonizingbacteria instead of the probable causative agent. The specimensfrom patients with respiratory tract infection were obtained as described by Sommers and Good [12]. A nebulization with warmed 0.9% sterile saline was done for 15 min, and then the induced expectorated sputum was collected for culture and Gram's stain. The specimens were considered good when there were >25 neutrophils and or , respectively) in the group with bacterial infection were compared with those in patients without bacterial infection (3375 ± 931 and 1361 ± 645 cells/ram'), no statistically significant difference was found. Granulocyte counts
