reviewed to examine whether an association exists between delayed ... racic Society criteria (3). ..... British Thoracic Society Research Committee: Commu-.
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Article
Vol. 15, No. 4
Eur. J. Clin. Microbiol. Infect. Dis., 1996, 15:286-290
Delay in Appropriate Therapy of Legionella Pneumonia Associated with Increased Mortality
C.H. Heath 1,2., D.I. Grove 1, D.EM. Looke 1,3
The prognostic significance of delayed therapy in Legionnaires' disease is poorly defined. Thirty-nine consecutive serologically confirmed cases of Legionnaires' disease were reviewed to examine whether an association exists between delayed therapy and prognosis. Clinical and laboratory factors predictive of mortality were also sought. Thirty-one cases (79%) were classified as having severe pneumonia at diagnosis. Thirty-six patients (92%) had community-acquired infection, and three patients (8%) had nosocomial disease. Ten patients died, resulting in a crude mortality rate of 26%. At the first assessment, variables noted for pneumonia associated with death were low diastolic blood pressure (p < 0.02), low serum albumin concentration (p < 0.04), and increased number of days from onset of pneumonia to hospitalisation (prodrome) (p < 0.02). However, multiple logistic regression analysis revealed that the prodrome was the only variable noted at diagnosis that achieved significance (p = 0.024). Mortality also correlated with both delay in the initiation of erythromycin therapy following admission (p < 0.001) and the total delay in starting erythromycin therapy (p < 0.001). It is therefore recommended that erythromycin be included early in the empiric therapy of severe community-acquired pneumonia.
T h e efficacy of e r y t h r o m y c i n t h e r a p y i n L e g i o n n a i r e s ' disease was r e c o g n i s e d in t h e late 1970s (1). H o w e v e r , n o s t u d i e s to d a t e h a v e c o n s i d e r e d t h e i n f l u e n c e of t h e t i m e of o n s e t o f t h e r a p y o n m o r t a l i t y in s p o r a d i c l e g i o n e l l o s i s . W e u n d e r t o o k a r e t r o s p e c t i v e s t u d y o f s p o r a d i c L e g i o n n a i r e s ' dise a s e o v e r a m o r e t h a n 1 5 - y e a r p e r i o d in a t e a c h i n g h o s p i t a l i n o r d e r to (1) d e t e r m i n e t h e effect of delay in starting appropriate antibiotic therapy on t h e c o u r s e of t h e disease, a n d (2) d e t e r m i n e w h a t clinical a n d l a b o r a t o r y v a r i a b l e s at t h e o n s e t o f pneumonia are useful prognostic markers. The p r i n c i p a l f i n d i n g of this s t u d y was t h a t d e l a y i n t h e i n i t i a t i o n of specific t h e r a p y for L e g i o n n a i r e s ' d i s e a s e is a s s o c i a t e d w i t h i n c r e a s e d m o r t a l i t y . 1 Department of Clinical Microbiology and Infectious Diseases, The Queen Elizabeth Hospital, Woodville Road, Woodville, South Australia 5011, Australia. 2 Department of Microbiology and Infectious Diseases, Flinders Medical Centre, Flinders Drive, Bedford Park, South Australia 5042, Australia. 3Department of Infectious Diseases, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Queensland 4102, Australia.
Patients and Methods Case Definition and Ascertainment. Cases were located by reviewing the hospital serology records from 1979 through 30 June 1993. Cases were defined as those with a fourfold rise in specific antibody to Legionella spp. by indirect fluorescent antibody testing. They were cross-checked with the database maintained at the Communicable Disease Control Unit (CDCU) in South Australia; no additional cases were identified. Patients with a single high titre were not included in the analysis because of uncertainty as to whether this titre represented current or past infection (2). No cases were culture positive without a fourfold increase in titre. Clinical and Laboratory Data. Commufiity-acquiredpneumonia was defined as presentation to hospital with a pneumonic illness or its development within 48 h of admission. Nosocomial pneumonia was defined as the onset of a pneumonic illness more than 48 h after admission. Symptoms and signs documented on the day of admission or on the day of onset of nosocomial pneumonia from all patients were recorded where available. Laboratory data recorded from the day of diagnosis of pneumonia included detailed biochemical, haematological, and arterial blood gas analyses. Radiological appearances on the day of admission or diagnosis of hospitalacquired pneumonia were abstracted from reports issued by a radiologist. Patients were designated for severity of pneumonia as severe or not severe, according to American Thoracic Society criteria (3). Patients were considered immuno-
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compromised if they were receiving cytotoxic chemotherapy for underlying malignancy or immunosuppressives for solid organ transplantation. Infections with Legionellapneumophila and Legionellalongbeachaewere compared for all clinical and laboratory parameters.
Serological Investigations. Serological investigations were performed in all cases at the Institute of Medical and Veterinary Sciences (IMVS), Adelaide, Australia. Serological tests were performed for Legionellapneumophila as described by Edelstein (4). From 1979-1988 tests were restricted to Legionellapneumophila serogroups 1 and 2. Since 1989, serological tests for Legionella longbeachaeand other serogroups of Legionellapneumophila have been available. Serological investigations for LegionelIalongbeachaewere performed as outlined by Winslow and Steele (5). Infection was considered proven if a fourfold rise in specific antibody to Legionella spp. was demonstrated, the lowest being an increase from < 1:32 to 1:128.
Microbiological Investigations. Respiratory specimens containing mucus were liquified with sputolysin (Behring Diagnostics, USA) and incubated at 37~ for 10 rain. Specimens were then centrifuged at 800 x g for 10 min; half was heat treated and the other half was inoculated directly onto buffered charcoal yeast extract (BCYE) agar and BCYE agar with antibiotics (Oxoid, Unipath, UK). Plates were incubated at 35~ for seven days and were examined daily for characteristic colonies of Legionella spp. Organisms that resembled Legionella spp. were referred to the IMVS for determination of species and serotyping. Before t986 Legionellaculture was not routinely performed in our laboratory but specimens were referred to the IMVS for isolation of this organism.
Therapy. Antibiotic regimens were reviewed to determine the nature and sequence of antibiotic administration both in hospital and before admission. Delay in the initiation of therapy specific for Legionnaires' disease was examined to determine if this had prognostic significance. We divided the delay in initiation of appropriate therapy into three stages: (1) the number of days from the onset of illness to hospitalisation (prodrome), (2) the number of days from hospitalisation to appropriate antibiotic administration, and (3) the total number of days from onset of pneumonia to the administration of an appropriate antibiotic. The need for additional supportive therapy such as mechanical ventilation, dialysis, and admission to the intensive care unit (ICU) was noted. StatisticalAnalysis. Univariate analysis was performed on all variables. Categorical data were analysed using the Fisher's exact test and ordinate data using the Mann-Whitney test. All statistical analyses, including multiple logistic regression analyses, were performed using SPSS (USA) statistics software. Variables achieving a p value of < 0.10 were entered into logistic regression analyses. Prodrome was entered into logistic regression analyses as we chose a model based on data available at diagnosis. All other time variables were not included in the logistic regression analyses as they were confounding variables and would not have been available at diagnosis. Logistic regression analysis was performed as a forward stepwise procedure. The variables used in the final multiple logistic regression analysis were age, respiratory rate, diastolic blood pressure, number of zones involved on the admission radiograph, blood urea concentration, immunosuppression, severity index, and the length of the prodroreal illness.
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Results
Patient Characteristics. T h i r t y - n i n e cases o f legionellosis w e r e d i a g n o s e d d u r i n g t h e s t u d y p e r i o d . A g e s r a n g e d f r o m 3 5 - 7 6 y e a r s ( m e d i a n , 59). T h e r e w e r e 26 m a l e s a n d 13 females. T e n p a t i e n t s died, giving a c r u d e m o r t a l i t y r a t e o f 2 6 % . T h e mortality rate for immunocompromised patients was 5 0 % . T h i r t y - s i x o f t h e cases w e r e c o m m u n i ty a c q u i r e d , a n d t h r e e w e r e n o s o c o m i a l . O n e case of c o m m u n i t y - a c q u i r e d p n e u m o n i a was assoc i a t e d with a d o c u m e n t e d e p i d e m i c of Legionella longbeachae i n f e c t i o n (6). U n d e r l y i n g d i s e a s e s n o t e d in t h e 37 a s s e s s a b l e p a t i e n t s i n c l u d e d l u n g d i s e a s e (16 cases, 4 3 % ) , h e a r t d i s e a s e (11 cases, 3 0 % ) , i m m u n o s u p p r e s s i o n (6 cases, 16% ), d i a b e tes m e l l i t u s (5 cases, 1 4 % ) , a n d c h r o n i c r e n a l failu r e (4 cases, 1 1 % ) . T h i r t y - o n e o f 39 p a t i e n t s h a d s e v e r e p n e u m o n i a as d e f i n e d u s i n g A m e r i c a n T h o r a c i c S o c i e t y c r i t e r i a (3). N e v e r t h e l e s s , this v a r i a b l e was n o t a s s o c i a t e d with i n c r e a s e d m o r t a l ity (univariate analysis, p = 0.07, logistic r e g r e s s i o n analysis, p = 0.159).
Clinical and Laboratory Data. D i a s t o l i c b l o o d p r e s s u r e was r e c o r d e d in 38 cases a n d r a n g e d f r o m 60 to 100 m m H g with a m e d i a n o f 72.5 m m Hg. In t h e p a t i e n t s w h o survived, t h e m e d i a n d i a s t o l ic b l o o d p r e s s u r e was 80 m m Hg, a n d in t h o s e w h o died, it was 68 m m H g (p < 0.02). T h e s e r u m alb u m i n c o n c e n t r a t i o n was m e a s u r e d in 30 p a t i e n t s a n d r a n g e d f r o m 21 to 46 g/1 w i t h a m e d i a n o f 34 g/1. In p a t i e n t s w h o s u r v i v e d t h e m e d i a n s e r u m alb u m i n c o n c e n t r a t i o n was 35 g/l, a n d in t h o s e w h o d i e d it was 31 g/1 (p < 0.04). N o o t h e r v a r i a b l e s w e r e a s s o c i a t e d w i t h i n c r e a s e d mortality. Clinical a n d l a b o r a t o r y d a t a f o r Legionella pneumophila a n d Legionella longbeachae i n f e c t i o n s w e r e similar. Radiology. R a d i o g r a p h s w e r e a v a i l a b l e f r o m t h e d a y o f p r e s e n t a t i o n w i t h p n e u m o n i a in all cases. Twenty-six p a t i e n t s ( 6 7 % ) w e r e r e p o r t e d as having o n l y a n a l v e o l a r infiltrate, e i g h t ( 2 1 % ) h a d b o t h an a l v e o l a r a n d b r o n c h o p n e u m o n i c infilt r a t e , a n d five ( 1 3 % ) h a d o n l y b r o n c h o p n e u m o n ic infiltrates. P l e u r a l effusions w e r e n o t e d in 12 cases ( 3 1 % ) . R a d i o g r a p h s w e r e s i m i l a r in Legionella pneumophila a n d Legionella longbeachae infections.
Serological Investigations. S e r o l o g i c a l tests w e r e positive for Legionella spp. in all cases. T h i r t y - o n e p a t i e n t s h a d p o s i t i v e s e r o l o g i c a l tests for Legionella pneumophila, o f w h i c h 27 w e r e d u e to Legionella pneumophila s e r o g r o u p 1. T h r e e cases h a d s e r o g r o u p 2 infection, a n d o n e case o f sero-
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group 14 infection was noted. In addition, eight cases were seropositive for Legionella Iongbeachae, with seven being positive for serogroup 1 and one for serogroup 2 infection. The interval between the initial and the diagnostic titre varied between 4 and 41 days, with a median of 13 days.
Microbiological Investigations. Specimens from 37 patients potentially containing the organism were submitted for culture. Cultures were positive in 10 cases but we were unable to determine the number of specimens plated onto appropriate selective media. Legionella spp. were identified in endotracheal secretions in seven cases and from sputum in six, with both sputa and endotracheal secretions being positive in four. Specimens obtained at bronchoscopy were positive in 4 of 10 patients tested. In each of these cases the organism was also found in sputum (2 cases) and/or endotracheal secretions (3 cases). Legionella spp. were recovered from lung biopsy or at postmortem in two patients. Blood culture was positive in one patient. All clinical isolates were of Legionella pneumophila only, despite little problem with growing Legionella longbeachae from reference cultures. Therapy. Intravenous erythromycin was used in all but two of the cases at some stage of the illness. Of the 35 patients with community-acquired infections who received erythromycin, 17 were given the drug on the day of admission. The remaining 18 cases initially received regimens with ineffective agents: amoxycillin (10 cases), benzylpenicillin (5 cases), cefotaxime (1 case), ceftazidime (1 case), and cephalothin (1 case). Four cases had a second course of antibiotics ineffective against legionellosis before appropriate therapy was begun: amoxycillin and gentamicin (2 cases), cefotaxime and tobramycin (1 case), and amoxycillin and ceftriaxone (1 case). The delay in therapy for those patients not given empiric erythromycin at diagnosis ranged from 1 to 10 days with a median of 5 days. All three cases of nosocomial pneumonia received erythronlycin; in two it was given on the day of diagnosis and in the third case there was a six-day delay. Erythromycin, when used, was given for a median of 18 days (range, 8-40 days). The median initial dose of erythromycin was 4 g/day with a range of 2-4 g/day. Two patients had mild disease and survived despite short courses of amoxycillin and gentamicin alone. The other antimicrobials used that may be effective against Legionella spp. were rifampicin and ciprofloxacin, usually in conjunction with erythromycin or roxithromycin. Adjuvant therapy
Eur. J. Clin. Microbiol. Infect. Dis.
with rifampicin was given in six patients for a median of eight days (range, 3-21 days). Three patients received rifampicin at diagnosis (1 died) and the other three patients had adjunctive rifampicin delayed for five, seven, or eight days (2 of these patients died). All patients given rifampicin had severe infection. Ciprofloxacin was added to erythromycin in two patients critically ill with community-acquired Legionnaires' disease, but both died within 96 hours of its administration. One patient was given oral roxithromycin after parenteral erythromycin had been used successfully in treating severe community-acquired legionellosis. Therapy for legionellosis caused by either species was similar.
Outcomes. The interval between the onset of symptoms and admission to hospital (prodrome) ranged from 2 to 14 days with a median of 5 days. For those patients who survived, the median prodrome was five days (range, 2-9 days), and for those who died it was seven days (range, 4-14 days) (p < 0.02). Prodrome was the only variable at the diagnosis of pneumonia to achieve prognostic significance with multiple logistic regression analysis (p = 0.024). Following diagnosis of pneumonia, the median delay before starting erythromycin therapy in the 34 assessable cases of legionellosis was two days (range, 1-10 days). For patients who died, the median was five days (range, 1-10 days), and for those who survived it was one day (range, 1-5 days) (p < 0.001). The total delay in starting erythromycin ranged from 1 to 12 days (median, 6 days) for survivors and from 8 to 23 days (median, 11 days) in those who died (p < 0.001). Respiratory failure necessitating mechanical ventilation was required in 17 cases (44%). Mechanical ventilation was used for a median of 17 days (range, 6-50 days). Admission to an ICU was required for 19 patients with a median duration of ICU stay of 18 days (range, 5-51 days). Dialysis for acute renal failure was required in eight cases. The total length of hospital stay varied from 4 to 76 days, with a median of 14 days. There were no relapses in the survivors following discharge.
Discussion
This study was a retrospective review of 39 serologically confirmed cases of Legionnaires' disease admitted to a single tertiary referral hospital over a 15-year period. Cases were defined by strict serological criteria- namely, a fourfold rise in specific antibody titre. The reported sensitivity of ris-
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ing titres for Legionella spp. is 75% with a specificity ranging from 95 to 99% (8). The specificity of serological tests is antigen dependent; seroconversion to Legionellapneumophila serogroup I is most reliable, whereas that to other species and serogroups is less so (7). Patients with a single high titre were not evaluated, as up to 31% of healthy South Australian adults have a single high titre suggestive of past silent infection with Legionellapneumophila (2). In addition, the sensitivity of a single high titre is not known and the specificity of a single high titre is only 50 to 70% (7). Exclusion of patients with a single high titre will have resulted in a reduction in the number of cases of Legionnaires' disease considered, but will have eliminated a number of cases with falsely positive serological tests. In addition, the lack of serological tests for Legionella longbeachae and Legionella pneumophila serogroups 3-14 prior to 1989 means that infection due to these organisms would have remained undiagnosed. Variations in testing procedure over the time of the study are difficult to control for and may have influenced the results obtained. A comparison between Legionella pneumophila and Legionella longbeachae infections regarding presentation, outcome, and diagnosis did not reveal any statistically significant differences except failure to culture Legionella longbeachae from clinical specimens. Culture of Legionella species from clinical specimens is the definitive diagnostic test but its sensitivity is low (7). Culture was positive in only a minority of our cases, suggesting that selective culture onto appropriate isolation media was not commonly performed or perhaps inadequate specimens were collected. No cases were culture positive in the absence of documented seroconversion. Ideally, specimens for culture should be taken before antibiotic treatment is initiated, but culture should be attempted regardless, as Legionella spp. have been isolated from specimens of patients treated for several days (7). Initial recognition of the efficacy of erythromycin occurred in the late 1970s in the context of treating groups of patients involved in epidemic disease (1, 8). However, the impact of delayed effective therapy was not addressed in these studies. The principal finding of the present study is that delay in the administration of effective therapy for Legionnaires' disease is associated with increased mortality. This is the first study of which
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we are aware that has demonstrated the prognostic importance of delayed therapy. Early effective therapy of Legionnaires' disease is recommended in most textbooks (7, 9); however, to date there has been no direct evidence from the literature to support this recommendation. The impact of other antimicrobials effective against Legionella spp. such as rifampicin, was difficult to interpret as their use was usually limited to adjunctive therapy with erythromycin. Legionnaires' disease was originally believed to cause what was called "atypical pneumonia". This was a clinical syndrome involving a nonproductive cough, diarrhoea, myalgia, confusion, hyponatremia, abnormal liver function tests, and a relatively normal total leukocyte count. It is now evident that the signs and symptoms of community-acquired and nosocomial Legionnaires' disease are neither atypical nor specific (9, 11). The severity of pneumonia is now commonly used to determine empirical antimicrobial therapy of pneumonia (3). Two severity indices for community-acquired pneumonia have been published (3, 12); we chose to use the severity index of the American Thoracic Society (3). Most of our cases (90%) had severe community-acquired pneumonia as defined by this index. The literature supports our finding that legionellosis has a tendency to cause severe pneumonia (7, 9, 10). Interestingly, severity of pneumonia, which one would expect to be confounded by delayed admission to hospital, was not associated with an increased mortality rate in our survey, although it approached a level of significance. Prognostic variables of Legionnaires' disease are well documented and are similar to those of other community-acquired pneumonias (13). This study indicates that a prolonged prodromal illness, low diastolic blood pressure, and low serum albumin concentration are prognostically significant. The recommendation for empirical therapy of "severe" community-acquired pneumonia with a regimen including erythromycin is supported by our observations (14).
Acknowledgements We thank Mrs. C. Walker and Dr. S. Cameron from the CDCU, Dr. T.W. Steele and Mr. W.E. Winslow from the IMVS, and Mr. M. Bond from the Cochrane Collaborationin the Department of General Practice, Flinders Medical Centre, for advice on the statisticalanalyses.
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