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I‘he Netherlands JOURNALOF ELSEVTER NetherlandsJournal of Medicine 4Y (I 996) I Y6620 I

Original article Severe Legionnaire’s disease requiring intensive care treatment

I.C. van Riemsdijk-van Overbeeke s’, B. van den Berg ’

Abstract

Bwkgwund: Legionnaire’s disease is well known as severe requiring intensive care treatment in many cases. In this study the clinical course is described of patients admitted to the medical ICU of the University Hospital of Rotterdam for respiratory distress due to Legionnaire’s disease. Methods: From the register of admissions to the medical ICU all patients suffering from Legionnaire’s disease were identified. All data on clinical signs and symptoms present on admission were collected. The circumstances in which the infections were contracted were sought, as well as the tests establishing the diagnosis. The occurrence of various organ failures and complications were noted, as were the causes of death on the KU. Resdts: From 1978 till 1995 the diagnosis of Legionellu pneumonia was made in I7 patients admitted to the ICU: in I3 patients a community-acquired infection was established. As in I2 patients Legionnaire‘s disease was diagnosed on serological tests, it took several weeks before the diagnosis could be established in these patients. In all patients the circumstances predisposing to Legionnaire’s disease were noted. Respiratory distress was present in all patients, ventilatory support was required in 14. Apart from this, both profound and renal failure were commonly encountered. As complications jaundice, rhabdomyolysis and polyneuropathy were frequently noted. Three patients died: 2 due to irreversible shock and I due to hospital-acquired . Cottr~lusion: Legionnaire’s disease can develop into life-threatening pneumonia requiring intensive care treatment in previously healthy subjects. As the clinical features are aspecific. careful search for predisposing circumstances such as recent travel or use of a contaminated water-supply is mandatory. As the diagnosis required positive serological tests in most patients, a considerable delay in diagnosis was noted. Despite the frequent occurrence of multiple organ failure, a favourable outcome can be anticipated in most cases.

K(a~ord\: Lc,~ion&~: Critical care: Multiple organ failure

1. Introduction in many cases intensive care treatment [I .2]. The incidence of Legionnaire’s disease has been reported Legionellu pneumophila is the causative agent of to vary from O-23% of all community-acquired Legionnaire’s disease, a severe pneumonia requiring requiring intensive care [3-61. Differ- ences in population as well as geographical and Correspondingauthor. Tel. ( + 3 1-IO) 463 9222; fax ( + l-10) seasonal data are assumed to account for the variabil- 463 5305. ity reported [2]. In some studies Legionella ranks

03002977/96/$15.00 Copyright 0 I996 Elsevier Science B.V. All rights reserved I’ll SO300-2977(96)00046-O I.C. ban Riemsdijk-wn Orrrberkr. B. can den Berg/ Netherlands .lorwnul of Medbne 49 (19961 196-201 197 second after Pneumocoarus on the list of commu- the illness and the development of various organ nity-acquired1 pneumonias on the failures and complications was calculated. As organ L’S]. failures respiratory, renal and circulatory insuffi- In the Netherlands all established cases of Legion- ciency were considered. was de- naire’s disease are registered. After an initial de- fined as hypoxaemia (PaO,/FiO, < 100) and/or the crease in the number of cases from 1988 to 1992 need for ventilatory support. Renal failure was de- (from 60 to ;!I cases per year), a gradual increase has fined as anuria/oliguria associated with serum crea- been noted in subsequent years (43, 52 and 42 cases tinine levels of > 600 ymol/l. Circulatory failure for 1993, 1!>94 and 1995, respectively). Over the was defined as a systolic blood pressure of I 90 years, predominantly isolated cases have been re- mmHg in the presence of an adequate fluid chal- ported with ithe exception of one epidemic affecting lenge. Jaundice, skeletal muscle damage, acute ab- Dutch tourisis in Spain [7]. domen, upper gastrointestinal bleeding and polyneu- The aim of the study is to describe the clinical ropathy were considered as complications. course of parients who were admitted to the medical Discharge from the ICU to the ward or death on intensive care unit of the University Hospital of the ICU was noted. Data on follow-up of the period Rotterdam for acute respiratory distress due to the following stay on the ICU were collected. Legionnaire’s disease. Clinical data on the presenta- tion, the complications during stay on the intensive care unit, and the course of the patients will be 3. Results (Table 1) presented. From 1978 to 1995, 17 patients suffering from Legionella pneumonia were admitted to the intensive care unit. At the same time another 10 patients with 2. Patients and methods Legionnaire’s disease admitted to the wards were identified. Twelve of 17 patients were admitted to From the register of all admissions to the medical the ICU in the summertime (June-September). The intensive care unit of the University Hospital of mean age of the patients was 52 years (range 25-69); Rotterdam since 1972, patients in whom Legion- 14 were male. Three patients died, all male, with a naire’s disease had been diagnosed were identified. mean age of 60 years. In addition, all patients with Legionnaire’s disease The mean duration of intensive care treatment were identified from the files of all admissions to amounted to 22 days (range 4-99); no difference this hospital, registered under the heading ‘pneumo- nia due to other specified bacteria’ (ICD9). From the patients’ files all clinical signs and symptoms present on admission to the ICU were noted. The various Table I items suggestive of the circumstances in which the Organ failures and complications in 17 patients with Legionnaire’s infections were contracted were sought in the case disease requiring intensive care treatment notes. On admission to the ICU the APACHE-II Number of patients score was obtained for each patient [8]. Results of Respiratory distress 17 routine laboratory studies (liver and kidney function Respiratory failure 14 tests) were collected. Chest X-rays obtained on ad- Circulatory shock 5 Renal failure 8 mission were reviewed. The diagnosis of Legion- Renal replacement therapy 7 naire’s disea:sewas established by serological testing, Jaundice 8 immunofluorescence or culture of sputum. A 4-fold Rhabdomyolysis 3 rise in antibody titre to at least 128 was considered Suspected peritonitis 3 evidence of acute infection [l]. The starting date and Upper gastro-intestinal haemorrhage 4 Polyneuropathy 8 the duration of therapy were noted. For each patient the number of days between the onset of For definitions of the various items, see text. was established between survivors and non-survivors onset of the disease and the start of erythromycin in the duration of IC treatment. varied from 2 to 13 days with a mean of 6 days. In 6 patients rifampicin was added to the erythromycin. The Apache II score was obtained for each patient 3.1. Cir.cumstunces in which the infections MYI-e from the first 24 h on the ICU: the score amounted cmtl-acted to 1X (mean. range I l-3 I ). The actual death rate (18%) could be considered to be in agreement with In all patients a predisposing condition suggesting the predicted death rate (25%‘) as previously pub- the circumstances in which the infection had been lished [9]. contracted was noted. Eleven patients had travelled All patients presented with infiltrates in one or abroad for holidays within a week before the onset both lungs on the chest X-ray. In 9 patients both of their illness. Eight patients had visited Mediter- lungs were involved, in 6 the right lung (mostly ranean countries, 2 patients had stayed in Paris and 1 more than 1 lobe), and in only 2 patients the left lung patient had made a boat trip along the river Rhine. was involved. Two patients had used water from reservoirs sup- posed to be contaminated with Legionella; both 3.3. Batter-iolo

3.2. Clinicul ,features 3.4. Respiratory @lure

The clinical features on admission were aspecific. All patients were admitted to the ICU for respira- All patients presented with dyspnea and high fever tory distress. Life-threatening respiratory failure re- (> 39.5”C). Abdominal discomfort as nausea and quiring was encountered in diarrhoea (13 patients) and mental confusion were 14 patients. The time between onset of disease and frequently encountered (11 patients). The majority of the start of ventilatory support varied from 1 to 15 the patients had been admitted to the ward before days with a mean of 6 days. being transferred to the intensive care unit. As the As ventilatory mode, pressure-controlled ventila- diagnosis of Legionnaire’s disease was not consid- tion with a positive end-expiratory pressure of at ered on admission to the hospital in all patients, a least 5 cmHzO was applied in all patients. High considerable delay in the institution of the appropri- inspiratory oxygen concentrations were required to ate antibiotic therapy was noted in several cases. In achieve adequate oxygenation (FiO, > 40%). The all patients intravenous erythromycin was adminis- mean duration of mechanical ventilation was 18 days tered for at least 2 weeks. The time between the (range 6-51 days). I.C. oan Riemsdijk-can Owrbeeke, B. c,an den Berg /Netherlands Journal of Medicine 49 (19961 196-201 199

In 3 patients no ventilatory support was required. was observed in all patients. All survivors had nor- They were treated with oxygen delivered by face- mal liver function tests at discharge from hospital. masks. 3.8. Skeletal muscle damage 3.5. Circulatory failure and shock In most patients elevated creatine kinase (CK) On admission to the ICU 5 patients were in levels were encountered at admission to the ICU. In shock, requiring positive inotropic drugs such as 3 patients CK levels exceeding 1000 U/l (normal dopamine and norepinephrine to restore the circula- values O-l 10 U/l) were noted. No relation could be tion. In all patients a diagnosis of was established between the high CK levels and the made [ 101. Four patients had concomitant renal fail- development of renal failure. CK levels normalized ure. In these patients the administration of inotropic within 7 days in all patients. drugs had to be continued for prolonged periods of time (mean 11 days, range 3-17 days). Two patients died without recovering from circulatory shock after 4. Acute abdomen and gastro-intestinal bleeding 13 and 16 days of intensive care treatment, respec- tively. . In 3 patients peritonitis was suspected on admis- son to the ICU. Two patients underwent a laparo- 3.6. Acute renal failure tomy: no abdominal pathology was found in either case. Eight patients developed acute severe renal failure During their stay in the ICU in 4 patients gastro- within 16 days after onset of the illness. In 7 patients intestinal haemorrhage developed due to bleeding renal replacement therapy was applied by means of gastric or duodenal ulcers. These patients were all continuous arterio-venous haemodiafiltration mechanically ventilated and bleeding was at first (CAVHD). All but one regained normal renal func- detected between the 2nd and 4th week after onset of tion after 1 to 5 weeks (mean 3 weeks). None of the the disease. prophylaxis was not rou- patients underwent a renal biopsy to determine the tinely provided. All patients underwent endoscopy pathophysiology of the renal failure. One patient with local injection therapy with etoxysclerol and with renal failure requiring renal replacement ther- epinephrine and were treated with systemic anti-ulcer apy died. therapy.

3.7. Jaundice 4.1. Polyneuropathy

In 8 patients jaundice (defined as serum bilirubin Eight patients suffered from severe polyneuropa- > 35 kmol/l) was observed. In all patients elevated thy (PNP), varying from mono- to tetraparesis. It levels of alkaline phosphatase, glutamyl-transferase developed slowly but progressively in the first 2 and/or aspartate aminotransferase CAST) and ala- weeks of the illness. In all patients with PNP ventila- nine aminotransferase (ALT) were observed during tory support was applied. stay on the ICU. No relation between circulatory In 3 patients a diagnosis of axonal PNP was failure and disturbed liver tests could be established. confirmed by electromyography. No difference in the severity of hyperbilirubinaemia Long-term rehabilitation was required in all pa- was observed between patients who were treated tients and resulted in full recovery in all but one. with erythromycin and rifampicin or with erythro- mycin alone. 4.2, Mortality Ultrasound studies were performed in all patients. Using this te’chnique extrahepatic bile duct obstruc- Three patients died on the ICU. Two patients tion could be ,excluded and a normal liver parenchyma were previously healthy and had community ac- quired pneumonia. Both were in shock on admission irreversible shock, secondary infections with Psezr- to the ICU and died without recovering from circula- domotzus were implicated. This underlines the risks tory failure. In both cases blood cultures at the time of nosocomial infections in these patients. of death revealed Pseudomonas set-uginosa. One Acute renal failure is reported in 30-405; of patient with a nosocomial pneumonia died. In this severe Lrgicwrllu pneumonia and is associated with patient temporal arteritis had been diagnosed and a poor prognosis [4.11,12]. Mortality rates up to 50% high-dose corticosteroids had been started 4 weeks in patients with Legionnaire’s disease complicated before the onset of the pneumonia. Eleven days after by acute renal failure have been reported [ 121.In this admission to the ICU the patient died of cardiac study continuous arterio-venous haemodiafiltration arrest related to severe sepsis. (CAVHD) was applied for acute renal failure. As only I of the 8 patients with renal failure died, it is suggested that the early start of CAVHD contributed 5. Discussion to the favourable outcome. Continuous haemodiafil- tration techniques are today the first choice of renal In this retrospective study the clinical course of replacement therapy in critically ill patients with patients admitted to the ICU for Legionnaire’s dis- severe sepsis. CAVHD may improve the outcome of ease has been reviewed. The 17 patients described in these patients due to the removal of inflammatory this study could be divided into two groups: 13 agents such as cytokines. interleukins and tumour patients with community-acquired pneumonia and 4 necrosis factor [ 131. patients with nosocomial pneumonia. In this patient Jaundice and disturbed liver tests are common in group recent travel to the southern part of Europe severe Lcgionella infections. The incidence varies proved to be the most frequent predisposing circum- from 40 to 60% [4, I 1,141. In 8 patients in this study stance for community-acquired Legionnaire’s dis- jaundice was noted. all without signs of liver failure. ease. All patients with nosocomial Legionnaire’s dis- Although hyperbilirubinaemia has been closely re- ease were immunocompromised, underlining the im- lated to rifampicin use in the literature, in this study munocompromised state as a risk factor for this type no difference in bilirubin levels was found between of infection. patients treated with or without rifampicin [ 1 I]. Although advanced age is considered a risk factor Muscular damage and rhabdomyolysis have been in the literature, we encountered predominantly mid- described in case reports of Legionnaire’s disease dle-aged subjects [I]. In accordance with the litera- [ 151. In this study elevated creatine kinase (CK) ture a male preponderance (M/F ratio 14:3) was levels were frequently encountered: in 3 patients CK established. levels in the range of rhabdomyolysis were noted on In the literature a mortality of 27% in patients admission to the intensive care. Skeletal muscle with Legionella pneumonia requiring intensive care damage was not found to result in renal failure: treatment is reported [ 1 I]. The overall mortality in ample intravenous fluid infusion, routinely applied in this study group amounted to 18%, which compared the ICU from the first day of admission, may have favourably with the mortality of all community- prevented renal failure to develop [ 161. acquired pneumonias admitted to the ICU (22-480/c) Gastro-intestinal symptoms such as nausea, vom- [3-61. - iting and diarrhoea are commonly reported in Le- All patients were admitted to the ICU for respira- gionnaire’s disease [I]. In this study the clinical tory distress; in 14 mechanical ventilatory support diagnosis of peritonitis in 3 patients prompted a was required. Although high inspiratory oxygen lev- laparotomy that did not reveal any abdominal pathol- els and high positive end-expiratory pressures were ogy. In 4 patients gastro-intestinal haemorrhage due temporarily required, adequate oxygenation could be to stress ulcers was noted. The incidence of stressul- achieved in all patients. cer bleeding in this patient group is considered high Circulatory shock in Legionnaire’s disease is re- compared to recently published studies [ 17,181. In all lated to a poor prognosis with mortality rates up to patients bleeding gastric or duodenal ulcers were 60% [l 11. In both patients in this study who died of found, in agreement with this finding the bleeding 1.C. ran Riemsdijk-uan Owr-heeke. B. can den Berg/Netherlands /ownal of Medicine 49 (19961 196-201 201 developed late in the course of the disease. 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