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(Chest. 2003;124:543-547.)
© 2003 American College of Chest Physicians

Legionnaires Disease and HIV Infection*

Maria Luisa Pedro-Botet, MD, PhD; Miquel Sabrià, MD, PhD; Nieves Sopena, MD, PhD; Marian García-Núñez, BSc; María Jesús Dominguez, MD; Esteban Reynaga, MD and Celestino Rey-Joly, MD, PhD

* From the Infectious Disease Unit (Drs. Pedro-Botet, Sabrià, Sopena, Reynaga, and Ms. García-Núñez) and Department of Internal Medicine (Drs. Dominguez and Rey-Joly), University Hospital "Germans Trias i Pujol," Universitat Autònoma, Badalona, Spain.

Correspondence to: Maria Luisa Pedro-Botet, MD, PhD, Infectious Diseases Unit, Hospital Universitario Germans Trias i Pujol, Crtra/del Canyet s/n, Badalona 08916, Spain; e-mail: mlpbotet{at}ns.hugtip.scs.es


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: To compare the outcome of Legionnaires disease (LD) in patients with and without HIV infection.

Design: Retrospective review of clinical charts.

Setting: Six hundred-bed university hospital.

Patients: We studied the clinical findings of 64 patients without HIV and 15 patients with HIV. Patients with a serologic diagnosis only were not included. Patients with previous immunosuppressive therapy or transplant recipients were excluded from the former group. In the HIV group, the mean CD4 cell count was 347.5/µL, plasma viral load was undetectable in 50% of the patients, and only one patient (7%) was receiving cotrimoxazole as prophylaxis against Pneumocystis carinii at the time of pneumonia. No differences were observed in the two groups with respect to community or nosocomial acquisition, delay in the initiation of appropriate treatment, the use of macrolides or fluoroquinolones, and Fine score in cases of community-acquired LD.

Results: Univariate analysis showed that time to apyrexia was longer, and respiratory symptoms, bilateral infiltrates in chest radiograph, hyponatremia, increase in aspartate aminotransferase and creatine phosphokinase (CK), and respiratory failure were more frequent in the HIV group. Mortality was greater in patients with HIV, achieving a statistically significant value of 20%; however, multivariate analysis only confirmed these differences with respect to the increase in CK.

Conclusions: LD has a more severe clinical presentation and worse evolution in patients with HIV.

Key Words: AIDS • HIV • Legionella • Legionnaires disease


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Experimental models have shown that cell immunity plays an important role in the control and eradication of Legionella.1 Moreover, a trend has been described between immunosuppression and poor prognosis of Legionnaires disease (LD) in clinical series,2 with a higher frequency in very immunosuppressed patients such as transplant recipients.3

Patients with HIV infection have an important deterioration in cellular immunity. It therefore seems reasonable for LD to be more frequent in this context; however, few clinical reports have been described on LD in patients with HIV,4 5 6 7 and the same incidence has been reported in hospital-acquired LD in patients with HIV and without HIV.8 Some authors have suggested a poor outcome and more clinical complications of LD in patients with AIDS9 10 ; however, the outcome of LD in patients with HIV reported by other authors did not differ from the typical course of LD in nonimmunosuppressed patients without HIV.5 6 7 In addition, these descriptions were focused on anecdotal cases or small series.

Since 1983, 15 cases of LD have been diagnosed in patients with HIV in the University Hospital Germans Trias i Pujol. The description of these cases has been previously reported.8 LD in HIV cases in this series of patients showed a similar course to that observed in very immunosuppressed patients. The aim of the present study was to compare the clinical features and outcome of LD in patients with HIV and in patients without HIV (nonimmunosuppressed).


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Seventy-nine cases of pneumonia due to Legionella pneumophila serogroup 1 diagnosed from 1983 to December 2001 were selected for inclusion in the study. All had a positive Legionella urinary antigen test result. In six cases, cultures of respiratory specimens were positive for L pneumophila serogroup 1. Patients with serologic diagnosis only were excluded. The patients were classified into two groups based on HIV infection: group 1, 64 patients without HIV, excluding those with previous immunosuppressive therapy or transplant recipients; and group 2, 15 patients with HIV. HIV infection was obtained from the medical record. The information collected included personal data, individual risk factors, respiratory and extrarespiratory complications, radiologic manifestations, clinical relapse of legionellosis, community or nosocomial acquisition, delay in appropriate treatment, the use of ß-lactams as the initial empirical antibiotic treatment, type of appropriate antibiotic therapy (macrolides or fluoroquinolones), the Fine score for those of community origin11 and, finally, mortality attributable to LD.

A patient was considered to be a smoker if he/she smoked more than one pack per day within the last 5 years. Alcoholism was defined as consumption of > 80 g of alcohol per day. Acute respiratory failure was defined as a partial arterial oxygen level of < 60 mm Hg in a previously healthy patient or a relative decrease of > 10 mm Hg in a patient with COPD. Likewise, an increase of > 150 µmol/L from the baseline value of serum creatinine was considered as deterioration in renal function. Relapse (possible) of Legionella spp. pneumonia was defined by the reappearance of signs and symptoms of pneumonia with persistence of urinary antigen after finishing antibiotic treatment, with no other demonstrated etiology.

Data were analyzed by a statistical program for personal computer. Discrete variables were analyzed by univariate analysis using the {chi}2 method. The level of significance was set at a p value of 0.05. Variables with a level of 5% of significance in the univariate analysis and with clinical importance, excluding collinear and dependent variables, were used in a multivariate logistic regression analysis carried out with a software package (Version 8.0; SPSS; Chicago, IL).


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Group Characteristics
The risk factors for Legionella pneumonia, other than HIV infection, are shown in Table 1 . No statistically significant differences were observed in community or nosocomial acquisition, delay in the initiation of appropriate treatment, the use of macrolides or fluoroquinolones as antibiotic treatment and, Fine score in cases of community-acquired LD. Among individual risk factors, smoking was significantly more frequent in patients with HIV (p = 0.01). ß-Lactams were more frequently used as empirical initial pneumonia treatment in the HIV group than in the non-HIV group (57.1% and 25%, respectively), with this difference being statistically significant (p = 0.03).


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  		Table 1. Group Characteristics*

 
Regarding the HIV group, 10 patients (77%) were receiving highly active antiretroviral therapy. The mean of CD4-positive lymphocytes was 347.5/µL (range, 6 to 670/µL), being > 200/µL in nine patients (64.2%). Five of 10 patients had an undetectable viral load. Only one patient (7%) was receiving cotrimoxazole as prophylaxis against Pneumocystis carinii. One patient with Kaposi sarcoma was receiving chemotherapy, and another patient with Hodgkin disease was receiving chemotherapy and corticoids.8

Clinical Outcome According to HIV Infection
Time to Apyrexia and Relapse of Legionellosis:
The patients in the non-HIV group had a mean of 55.9 h of fever following the initiation of an appropriate antibiotic, while this mean was of 91.8 h in the HIV group. Seven HIV-positive patients (53.8%) remained febrile for > 72 h, while this occurred in nine patients without HIV (15.8%), with the difference being statistically significant (p = 0.007). Clinical relapse of pneumonia due to Legionella was only seen in one HIV-positive patient.

Clinical, Radiologic, and Analytical Features:
As shown in Table 2 , respiratory symptoms were more frequent in the HIV group (92.3%) than in the non-HIV group (65.6%), with dyspnea and cough achieving statistical significance (p = 0.003 and p = 0.03, respectively). There were no differences in extrarespiratory manifestations between the two groups.


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  		Table 2. Clinical Outcome of LD According to HIV Infection*

 
A greater frequency of bilateral chest radiograph involvement was observed in the HIV group (53.3%) than in the non-HIV group (17.2%), with this difference being statistically significant (p = 0.006). Regarding analytical parameters, hyponatremia (p = 0.001) and an increase in creatine phosphokinase (CK) [p = 0.0005] and in aspartate aminotransferase (AST) [p = 0.006] were significantly more frequent in the HIV group.

Complications and Related Mortality:
As shown in Table 3 , complications were more frequent in the HIV group (85.7%) than in the non-HIV group (46.9%) [p = 0.02]. Eleven patients (78.6%) in the former group had respiratory failure, with a prevalence of 43.8% in the latter group (p = 0.04). Finally, mortality related to LD was greater in patients with HIV, achieving a statistically significant value of 20% (p = 0.02). On multivariate analysis (Table 4 ), only an increase in CK remained statistically significant (p = 0.03).


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  		Table 3. Complications and Related Mortality to LD*

 

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  		Table 4. Multivariate Analysis

 

   Discussion
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 Abstract
 Introduction
 Materials and Methods
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References
 
Previous descriptions of LD in patients with HIV are scarce. A report from the National Heart, Lung, and Blood Institute Workshop identified Legionella as the cause of 2% of 441 episodes of severe pulmonary disorders in patients with HIV.12 Not one isolate of Legionella was recovered from 79 episodes of fever and pulmonary infiltrates in 61 HIV-infected patients submitted to bronchoscopic procedures.6 Telescoping plugged catheters applied in 71 episodes of fever in 66 patients with HIV only identified one case of Legionella.13 From 1983 to 2001, 15 HIV patients with LD were seen in the Hospital Universitario Germans Trias i Pujol and, moreover, the incidence of LD in these patients seemed to be similar to that in those without HIV infection.8 Some authors suggest that prophylaxis with cotrimoxazole for P carinii may justify the low prevalence of this disease in HIV-infected patients.5

Neither clinical presentation nor radiographic appearance seem to be helpful for diagnosing LD.5 Some authors4 5 9 10 have suggested that more severe disease, chest radiograph bilateral infiltrates or cavitation, or clinical relapse are more frequent in patients with HIV; however, studies2 14 15 on the influence of patient immunity in the evolution of LD suggest that the greater the immunosuppression the more complications are observed. Thus, the severe impairment in cellular immunity in patients with HIV may lead to a more torpid evolution and to a higher mortality.

This is the first study comparing LD in patients with and without HIV. The definitive diagnosis of LD in all the cases of this series makes this study more consistent with respect to previous descriptive studies4 5 16 using direct fluorescent antibody of respiratory specimens or serology. Time to apyrexia after starting therapy was longer in the former group. The HIV group had more respiratory symptoms, hyponatremia, increase in CK and AST, and bilateral pulmonary infiltrates. Respiratory failure was also more frequent and attributable mortality was higher (20% vs 1.6%) in these patients. Although only the increase in CK achieved statistical significance on multivariate analysis, a trend to a worse clinical presentation and evolution in the HIV group was evident. Compared with a previous study2 by our group in a large series of hospital-acquired LD, this attributable mortality of 20% is the highest ranking value in patients with LD.

The increase in CK was the only variable showing significance on multivariate analysis. Elevation of CK was also discriminatory in a previous study comparing community-acquired pneumonia caused by Legionella and by other bacteria.17 Thus, although elevations in CK levels have been described in some patients with LD,18 the figure of 70% (five cases with values > 1,000 IU) observed in this study seems to be much too high. Nonetheless, the antiretroviral therapy received by these patients19 20 and the severity of Legionella infection itself may justify the higher percentage and the extreme values observed in this subset.

Hyponatremia was statistically more frequent in the HIV group and almost achieved statistical significance on multivariate analysis (p = 0.06). Hyponatremia was frequently described in the first reported series of LD when microbiological diagnosis was difficult, and initiation of an adequate antibiotic treatment was usually delayed.21 Hyponatremia was also a well-known finding in patients with AIDS in the era prior to highly active antiretroviral therapy, especially in very ill patients.22 Hypovolemia or inappropriate antidiuretic hormone secretion syndrome has been related to the decrease in sodium observed in these patients.

There were no differences in extrarespiratory manifestations between the two groups. Neither did renal failure, shock, mechanical ventilation, pleural effusion, or pulmonary cavitation show any statistical differences; however, the only case of clinical relapse in this study was observed in the HIV group.

The small size of the HIV group and the underlying diseases coexisting in some patients with HIV are the main limitations of our study; however, this is the largest series of LD in patients with HIV reported. The evolution of LD in very immunosuppressed patients, such as transplant recipients or those undergoing chemotherapy or corticotherapy, is torpid. Clinical and radiologic complications are well documented, and mortality ranges from 18 to 75%.2 3 Since our initial hypothesis was that the clinical evolution of patients with HIV may be similar to that of immunosuppressed patients, these latter patients were excluded from the control group to thereby construct a more comprehensive comparative analysis. However, two patients in the HIV group receiving chemotherapy and one patient receiving corticoids were not excluded because of the small size of this study arm. The exclusion of these patients did not modify the negative trend observed in the HIV group (Tables 2 , 3) . Variables such as the origin of Legionella pneumonia, delay in the initiation of appropriate antibiotic, the use of macrolides or fluoroquinolones as LD treatment, and the Fine score11 (for community-acquired pneumonia), which may influence the evolution of LD, did not show any differences between the two groups.

Based on the results obtained in this study, we conclude that LD in patients with HIV is a severe clinical and radiologic illness with a high mortality, and the increase in CK levels and, probably, hyponatremia are discriminatory for HIV infection. Despite the absence of important statistical differences, a trend to a worse outcome of LD was observed in patients with HIV with respect to the group of patients without HIV.


   Footnotes
 
Abbreviations: AST = aspartate aminotransferase; CK = creatine phosphokinase; LD = Legionnaires disease

Received for publication October 9, 2002. Accepted for publication January 21, 2003.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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