IV. Specific Syndromes

A. Bacterial Pneumonia

Bacterial pneumonia is an important cause of morbidity and mortality, particularly among IDU.^{(7, 8)} The clinical presentation, etiological agents, and outcome from bacterial pneumonia depend on the stage of disease, method of diagnosis, and on whether the infection is community or nosocomially acquired. In recent years, bacterial pneumonias account for 40-50% of hospital admissions for lower respiratory tract infections among HIV-infected adults.⁽³³⁾ The most common pathogens reported in several recent series were Streptococcus pneumoniae, Hemophilus influenzae, Staphylococcal aureus, and Pseudomonas aeruginosa.^{(7, 34, 35)} Among patients with AIDS and a pulmonary cavity in one small series, bacteria other than tuberculosis were identified as the etiological agent in more than half of the cases.⁽³⁶⁾ Higher rates of bacteremia, higher relapse rates, and higher mortality have been associated with episodes of pneumococcal pneumonia in HIV infection.^{(37, 38)}

Risk factors for developing a first episode of bacterial pneumonia were examined in a prospective study of IDU between 1988 and 1992.⁽³⁹⁾ Independent predictors of bacterial pneumonia included a CD4 cell count of <200/mm³, age between 30-40 years, and smoking drugs (but not cigarettes).

Pseudomonas has recently been recognized as an emerging pathogen in late HIV infection as evidenced by a growing literature on the subject.^(40-45) In two series, increases in the incidence of infections due to Pseudomonas species have been noted between 1988 and 1992.^{(41, 45)} Pulmonary disease appears to be the most common site of infection, with cases ranging from fulminant pneumonia with bacteremia to cavitary lung disease to a more indolent respiratory infection, which tends to recur.^{(40, 41)} Community-acquired infections are common, ranging from 50% to >90% of the cases.^{(41, 46)} Relapse and recurrence are reported frequently, and in most series the classic risk factors of neutropenia and use of corticosteroids are absent.

Fichtenbaum and colleagues evaluated risk factors for Pseudomonas infection in a case control study involving 37 episodes of Pseudomonas aeruginosa infection in 25 patients. Risk factors for developing community-acquired infection with this pathogen included a prior diagnosis of AIDS, a greater number of AIDS-defining illnesses, a greater number of hospitalizations, and antibiotic use during the 2 weeks before admission. Use of antiretroviral therapy, neutropenia, and type of PCP prophylaxis were not found to be risk factors in this small study. The mean CD4 count of patients in this series was 11/mm³, and the mortality rate from Pseudomonas infection was 36%.⁽⁴¹⁾ Clinicians should be aware of the growing problem of Pseudomonas infection in late HIV disease and should tailor empirical antibiotic regimens with this in mind. Further data on the relationship between the chronic administration of TMP-SMX and the incidence of serious Pseudomonas infections are needed.

Unusual pathogens that cause bacterial pneumonia in HIV-infected patients and deserve special mention are Rhodococcus equi and Nocardia species. The main reason for highlighting these pathogens is that they are often associated with a delay in diagnosis because they have not been considered.^(47-49)

R. equi is an aerobic, gram-positive, nonmotile pleomorphic bacillus, which causes disease in humans and in farm animals. More than one hundred cases of R. equi pulmonary disease have been reported in patients with HIV infection.^(48-52) Infection with Rhodococcus is characterized by an insidious onset of respiratory symptoms and fever. The most common radiographic appearance is cavitary lung disease. The organism is easy to isolate from sputum or blood and grows on standard media, however, it can easily be overlooked as a contaminant. Extrapulmonary diseases including brain abscess, enteritis, and regional adenitis have all been reported.⁽⁴⁹⁾ Prolonged antibiotic therapy is necessary to avoid relapse. Successful treatment has been reported with the combination of erythromycin and rifampin.⁽⁴⁹⁾ Mortality rates range from 25 to 55%;^{(48, 51)} these high rates may be due in part to a delay in diagnosis.

The presence of specific antibody to R. equi was associated with improved outcome in a small series.⁽⁵³⁾ Antibody to R. equi has been detected in commercial preparations of immunoglobulin;⁽⁵³⁾ the role of IVIG as an adjunct to antimicrobial therapy requires further investigation.

Nocardia has been infrequently reported as a cause of pulmonary disease in AIDS patients.⁽⁴⁷⁾ Most of the patients reported have had advanced HIV disease.⁽⁵⁴⁾ The radiographic appearance is variable, and cases have been reported with all of the following findings: lobar or multilobar consolidation, solitary masses, cavitary disease, and pleural effusions.⁽⁵⁵⁾ Disseminated disease is common with neurological and cutaneous manifestations in about a quarter of patients in a recent series.⁽⁴⁷⁾ There are no published comparative trials to guide therapy. Susceptibility testing by a reference laboratory should be considered, particularly if the patient has been receiving prophylaxis with trimethoprim-sulfamethoxazole. Nocardia should be suspected in any patient with the subacute onset of pulmonary disease, especially if a cavitary or mass lesion is present.

Recently a case of pneumonia and sinusitis due to Bordetella bronchiseptica was reported in a patient with AIDS.⁽⁵⁶⁾ The notable feature of this case and in seven previous cases in the literature was the presentation with interstitial infiltrates, a severe, disabling, petussoid cough, and the absence of fever. Sinusitis requiring surgical drainage was also reported. Prolonged therapy with imipenim/cilastin followed by amoxacillin/clavulanate resulted in a resolution of symptoms in this single case. Infection caused by Bortetella species should be considered in patients with HIV infection who present with a severe cough, even in the absence of fever.

B. Bacteremia

There are limited data on the incidence of bacteremia in the course of HIV infection. Injection drug use, permanent indwelling intravascular catheters, and lower CD4 counts appear to increase the risk for developing bacteremia. As noted above, bacteremia/sepsis is one of the most common bacterial infections among hospitalized AIDS patients.⁽³¹⁾ The microbiology of bacteremias varies by the patient population studied and frequency of indwelling lines. In a recent retrospective study of 133 bacteremic episodes, S. aureus was the most common organism isolated (26%), followed in order of frequency by Salmonella enteritidis, coagulase-negative staphylococcal species, enterococcus, Pseudomonas, pneumococcus, and other streptococcal species. Patients with AIDS were at higher risk than HIV-infected patients with earlier disease. In addition, indwelling catheters were an important cause of bacteremia, in particular as a cause of staphylococcal infections. In another retrospective series of bacteremic episodes from Rome, the pathogen isolated appeared to be related to CD4 count.⁽⁵⁷⁾ S. aureus appeared to be more common at higher CD4 counts, while gram-negative bacilli and S. epidermidis were more common at lower CD4 counts. A review of 131 of bacteremic episodes from Miami identified 69% as primary blood stream infections (including catheter infections). In this series, 33 episodes of bacteremia were fatal.⁽⁵⁸⁾ S. aureus was identified as the pathogen in 53% of the primary bacteremias, and 68% of the nosocomial staphylococcal isolates were methicillin resistant. Use of trimethoprim-sulfamethoxazole prophylaxis appeared to reduce the risk of bacteremia in this study.

Several recent series of catheter-related bacteremias suggest a growing morbidity from these infections.^(59-62) In a series of catheter-associated bacteremias from New York Hospital, the median time from catheter insertion to infection was 5 weeks, and gram-negative bacilli were the most common isolates (42%), followed by S. epidermidis (23%) and S. aureus (10%).⁽⁶²⁾ A more in-depth investigation of catheter-related bacteremias in AIDS patients receiving therapy for CMV retinitis by Stanley and colleagues estimated the infection rate to be 0.20 serious infections per 100 catheter-days.⁽⁶⁰⁾ The risk of catheter infection did not vary by the drug used to treat CMV infection (ganciclovir or foscarnet); however, a higher rate of infection was seen with percutaneous compared to subcutaneously tunneled catheters.

Due to the morbidity associated with staphylococcal infections, attempts have been made to reduce nasal staphylococcal carriage in HIV-infected patients. Hirschhorn et al. identified nasal staphylococcus carriage in 37% of 207 HIV-infected patients screened.⁽⁶³⁾ Preliminary results from a placebo-controlled, randomized trial by this group of investigators using mupirocin twice daily for 5 days suggest that a reduction in the rate of staphylococcal colonization occurs with mupirocin. Whether a reduction in serious staphylococcal infections can be achieved with this approach remains to be determined.

C. Endocarditis

The relationship between endocarditis and HIV infection continues to be an area of active investigation.^{(37, 64-66)} S. aureus remains the most common pathogen. In a prospective cohort study of injection drug users, the presence of HIV infection and a lower CD4 count appeared to increase the risk of developing endocarditis.⁽⁶⁴⁾ In a retrospective review of cases of endocarditis from Yale, HIV infection was associated with a higher recurrence rate and higher in-hospital mortality.⁽³⁷⁾ A review of 144 cases of endowditis from Cook County found no differences in the clinical presentation of endocarditis among HIV-infected patients; however, a higher mortality was identified in patients with CD4 counts of <200/mm³. This study found that HIV-infected patients with staphylococcal endocarditis were less likely to have techoic acid antibodies than uninfected patients; how this finding relates to outcome deserves further study.

D. Bacillary Angiomatosis

Bacillary angiomatosis (BA) is a syndrome with diverse manifestations, including cutaneous angiomatous lesions, fever and bacteremia, lymphadenitis, neurological disease, and visceral parenchymal bacillary peliosis of the liver and spleen, which occurs in HIV-infected and other immunocompromised patients. The clinical features, microbiology, and history of this syndrome have recently been extensively reviewed.^(67-72) The causative agents are Rochalimaea henselae and R. guintana; these organisms have been cultured and identified by PCR from the blood, skin lesions, and visceral organs of patients with BA.^{(73, 74)} The angiomatous skin lesions of BA may resemble Kaposi's sarcoma. The diagnosis can be established by the histological appearance and by staining with Warthin-Starry stain or by culture of the organism.

Recently, cats have been determined to be a reservoir for acquisition of bacillary angiomatosis.^{(69, 75, 76)} In a case-control study of 42 HIV-infected patients with histologically proven BA, the clinical manifestations included fever in nearly all patients, skin lesions in a third, lymphadenopathy in nearly half, and subcutaneous nodules in one quarter.⁽⁷⁵⁾ Compared to controls, patients with bacillary angiomatosis were more likely to have been bitten or scratched by a cat; no other environmental exposures were identified. R. henselae was cultured from the blood from each of seven cats who had contact with four patients with confirmed BA.⁽⁶⁹⁾ The prevalence of R. henselae in cats was determined to be 41% (by blood culture) in asymptomatic cats in San Francisco and 15% (by anti-body) in cats in Baltimore. In addition the organism was identified in the fleas from bacteremic cats in one study.⁽⁶⁹⁾ These authors suggest that treatment of cats and control of flea infestation may reduce human exposure to R. henselae.⁽⁶⁹⁾

In the absence of controlled trials, most authors recommend erythromycin 500 mg four times daily for several months as therapy for bacillary angiomatosis.^{(67, 70, 71)} Anecdotal reports also suggest a response to once daily therapy with azithromycin.⁽⁷⁷⁾

An association between antibody to R. henselae and HIV-related neurological disease has been recently suggested.^{(35, 78-80)} R. henselae DNA has been detected in the cerebrospinal fluid of patients with CSF IgM but not IgG antibodies to R. henselae.⁽⁸¹⁾ In one study seroprevalence for R. henselae was significantly higher in HIV-infected patients with neurological disease than in patients without neurological complications.⁽⁷⁹⁾ Using data from the MACS study, Schwartzman and colleagues identified an association between the presence of R. henselae IgM antibodies and neuropsychological decline or dementia (controlling for CD4 counts and age).⁽³⁵⁾ In this study HIV-infected subjects with IgM antibodies to R. henselae were nearly twice as likely as those without antibody to develop neuropsychological decline in the next 5 years. These authors also identified cat ownership as arisk factor for developing antibody. Further investigation is needed to determine the role of Rochalimaea in neurological complications of HIV infection.

E. Sinusitis

Sinusitis has been recognized as a growing problem among HIV-infected adults, with a reported prevalence of about 30%.⁽⁸²⁾ The role of bacteria in pathogenesis of this clinical syndrome remains uncertain; however, bacterial superinfection frequently occurs. Recent retrospective series of sinusitis identify Pseudomonas as an emerging pathogen along with staphylococcal species.^{(83, 84)} Therapy includes antibiotics (often requiring parenteral therapy) and decongestants. The role of surgical drainage for the treatment of sinusitis in this setting needs to be clarified.