The most significant findings of our study can be summarized as follows: (i) HIV patients with BP have higher plasma CRP and IL-8 levels at admission than patients with PCP and mycobacteriosis; (ii) the plasma TNF-α value is higher in HIV patients with mycobacteriosis than in HIV patients with BP or PCP; (iii) plasma IL-8 is an independent factor associated with mortality in HIV-infected patients with pulmonary infections.
The local and systemic inflammatory response in BP, with special emphasis on the patterns of cytokines and levels of CRP, has been studied in recent years in the immunocompetent population (20
). An increase in proinflammatory cytokines, such as IL-1β, IL-6, and TNF-α, as well as acute-phase proteins, such as CRP, has been described in BP (20
). IL-8 seems to be another inflammation-associated cytokine. It is a chemokine with neutrophil-activating capacity that has been shown to be increased in the pneumonic lung but not in the nonpneumonic lung (1
). IL-10 is an anti-inflammatory cytokine that inhibits the production of proinflammatory cytokines by monocytes and macrophages (9
). In recent studies, a relationship between IL-10 levels and the severity of community-acquired pneumonia has been demonstrated (15
). The inflammatory response in BP has not been studied in HIV-infected patients.
In our study, HIV patients with BP had elevated levels of the proinflammatory cytokines IL-6, TNF-α, and IL-8 in plasma. Additionally, the plasma CRP level was elevated. Overall, these results are similar to those found in the general population with BP, although we found neither high serum IL-1β levels nor high levels of the anti-inflammatory cytokine IL-10. Interestingly, although IL-8 in BP is usually compartmentalized in the involved lung and rarely spills over into the serum (6
), in our study there were detectable plasma IL-8 levels in 75% of HIV-infected patients with BP. In a previous study of BP in the general population, serum IL-8 was detectable in only 25% of patients (6
). In relation to the proinflammatory cytokines IL-1β, IL-6, and TNF-α, Dehoux et al. found that only levels of IL-6 were mildly increased in the sera of patients with BP in the general population, whereas the increased levels of the other cytokines were confined to the lungs alone (10
). However, other studies have documented the presence of systemic inflammation in patients with more severe BP and found that serum IL-6 and TNF-α levels correlated with the severity of pneumonia and mortality (3
). Thus, in one study of consecutive patients with BP, serum IL-6 and TNF-α were present only in 23 and 41% of patients, respectively, whereas in another study of patients with severe pneumonia requiring mechanical ventilation, IL-6 and TNF-α were detected in all patients (3
). In the present study, a cytokine pattern similar to that found in patients with severe pneumonia was observed in HIV-infected patients with BP: 99 and 100% of patients had detectable plasma IL-6 and TNF-α levels, respectively, However, our patients with BP did not show clinical criteria of severity: only 5 out of 118 (4%) required admission to the intensive care unit, and 4 (3%) required mechanical ventilation, with 3% mortality. In any case, the serum cytokine and CRP profile found in HIV patients with BP versus the other main diagnostic groups—PCP and mycobacteriosis—is quite characteristic and allows us to distinguish BP from the other processes with good sensitivity, specificity, and predictive values.
In this study, the plasma TNF-α levels were elevated in patients with BP, mycobacteriosis, and PCP. However, they were significantly higher in mycobacteriosis than in the other diagnostic groups (Table ). Indeed, a TNF-α value of ≥60 pg/ml had a very high NPV for the diagnosis of mycobacteriosis (97%). It is known that TNF-α contributes to the host defense mechanisms in mycobacterial infection (8
). Studies of mice have demonstrated that TNF-α is important in granuloma formation and in controlling the extent of mycobacteriosis (8
). In humans, the use of anti-TNF-α monoclonal antibodies, such as infliximab, has been associated with increased rates of tuberculosis reactivation (19
). In immunocompetent tuberculosis patients, TNF-α production is present at the site of disease but is seldom found in the circulation (18
). Nevertheless, recent reports have indicated that the plasma TNF-α levels may be correlated with tuberculosis severity and activity (4
). It has also been demonstrated that Mycobacterium tuberculosis
phagocytosis induces greater TNF-α production in HIV-infected macrophages than in uninfected cells (17
). In patients with HIV infection and active tuberculosis, serial measurement of plasma TNF-α levels correlated with the response to antituberculosis treatment (16
). However, a possible role of plasma TNF-α levels in the diagnosis of mycobacteriosis in HIV-infected patients has not been reported. The high incidence of mycobacteriosis and the frequent association of mycobacteriosis with other pulmonary infections in HIV patients, as well as the epidemiological relevance of this diagnosis, support the importance of excluding mycobacteriosis at admission (5
). However, direct microbiologic diagnosis is not always possible at admission and acid-fast smears in sputum are not always positive in mycobacteriosis patients. Since TNF-α has a very high NPV, it could be used as a tool to exclude the mycobacteriosis diagnosis in these patients.
Could some of the differences in cytokine levels observed in this study be due to different stages of HIV disease itself and not necessarily all be due to BP or mycobacterial infections? Immune dysregulation increases with more advanced HIV infection, even in the absence of opportunistic infections, and is associated with increased levels of proinflammatory cytokines, including IL-1β, IL-6, and TNF-α. Additionally, decreased production of important Th1 inmunoregulatory cytokines (such as IL-2 and gamma interferon, which are critical for cell-mediated immune responses) and increased production of the Th2 cytokines, such as IL-10, which are important in humoral immunity, are observed in more advanced HIV infection (7
). However, we were able to demonstrate that a high level of plasma CRP at admission is associated with BP, independent of the immunologic and virologic status of HIV-infected patients. We observed that plasma levels of IL-10 and TNF-α have a linear correlation with CD4 lymphocyte counts, and therefore, confirmed that they are correlated with more advanced HIV infection. Nevertheless, TNF-α is also independently associated with mycobacterial infections, since there are no differences in CD4 lymphocyte counts between patients with and without mycobacterial infections.
There were not enough death events in each diagnostic group to analyze prognostic factors in each of them. In the overall group of HIV-infected patients with PIs, elevated plasma IL-8 levels (higher than 61 pg/ml) were independently associated with higher mortality. Although etiological diagnosis does not seem to be a factor related to this association, this cannot be asserted absolutely. In patients who died, all the studied serum cytokines and CRP were higher than in survivors (Table ). Because of the profound cytokine dysregulation associated with HIV infection, some of these findings could actually be due to an advanced HIV status. However, when virologic and inmunologic statuses were also considered, IL-8 was independently related to higher mortality. This finding underlines the importance of the systemic inflammatory response of the host in the prognosis of pulmonary infections in this group of patients.
In conclusion, differences in the pattern of systemic inflammatory responses found in HIV-infected patients with PIs could be very useful noninvasive and early tools in the initial diagnosis of BP and mycobacteriosis. Thus, a CRP value of ≥10 mg/dl plus an IL-8 value of ≥20 pg/ml would allow the establishment of a diagnosis of BP versus PCP or mycobacteriosis with a PPV and NPV of 71 and 82%, respectively. Moreover, a TNF-α value of ≥60 pg/ml could be used for early exclusion of the mycobacteriosis diagnosis in these patients based on its high NVP (97%). Direct microbiologic diagnosis is not always possible at admission, and acid-fast smears in sputum are not always positive in patients with mycobacteriosis, which underlines the importance of having other quick and reliable diagnostic tools. The high incidence of mycobacteriosis and the frequent association of mycobacteriosis with other pulmonary infections in HIV patients, as well as the epidemiologic relevance of this diagnosis, support the importance of excluding mycobacteriosis at admission (5
). More prospective studies are needed to evaluate the role of IL-8 in the outcome of each diagnostic group and to establish if the plasma IL-8 level could have value in the decision about initial treatment of PIs in HIV-infected patients.