As the combination of chemotherapy plus rituximab has been employed with increasing frequency for the treatment of NHL, reports of treatment-associated IP have similarly become increasingly common. However, the exact incidence of IP among lymphoma patients remains uncertain owing to high variability among previous studies. In one retrospective analysis of 2212 consecutive Chinese lymphoma patients, overall IP incidence was determined to be 3.75%, with rates of 3.9% (7/287) and 2.4% (76/925) in patients with Hodgkin and non-Hodgkin lymphoma, respectively9. However, in other studies the reported incidence of IP among NHL patients undergoing CHOP-based chemotherapy with or without rituximab has ranged from 1.3% in a study by Giselle Salmasi et al7. to 14.8% in a study by Wang qian et al14. Other groups have reported values within this range, including reports of 4.4% (5/114 patients) by Toshiro Kurokawa et al15, 6.2% (8/129 patients) by Katsuya Hiroo el al13, 7% (5/71 patients) by Lim KH et al16, and 4.9% (26/529 patients) by Huang et al17. These studies have also suggested that the addition of rituximab to therapeutic regimens may increase IP incidence. In the present study, we observed an IP incidence of 21.4% in patients not receiving any preventive treatment, with this rate being higher than that in previous reports. There are several possible reasons for this difference. As an anti-CD20 antibody with an extended in vivo half-life, rituximab possesses broad immunomodulatory activity. It can induce B cell apoptosis, alter complement activation, and induce cytokine release, thereby potentially interfering with normal cytotoxic T cell responses and immune functionality so as to elevate the risk of opportunistic infection18. In this study, all patients received rituximab and chemotherapeutic treatments simultaneously, which may have also contributed to our overall findings. As patients in this study were being actively monitored for IP, this too may have increased the overall IP incidence rate given that it led to disease detection in otherwise asymptomatic patients. Other possible causes for elevated IP rates include differences in the baseline characteristics of patient populations, the chemotherapy regimens administered, chemotherapeutic dose intensity, diagnostic techniques, the small size of previous studies, or the fact that we employed a longer observation period. Therefore, our results suggest that there is clear value in administering prophylactic IP treatment to NHL patients undergoing RCHOP therapy.
A number of pathological changes occur in the context of IP including the inflammation of the interstitial tissue surrounding the alveolar epithelium, leading to significant adverse alterations in local lymphatic and vascular systems19. A number of different factors can give rise to IP, including pathogens, environmental/chemical damage, or immune-mediated inflammation. Among patients undergoing immunochemotherapeutic treatment, however, opportunistic infections remain the leading cause of IP. While viruses, bacteria, and fungi all have the potential to cause IP, PCP is one of the most prominent and deadly pathogens responsible for this condition. As such it is vital that at-risk patients be administered prophylactic medicines that can reduce the risk of PCP infection in a safe, convenient, and cost-effective manner. TMP-SMX, which is composed of sulfamethoxazole (SMX) and trimethoprim (TMP), is a sulfa antibiotic that offers good antibacterial efficacy against a range of bacteria while having a low frequency of adverse reactions20. TMP-SMX is the first-line agent used for PCP prophylaxis in HIV-infected individuals21,22. Even among immunocompromised individuals not infected by HIV, the preventive use of TMP-SMX during chemotherapy may decrease the incidence of PCP15,23. Toshiro et al. found that the prophylactic administration of TMP-SMX to NHL patients undergoing RCHOP-based treatment led to no patients developing PCP infections15. With adequate drug adherence and tolerance, TMP-SMX prophylaxis has been shown to protect against 89% of PCP cases24,25. Moreover, TMP-SMX is widely available and inexpensive, at a price of just 2 dollars per 100 tablets in China. As such, TMP-SMX was selected as a prophylactic agent for use in this study.
To the best of our knowledge, no previous studies have examined the use of prophylactic TMP-SMX as a means of preventing IP infections in patients with lymphoma. Extant data regarding the efficiency of prophylactic TMP-SMX treatment is thus mainly derived from studies pertaining to PCP infections. Hughes et al. first demonstrated the successful use of TMP-SMX to treat pediatric oncology patients in 1977, with untreated patients suffering a 21% PCP incidence and treated patients suffering a 0% incidence rate when TMP-SMX was administered either daily or 3 days per week26,27. More recently, many studies have confirmed the efficiency of TMP-SMX prophylaxis as a means of decreasing the incidence of PCP in adult patients with lymphoma and in pediatric oncology patients15,28-31. A meta-analysis of twelve randomized trials found that TMP-SMX administration was linked to a 91% drop in the incidence of PCP, with a significant reduction in PCP-related mortality23. Consistent with these findings, in the present study we found that prophylactic TMP-SMX treatment significantly decreased the incidence of IP in B cell lymphoma patients undergoing R-CHOP-like chemotherapy from 21.4% to 8.0% (p<0.001).
The optimal administration schedule for prophylactic TMP-SMX is not well defined. Most previous studies have concluded that intermittent dosing with TMP-SMX is an effective alternative prophylactic regimen. TMP-SMX is thus variously administered twice daily two times per week30, two consecutive days per week28,32,33, twice weekly31, or three days per week27. Intermittent TMP/SMZ is an effective means of preventing PCP and can lower associated costs and rate of fungal infections. However, this dosing is not universal, as in one study by Toshiro et al. patients were instead administered one TMP-SMX tablet daily throughout the course chemotherapy15. A meta-analysis concluded that lower doses of TMP-SMX were an effective means of improving tolerance without compromising primary prophylactic efficacy34. No differences between once-daily and thrice-weekly administration schedules have been found23. Patients in the present study were administered one tablet of TMP-SMX per day, and this approach was convenient and easy to implement.
According to previous reports, roughly 30% - 40% of patients stop TMP-SMX therapy as a result of poor drug tolerance when receiving intermittent prophylactic treatment35. The most common adverse events linked with such discontinuation include skin rash, myelosuppression, nausea, fever, renal and liver toxicity, and hyperkalemia36-39. The observed adverse events associated with TMP-SMX prophylaxis in the present study were consistent with these previous reports, however the overall tolerance for this daily TMP-SMX regimen was high, with no instances of discontinuation due to adverse reactions. Moreover, the incidence of leukopenia and nausea and vomiting was low, which may be explained by the fact that patients were allowed to receive prophylactic G-CSF injections after chemotherapy and antiemetic treatments in this study.
We found that a history of diabetes, being male, and not undergoing prophylactic TMP-SMX treatment were independent risk factors associated with IP incidence. In diabetic patients, hyperglycemia can affect the chemotaxis, adhesion, phagocytosis and intracellular bactericidal efficacy of immune cells. In addition, the thickening of the alveolar epithelium, vascular hyaline degeneration, and pulmonary microangiopathy that occurs in diabetic patients can affect lung function. These factors will damage immune function and thereby increase rates of opportunistic infections among patients with diabetes, who experience 30% more pneumonia-related mortality than do non-diabetic patient populations40. Males usually receive higher doses of rituximab, have a longer smoking history, and are more likely to have poorer basic lung function than females. Other IP-associated risk factors identified in previous studies have included the application of rituximab13-15,17,41, pre-treatment absolute lymphocyte counts <1x109/L 17, B symptoms (fever, weight loss, night sweat), a drug allergy history9,14, and increased intensity of corticosteroid exposure5,42,43.
This study has several limitations, and as such caution is warranted when interpreting our results. For one, BAL, as an important auxiliary examination procedure, was not widely used in this study. Only 7 patients received BAL and PCP infections were not detected in any of these patients. As such, we lack sufficient evidence regarding the specific cause of IP in this patient population. Secondly, 8% of patients in this study developed IP even after prophylactic TMP/SMX treatment, suggesting that there can be other causes for this condition. As such, further prospective studies are needed in order to explore other prophylactic drugs and their optimal administration in NHL patients. In addition, the retrospective nature of this study increases the risk of unintentional bias, potentially explaining the observed discrepancies regarding the rates of side effects associated with TMP-SMX.