Although immunochemotherapy-associated IP has been extensively studied; however, the exact incidence of IP among lymphoma patients remains unclear due to high data variability in previous studies. One retrospective analysis of 2212 Chinese lymphoma patients revealed an overall IP incidence rate of 3.75%, with 3.9% (7/287) and 2.4% (76/925) in patients with Hodgkin and NHL, respectively . Giselle et al. and Wang et al. reported that IP incidence among NHL patients undergoing CHOP-based chemotherapy was 1.3% and 14.8%, respectively [7,14]. Other groups have reported values within this range, including 4.4% (5/114 patients) by Toshiro Kurokawa et al. , 6.2% (8/129 patients) by Katsuya Hiroo el al. , 7% (5/71 patients) by Lim KH et al. , and 4.9% (26/529 patients) by Huang et al. . These studies also suggested that the addition of the rituximab to therapeutic regimen might be responsible for the increase of IP incidence. In the present study, we observed a higher IP incidence rate of 21.4% in patients who did not receive preventive treatment, compared with previous reports. There could be several reasons for this difference. First, all patients received rituximab, which possessed broad immunomodulatory activity, thus, elevating the risk of opportunistic infection . Second, these patients were actively monitored by CT, which may detect a higher number of asymptomatic patients. Other possible causes included differences in the baseline characteristics of the patient population, the chemotherapy regimens administered, the intensity of chemotherapeutic dosage, diagnostic techniques, or an extended observation period that was used in this study. Thus, our results suggest that IP is a common occurrence in NHL patients who are undergoing RCHOP therapy.
For patients undergoing immunochemotherapeutic treatment, opportunistic infections remain the leading cause of IP . While all pathogens, including viruses, bacteria, and fungi, could potentially cause IP, PCP is one of the most prominent and deadly pathogens. TMP-SMX is a sulfa antibiotic that offers broad antibacterial efficacy . TMP-SMX is the first-line agent used for PCP prophylaxis in HIV-infected individuals [21,22]. Even among immunocompromised individuals who are HIV-negative, the preventive use of TMP-SMX during chemotherapy may decrease the incidence of PCP [15,23]. Toshiro et al. found that the prophylactic administration of TMP-SMX to NHL patients, who are undergoing RCHOP-based treatment resulted in null cases of PCP infections . With adequate drug adherence and tolerance, TMP-SMX prophylaxis has been shown to protect against 89% of PCP cases [24,25]. Moreover, TMP-SMX is widely available and an inexpensive drug. Therefore, TMP-SMX was selected as the prophylactic agent in this study.
In 1977, Hughes et al. first demonstrated the successful use of TMP-SMX to treat pediatric cancer patients, where untreated patients had a 21% PCP incidence rate, and treated patients had a 0% PCP incidence rate when TMP-SMX was administered either daily or 3 days per week [26,27]. More recently, many studies have confirmed the efficiency of TMP-SMX prophylaxis as a means of decreasing the PCP incidence rate [15,28-31]. A meta-analysis of twelve randomized trials found that TMP-SMX administration was linked to a 91% drop in PCP incidence, with a significant reduction in PCP-related mortality .
However, the optimal administration schedule for prophylactic TMP-SMX treatment is not well-defined. In previous studies, TMP-SMX was administered either once daily , twice daily two times per week , two consecutive days per week [28,32,33], twice weekly , or three days per week . A meta-analysis concluded that lower doses of TMP-SMX were an effective means of improving tolerance without compromising the prophylactic efficacy [23,34]. Here, patients were administered one tablet of TMP-SMX per day, and this approach was convenient and easy to implement.
We found that a history of diabetes, being male, and not undergoing prophylactic TMP-SMX treatment were independent risk factors associated with IP. In diabetic patients, hyperglycemia affects the intracellular bactericidal efficacy of immune cells. Additionally, the thickening of the alveolar epithelium, degeneration of vascular hyaline, and pulmonary microangiopathy can affect lung function. Therefore, patients with diabetes had a 30% higher pneumonia-related mortality compared with non-diabetic patients . Males usually receive higher doses of rituximab, have a longer smoking history, and are more likely to have poorer basic lung function than females. However, this study did not find other IP-associated risk factors that were identified in previous studies, such as the use of rituximab [13-15,17,36], pre-treatment absolute lymphocyte counts <1x109/L , B symptoms, a history of drug allergy [9,14], and increased intensity of corticosteroid exposure [5,37,38].
This study had several limitations, which need to be considered while interpreting these results. There are several factors, other than infectious pathogens that can cause IP, such as environmental or chemical damage, or immune-mediated inflammation . Our study observed that the prophylactic use of TMP-SMX decreased the IP incidence rate; hence, we speculated that TMP-SMX mainly decreased infection caused by PCP. However, currently, there is insufficient evidence regarding pathogens that cause IP. For example, BAL was not widely used in this study. Of the seven patients who received BAL, none of them suffered from PCP infections. Also, most patients were unwilling to receive biopsy of lung lesions. Additionally, the retrospective nature of this study increased the risk of unintentional bias, potentially explaining the observed discrepancies regarding the rate of side effects associated with TMP-SMX. Therefore, further prospective studies are needed to explore other prophylactic drugs and optimal administration.