Nocardiosis is an uncommon yet potentially devastating infection. Nocardia tends to affect individuals with chronic lung disease or immunocompromising conditions, 2 groups increasing in number. Incidence of nocardiosis is likely to increase as well, and it is vital to have an approach to this complex disease. Here, we aim to review the presentation, diagnosis, and management of Nocardia in the modern era. We will also highlight areas of uncertainty in our understanding of nocardiosis and propose a general approach to nocardiosis therapy, accounting for response and tolerance of Nocardia treatment.

Nocardia often causes pulmonary infection among those with chronic pulmonary disease or immunocompromising conditions. Trimethoprim-sulfamethoxazole (TMP-SMX) is recommended as first-line treatment, though little data exists regarding outcomes of different dosing regimens.

We performed a multicenter retrospective cohort study of adult patients with non-disseminated pulmonary nocardiosis initially treated with TMP-SMX monotherapy. Patients' initial TMP-SMX dosing was categorized as high- (> 10 mg/kg/day), intermediate- (5-10 mg/kg/day) or low-dose (< 5 mg/kg/day). Outcomes included one-year mortality, post-treatment recurrence, and dose adjustment or early discontinuation of TMP-SMX. SMX serum concentrations and their effect on management were also assessed. Inverse probability of treatment weighting was applied to Cox regression analyses.

Ninety-one patients were included with 24 (26.4%), 37 (40.7%), and 30 (33.0%) treated with high-, intermediate-, and low-dose TMP-SMX, respectively. Patients who initially received low-dose (HR 0.07, 95% CI 0.01-0.68) and intermediate-dose TMP-SMX (HR 0.27, 95% CI 0.07-1.04) had lower risk of one-year mortality than the high-dose group. Risk of recurrence was similar between groups. Nineteen patients had peak SMX serum concentrations measured which resulted in 7 (36.8%) dose changes and was not associated with one-year mortality or recurrence. However, 66.7% of the high-dose group required TMP-SMX dose adjustment/discontinuation compared to 24.3% of the intermediate-dose and 26.7% of the low-dose groups (p = 0.001).

Low- and intermediate-dose TMP-SMX for non-disseminated pulmonary nocardiosis were not associated with poor outcomes compared to high-dose therapy, which had a higher rate of dose adjustment/early discontinuation. Historically used high-dose TMP-SMX may not be necessary for management of isolated pulmonary nocardiosis.

Nocardia recovery from pulmonary samples is challenging due to the lack of a specific medium and the abundance of overgrown respiratory flora. This study aimed to compare the amoeba plate test (APT), an amoebic coculture with Acanthamoeba castellanii, with the axenic culture to recover Nocardia from pulmonary samples. Nocardia serial dilutions (n = 15 strains from seven species, concentrations ranging: 107-102 CFU/mL) in water and spiked overgrown sputa (n = 8) were simultaneously plated on agar with amoebic monolayer (APT) and without (control). Culture positivity rates, minimal growth concentrations, growth times, and abundance of flora overgrowth were compared for each condition. In water, Nocardia culture positivity rates were not significantly different between APT (86%, 30/35) and control (94%, 33/35; P = 0.246). In sputa, APT resulted in greater Nocardia growth (63%, 22/35 vs 37%, 13/35; P = 0.008). In addition, the elimination of interfering flora was more frequent using APT (34%, 12/35 vs 11%, 4/35; P = 0.01), and the overall abundance of flora was lower (median [interquartile range, IQR]: 1 [0-2] vs 3 [1-3]; P < 0.0001). The most grown species using APT were N. mexicana and N. otitidiscaviarum, whereas N. abscessus and N. nova were the most fastidious to grow under both conditions. This study reports Nocardia's ability to grow in amoebic coculture, with some growth kinetic differences depending on the species, presumably implying their intra-amoebic multiplication. Furthermore, in APT, Nocardia recovery from overgrown sputa was greater, and flora decontamination was more effective. The present findings are strong arguments to implement APT as a complementary technique for Nocardia isolation from heavily contaminated samples.

The culture-proven diagnosis of Nocardiosis is challenging due to the difficulties in recovering Nocardia colonies from respiratory samples containing a complex polymicrobial flora. However, the isolation of Nocardia strains remains necessary to perform antibiotic susceptibility testing and adapt the antibiotic regimen of the patients. This study provides an innovative culture method based on a solid medium amoebic coculture, the amoeba plate test (APT), to cultivate Nocardia strains from clinical sputa samples. Nocardia grew across the APT amoebic monolayer. Moreover, the APT, which is already used in a reference center for the recovery of Legionella strains, exhibited good performances for Nocardia recovery and decontamination of interfering flora, thereby representing a promising second line tool to improve Nocardia culture.

Disseminated nocardiosis is a rare and potentially fatal disease, with a higher incidence in immunocompromised patients, such as those living with human immunodeficiency virus (HIV) or hematological malignancies, including lymphoma. Information on Nocardia spp. infection in Venezuela is limited.

We present the case of a 62-year-old male patient, recently diagnosed with HIV, who exhibited prolonged fever and unintentional weight loss. Paraclinical tests revealed pancytopenia and a marked elevation of lactate dehydrogenase. Disseminated histoplasmosis was suspected, prompting a bone marrow (BM) aspirate. Culture and molecular studies for Histoplasma spp. and Mycobacterium tuberculosis in BM samples were negative. Antiretroviral therapy with tenofovir/lamivudine/dolutegravir was initiated, but the patient subsequently experienced clinical deterioration, including ascites, pericardial effusion, and respiratory failure. Post-mortem biopsy and immunohistochemistry identified non-Hodgkin's lymphoma of B-cell lineage, and mycological culture of BM isolated Nocardia farcinica.

Disseminated nocardiosis may mimic histoplasmosis. Nocardia spp. infection should be considered in HIV patients, particularly in advanced stages of infection.

The prolonged treatment recommended for nocardiosis does not rely on strong evidence. Consequently, some clinicians opt shorter therapy in certain circumstances. We assessed the effectiveness of shorter therapy.

A multi-center retrospective cohort study comprising individuals diagnosed with nocardiosis between 2007 and 2022. We classified all patients who survived 90 days into three groups according to treatment duration: short (≤ 90 days), intermediate (91-180 days), and prolonged (> 180 days). We compared baseline characteristics (comorbidities, immune status) and nocardiosis manifestations across the unadjusted treatment groups, one-year all-cause mortality, disease relapse, and antibiotic-related adverse events to identify patients who may safely receive the short course.

We detected 176 patients with nocardiosis, their median age was 65 years; 74 (42%) were women. Forty-three (24%) patients died within 90 days. Of the remaining 133, 37 (28%) patients received short therapy, 40 (30%) intermediate, and 56 (42%) prolonged treatment duration. Longer courses were more likely to be administered to patients with immunosuppression, disseminated nocardiosis, and N. farcinica infection. Within a year, 20 (15%) individuals died and 2 (2%) relapsed. Treatment duration was not associated with either mortality (p = 0.945) or relapse (p = 0.509). Nocardiosis was the cause of death in only one patient, receiving a prolonged course. Of 73 patients with solitary pulmonary nocardiosis, 20 (27%) received short duration. None relapsed and 2 (10%) died, both immunocompromised. The rate of AE was similar across the groups.

With clinically guided case-by-case patient selection nocardiosis can be safely treated for durations significantly shorter than traditionally recommended.

In China, due to the large population, infections caused by Nocardia may not be as rare. Unfortunately, there is still inadequate knowledge of the clinical impact caused by Nocardia. This study aimed to compare the clinical characteristics and treatment of localized and disseminated nocardiosis.

The clinical and microbiological data of patients diagnosed with nocardiosis in a tertiary hospital in Beijing from July 2011 to July 2021 were collected and retrospectively analyzed.

Among the 54 nocardiosis cases, 34 cases were in the localized infection group, while 20 cases in the disseminated infection group. The proportion of patients with chronic structural lung disease was higher in the localized group (P=0.010). In contrast, patients with disseminated infections were more prone to receive long-term glucocorticoids and/or immunosuppressants (P=0.027). Pulmonary nodules were prominent features of imaging changes in patients with disseminated infections (P=0.027) whereas bronchial dilatation was more common in patients with localized infections (P=0.025). In addition, the disseminated group had longer average hospitalization days relative to the localized group (P=0.016), but there was no significant difference in mortality between them (P=0.942).

There were differences in the clinical profiles between patients with localized and disseminated nocardiosis in terms of clinical presentation, infection site, radiological features, treatment, and prognosis. These findings may provide references for the management and treatment of patients with nocardiosis.

Nocardia gipuzkoensis was first described as a novel and distinct species in 2020 by Imen Nouioui and pulmonary nocardiosis associated with N. gipuzkoensis was once reported in two bronchiectasis patients. Noteworthy, both reported N. gipuzkoensis cases showed sensitivity to trimethoprim/sulfamethoxazol (TMP-SMZ), which are usually recommended for empirical therapy.

We reported the third case of N. gipuzkoensis infection in a 16-year-old girl with chief complaints of cough and persistent chest and back pain. No underlying immuno-suppressive conditions and glucocorticoid use was revealed. Patchy lesions next to the spine and located in the posterior basal segment of the lower lobes of the left lung were seen in thorax computed tomography (CT), but no pathogenic bacteria were detected according to routine laboratory testings.

Metagenomic next-generation sequencing (mNGS) combined with whole-genome sequencing (WGS) was used to classified our isolate from bronchoalveolar lavage fluid (BALF) as N. gipuzkoensis. It is worth mentioning that drug susceptibility testing of our isolate showed resistance to TMP-SMZ, which was never reported before. The patient improved remarkably both clinically and radiographically according to the treatment with imipenem-cilastatin infusion alone.

mNGS and WGS showed excellent performance in identifying the Nocardia genus to the species level and improving the detection rate of N. gipuzkoensis ignored by traditional culture. Different from previously reported cases, the N. gipuzkoensis infection case showed resistance to TMP-SMZ, which is an unprecedented finding and a crucial addition to our understanding of the antibacterial spectrum of N. gipuzkoensis. The successful treatment with imipenem-cilastatin infusion alone in this case is a testament to the importance of precise identification and tailored antibiotic therapy.

Nocardiosis, a bacterial opportunistic infection caused by Nocardia spp, has recently been reported in patients with anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies, but insufficient data are available about disease presentation, outcomes, and occurrence of autoimmune pulmonary alveolar proteinosis (aPAP) in this population.

We performed a prospective, multicenter, nationwide study in France and included patients with a Nocardia infection who had anti-GM-CSF autoantibodies. We describe their clinical, microbiological, and radiological characteristics, and their outcome at 1 year of follow-up.

Twenty patients (18 [90%] male) were included, with a median age of 69 (interquartile range, 44-75) years. The organs most frequently involved were the brain (14/20 [70%]) and the lung (12/20 [60%]). Half of the infections were disseminated (10/20 [50%]). Nocardia identification was predominantly made in abscess fluid (17/20 [85%]), among which 10 (59%) were brain abscesses. The 1-year all-cause mortality was 5% (1/20), and only 1 case of aPAP (1/20 [5%]) occurred during the follow-up period.

Nocardiosis with anti-GM-CSF autoantibodies is associated with a low mortality rate despite a high incidence of brain involvement. Although the occurrence of aPAP was infrequent during the 1-year follow-up period, long-term clinical data are needed to fully understand the potential relationship between nocardiosis, anti-GM-CSF autoantibodies, and aPAP.

Pulmonary nocardiosis is a rare opportunistic infection with occasional systemic dissemination. This study aimed to investigate the computed tomography (CT) findings and prognosis of pulmonary nocardiosis associated with dissemination.

We conducted a retrospective analysis of patients diagnosed with pulmonary nocardiosis between March 2001 and September 2023. We reviewed the chest CT findings and categorized them based on the dominant CT findings as consolidation, nodules and/or masses, consolidation with multiple nodules, and nodular bronchiectasis. We compared chest CT findings between localized and disseminated pulmonary nocardiosis and identified significant prognostic factors associated with 12-month mortality using multivariate Cox regression analysis.

Pulmonary nocardiosis was diagnosed in 75 patients, of whom 14 (18.7%) had dissemination, including involvement of the brain in 9 (64.3%) cases, soft tissue in 3 (21.4%) cases and positive blood cultures in 3 (21.4%) cases. Disseminated pulmonary nocardiosis showed a higher frequency of cavitation (64.3% vs. 32.8%, P = 0.029) and pleural effusion (64.3% vs. 29.5%, P = 0.014) compared to localized infection. The 12-month mortality rate was 25.3%. The presence of dissemination was not a significant prognostic factor (hazard ratio [HR], 0.80; confidence interval [CI], 0.23-2.75; P = 0.724). Malignancy (HR, 9.73; CI, 2.32-40.72; P = 0.002), use of steroid medication (HR, 3.72; CI, 1.33-10.38; P = 0.012), and a CT pattern of consolidation with multiple nodules (HR, 4.99; CI, 1.41-17.70; P = 0.013) were associated with higher mortality rates.

Pulmonary nocardiosis with dissemination showed more frequent cavitation and pleural effusion compared to cases without dissemination, but dissemination alone did not affect the mortality rate of pulmonary nocardiosis.

Nocardia farcinica, an aerobic, Gram-positive bacterium belonging to the genus Nocardia, is a challenging opportunistic pathogen, particularly impacting immunocompromised individuals. The prevalence of human disease has witnessed a notable rise over the past two decades, correlating with an expanding population of immunocompromised individuals and advancements in the detection and identification of Nocardia spp. within clinical laboratories. This case is of a 59-year-old male with compromised immunity due to immunosuppressive medication use following a renal transplant who had an array of presentations before confirming a diagnosis of disseminated nocardiosis. The challenges faced in our case provide valuable insights into the complexities associated with diagnosing and managing Nocardia infections in immunocompromised populations, informing future clinical practice and research endeavors.

A man in his 80s with a history of sarcoidosis on chronic prednisone presented to the emergency department with several days of dyspnoea. A chest X-ray showed signs of pneumonia, and the patient was admitted. Blood and pleural fluid cultures grew Nocardia farcinica; therefore, the patient was started on treatment with trimethoprim-sulbactam and imipenem. Brain imaging showed evidence of dissemination of the infection to the central nervous system (CNS). The patient's admission was complicated by pleural effusions, acute kidney injury and pancytopenia, and therefore, his antibiotic regimen was ultimately transitioned from trimethoprim-sulfamethoxazole (TMP-SMX), meropenem and linezolid to imipenem and tedizolid. The patient received imipenem and tedizolid for the remainder of the admission. A repeat MRI of the brain was performed after 6 weeks of this dual antibiotic therapy, which unfortunately revealed persistent CNS disease. His regimen was then broadened to TMP-SMX, linezolid and imipenem. Despite these measures, however, the patient ultimately passed away from the infection.

Specific pretransplant infections have been associated with poor posttransplant outcomes. However, the impact of pretransplant Nocardia isolation has not been studied.

We performed a retrospective study from three centers in Arizona, Florida, and Minnesota of patients with Nocardia infection or colonization who subsequently underwent solid organ or hematopoietic stem cell transplantation from November 2011 through April 2022. Outcomes included posttransplant Nocardia infection and mortality.

Nine patients with pretransplant Nocardia were included. Two patients were deemed colonized with Nocardia, and the remaining seven had nocardiosis. These patients underwent bilateral lung (N = 5), heart (N = 1), heart-kidney (N = 1), liver-kidney (N = 1), and allogeneic stem cell transplantation (N = 1) at a median of 283 (interquartile range [IQR] 152-283) days after Nocardia isolation. Two (22.2%) patients had disseminated infection, and two were receiving active Nocardia treatment at the time of transplantation. One Nocardia isolate was resistant to trimethoprim-sulfamethoxazole (TMP-SMX) and all patients received TMP-SMX prophylaxis posttransplant, often for extended durations. No patients developed posttransplant nocardiosis during a median follow-up of 1.96 (IQR 0.90-6.33) years. Two patients died during follow-up, both without evidence of nocardiosis.

This study did not identify any episodes of posttransplant nocardiosis among nine patients with pretransplant Nocardia isolation. As patients with the most severe infections may have been denied transplantation, further studies with larger sample sizes are needed to better analyze any impact of pretransplant Nocardia on posttransplant outcomes. However, among patients who receive posttransplant TMP-SMX prophylaxis, these data suggest pretransplant Nocardia isolation may not impart a heightened risk of posttransplant nocardiosis.

Nocardia is an opportunistic pathogen that primarily affects immunocompromised individuals, including solid organ transplant (SOT) recipients. Up to 2.65% of SOT recipients develop nocardiosis; however, few studies have examined risk factors and prophylaxis for nocardiosis.

We performed a multicenter, matched nested case-control study of adult SOT recipients with culture-confirmed nocardiosis from 2000 through 2020. Controls were matched up to 2:1 by sex, first transplanted organ, year of transplant, transplant center, and adequate post-transplant follow-up. Multivariable conditional logistic regression was performed to analyze associations with nocardiosis. Cox proportional hazards regression compared 12-month mortality between infection and uninfected patients.

One hundred and twenty-three SOT recipients were matched to 245 uninfected controls. Elevated calcineurin inhibitor level, acute rejection, cytomegalovirus infection, lymphopenia, higher prednisone dose, and older age were significantly associated with nocardiosis while trimethoprim-sulfamethoxazole prophylaxis was protective (odds ratio [OR] .34; 95% confidence interval [CI] .13-.84). The effect of prophylaxis was similar, though not always statistically significant, in sensitivity analyses that only included prophylaxis dosed more than twice-per-week (OR .30; 95% CI .11-.80) or restricted to years 2015-2020 (OR .33, 95% CI .09-1.21). Nocardiosis was associated with increased 12-month mortality (hazard ratio 5.47; 95% confidence interval 2.42-12.35).

Multiple measures of immunosuppression and lack of trimethoprim-sulfamethoxazole prophylaxis were associated with nocardiosis in SOT recipients. Effectiveness of prophylaxis may be related to trimethoprim-sulfamethoxazole dose or frequency. Trimethoprim-sulfamethoxazole should be preferentially utilized over alternative agents in SOT recipients with augmented immunosuppression or signs of heightened immunocompromise.

Nocardiosis is a rare bacterial infection caused by Nocardia spp. However, an increasing incidence has been described whereby data about epidemiology and prognosis are essential.

A retrospective descriptive study was conducted among patients with positive Nocardia spp. culture, from January 2019 to January 2023, at a Terciary Hospital in Portugal.

Nocardiosis was considered in 18 cases with a median age of 63.8-years-old. At least one immunosuppressive cause was identified in 70% of patients. Five patients had Disseminated Nocardiosis (DN). The lung was the most common site of clinical disease (77.8%) and Nocardia was most commonly identified in respiratory tract samples. The most frequently isolated species were Nocardia nova/africana (n = 7) followed by Nocardia cyriacigeorgica (n = 3) and Nocardia pseudobrasiliensis (n = 3). The majority of the patients (94.4%) received antibiotic therapy, of whom as many as 55.6% were treated with monotherapy. The most frequently prescribed antibiotic was trimethoprim-sulfamethoxazole. Selected antimicrobial agents were generally effective, with linezolid and cotrimoxazole (100% Susceptibility [S]) and amikacin (94% S) having the most activity against Nocardia species. The median (IQR) duration of treatment was 24.2 (1‒51.4) weeks for DN; The overall one-year case fatality was 33.3% (n = 6) and was higher in the DN (66.7%). No recurrence was observed.

Nocardiosis is an emerging infectious disease with a poor prognosis, particularly in DN. This review offers essential epidemiological insights and underscores the importance of gaining a better understanding of the microbiology of nocardiosis. Such knowledge can lead to the optimization of antimicrobial therapy and, when necessary, guide appropriate surgical interventions to prevent unfavorable outcomes.

Nocardia primarily infects patients who are immunocompromised or those with chronic lung disease. Although disseminated infection is widely recognized as an important prognostic factor, studies have been mixed on its impact on outcomes of nocardiosis.

We performed a retrospective cohort study of adults with culture-confirmed nocardiosis. Advanced infection was defined as disseminated infection, cavitary pulmonary infection, or pleural infection. The primary outcome was 1-year mortality, as analyzed by multivariable Cox regression.

Of 511 patients with culture growth of Nocardia, 374 (73.2%) who had clinical infection were included. The most common infection sites were pulmonary (82.6%), skin (17.9%), and central nervous system (14.2%). In total, 117 (31.3%) patients had advanced infection, including 74 (19.8%) with disseminated infection, 50 (13.4%) with cavitary infection, and 18 (4.8%) with pleural infection. Fifty-nine (15.8%) patients died within 1 year. In multivariable models, disseminated infection was not associated with mortality (hazard ratio, 1.16; 95% CI, .62-2.16; P = .650) while advanced infection was (hazard ratio, 2.48; 95% CI, 1.37-4.49; P = .003). N. farcinica, higher Charlson Comorbidity Index, and culture-confirmed pleural infection were also associated with mortality. Immunocompromised status and combination therapy were not associated with mortality.

Advanced infection, rather than dissemination alone, predicted worse 1-year mortality after nocardiosis. N. farcinica was associated with mortality, even after adjusting for extent of infection. While patients who were immunocompromised had high rates of disseminated and advanced infection, immunocompromised status did not predict mortality after adjustment. Future studies should account for high-risk characteristics and specific infection sites rather than dissemination alone.

Nocardia are Gram-positive, aerobic, filamentous bacteria that can cause localized or disseminated infections. Immunocompromised patients are at a higher risk of developing Nocardia infection and further dissemination of the disease. To date, limited data have documented the relationship between nocardiosis and alcoholic liver disease.

We report the case of a 47-year-old man with a known history of alcoholic liver cirrhosis. The patient presented to our emergency department with redness, swelling in the left eye, and diminished bilateral vision. Fundus examination of the left eye was obscured, while that of the right eye was consistent with subretinal abscess. Therefore, endogenous endophthalmitis was suspected. Imaging revealed two ring-enhancing lesions in the brain, and multiple bilateral small cystic and cavitary lung lesions. Unfortunately, the left eye eventually eviscerated due to the rapid progression of the disease. Cultures from the left eye were positive for Nocardia farcinica. The patient was started on imipenem, trimethoprim/sulfamethoxazole, and amikacin based on culture sensitivity. The patient's hospitalization course was complicated by his aggressive and advanced condition, which led to his death.

Although the patient's condition initially improved with the recommended antibiotic regimens, it led to death owing to the patient's advanced condition. Early detection of nocardial infection in patients with typical or atypical immunosuppressive conditions may improve overall mortality and morbidity. Liver cirrhosis disrupts cell-mediated immunity and may increase the risk of Nocardia infection.

Nocardiosis occurs in up to 1.7% of hematopoietic stem cell transplantation (HSCT) recipients. Risk factors for its development and subsequent outcomes have been incompletely studied. The present study evaluated risk factors for nocardiosis in HSCT recipients and an association with 12-month mortality following Nocardia infection. We performed a nested case-control study of HSCT recipients at 3 transplantation centers between 2011 and 2021. Allogeneic HSCT recipients were matched 1:4 to controls based on age, sex, date of transplantation, and transplantation site. Because of theorized differences in the risk for nocardiosis between allogeneic HSCT recipients and autologous HSCT recipients and a low number of infected autologous HSCT recipients, only allogeneic HSCT recipients were matched to controls. Associations with nocardiosis in the allogeneic group were assessed by multivariable conditional logistic regression. Outcomes of all HSCT recipients with nocardiosis included 12-month mortality and post-treatment recurrence. Twenty-seven HSCT recipients were diagnosed with nocardiosis, including 20 allogeneic HSCT recipients and 7 autologous HSCT recipients. Twenty (74.1%) had localized pulmonary infection, 4 (14.8%) had disseminated infection, and 3 (11.1%) had localized skin infection. The allogeneic recipients were diagnosed at a median of 12.2 months after transplantation, compared with 41 months for the autologous recipients. All autologous HSCT recipients had alternative reasons for ongoing immunosuppression at diagnosis, most frequently therapy for relapsed hematologic disease. No infected patients were receiving trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis. In multivariable analysis of 20 allogeneic patients and 80 matched controls, graft-versus-host disease (GVHD) requiring current immunosuppression and lack of prophylaxis were associated with nocardiosis. Nocardiosis was significantly associated with subsequent mortality, with a 12-month mortality rate of 29.6%; however, no patients who completed treatment experienced Nocardia recurrence. OUR DATA INDICATE THAT: intensified immunosuppression following allogeneic HSCT, such as treatment for GVHD, is associated with the development of nocardiosis. Nocardiosis occurs more distantly from transplantation in autologous recipients, possibly driven by therapy for relapsed hematologic disease. No patients receiving TMP-SMX prophylaxis developed nocardiosis. Nocardia infection is associated with high mortality, and further strategies for prevention and treatment are needed.