{'fraction_non_alphanumeric': 0.026528444029490356, 'fraction_numerical': 0.02005730659025788, 'mean_word_length': 5.270084779975777, 'pattern_counts': {'":': 0, '<': 1, '<?xml version=': 0, '>': 7, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 1, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Infection prevention in sarcoidosis: proposal for vaccination and prophylactic therapy

Sarcoidosis is a systemic inflammatory disease characterized by granuloma formation in affected organs and caused by dysregulated immune response to an unknown antigen. Sarcoidosis patients receiving immunosuppressive medications are at increased risk of infection. Lymphopenia is also commonly seen among patient with sarcoidosis. In this review, risk of infections, including opportunistic infections, will be outlined. Recommendations for vaccinations and prophylactic therapy based on literature review will also be summarized. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (2): 87-98).


Introduction
Sarcoidosis is a systemic disorder that develops in response to an unknown antigen and is typically characterized by a heightened local inflammatory reaction characterized by granuloma formation and cytokine secretion in affected organs. Patients with sarcoidosis have been noted to have an increased risk of infection requiring hospitalization, especially pneumonia and some opportunistic infections 1,2,3 . Although not fully elucidated, several mechanisms inherent to sarcoidosis and likely a result of the complex dysregulated immune response observed in sarcoidosis (such as peripheral anergy as well as loss of local defenses when bronchiectasis and cavitations develop), contribute to this increased infectious susceptibility 1,2,3 . Clinically significant peripheral lymphopenia and hypogammaglobulinemia are usually seen in association with immunosuppressive therapy, including corticosteroids. Additionally, patients with symptomatic disease are frequently treated with immunosuppressive medications which further disrupts inherent immunologic mechanisms.
As with other inflammatory diseases, on account of the immunosuppressive effects of the disease itself and the use of immunosuppressive medications, it is important to prevent infectious diseases and associated complications in sarcoidosis patients. Vaccination is generally regarded as a safe, efficacious and low-cost method that may reduce morbidity and mortality associated with sarcoidosis patients and prophylactic therapies may further be a safe and cost-effective manner of prevention 4,5,6 . It is therefore imperative to ensure patients are properly vaccinated and placed on prophylactic therapy when indicated to prevent infections. However, it has been observed that lack of physician rescommendation to do so is a predominant factor to the low rates of vaccination among immunosuppressed patients 7 . Specifically in sarcoidosis, and further contributing to low rates of vaccination and prophylaxis, we recognize that currently there are no guidelines on immunization or prophylaxis practices. Although data cannot be clearly extrapolated from other diseases, the recommendations for patients with autoimmune diseases and some forms of immunosuppression are likely applicable to sarcoidosis patients. In this review, we will outline the risk of infection in patients with sarcoidosis and immunosuppressive medications and recommendations for vaccinations and prophylactic therapy for sarcoidosis patients will be proposed.

Oral immunosuppressants commonly used in sarcoidosis
Of the oral immunosuppressant medications, glucocorticoids are found to be the highest risk for the development of infection. In a study done by Bernatsky, the relative risk of infections requiring hospitalization in those taking glucocorticoids was 2.56 (95% CI 2.29-2.85) 8 . Another study showed the relative risk of infections from glucocorticoids was 1.6 (95% CI 1.3-1.9), and the rates of infection increased with higher doses 9 . However, patients taking less than 10mg of prednisone daily (or its equivalent) did not have higher infection rates compared to those not taking glucocorticoids 10 . Furthermore, risk of infection increased in patients taking combination therapy, either glucocorticoids plus a steroid-sparing agent or more than one steroid-sparing agent together.
Methotrexate can cause cytopenias in about 5.2% of patients, which can, in part, predispose patients to infections 11 . However, a Cochrane review by Lopez-Olivo et al shows that the relative risk of serious adverse events in patients treated with methotrexate as compared to placebo is 1.44 (95% CI 0. 36-5.74)  Azathioprine, a purine analog, is converted to 6-mercaptopurine, then further degraded into its nontoxic metabolites by thiopurine methlytransferase. Azathioprine may cause myelosuppression, increasing its infectious risk profile. Those patients with a deficiency in thiopurine methyltransferase are at increased risk of azathioprine toxicity and lower doses of azathioprine should be used or avoided completely, and cell counts closely monitored 13 . A Cochran Review by Suarez-Alamazor et al shows the odds ratio of developing cytopenias with azathioprine as compared to placebo was 6.84 (95% CI 0.69-68.05) 14 . In a study completed by Bernatsky, the relative risk of infections requiring hospitalizations in patients taking azathioprine compared to placebo was 1.52 (95% CI 1.18-1.97) 8 .
Other oral disease modifying anti-sarcoid drugs (DMASD) are commonly used off-lable in sarcoidosis patients. However the risk of significant immunosuppression with these agents is unknown 15 .

Biologic Therapy Commonly Used in Sarcoidosis
Biologic therapy carries an increased risk of numerous types of infections. In a study conducted on 3,111 veteran patients with rheumatoid arthritis (RA), who had 4,158 treatment episodes with a biologic (defined as new biologic treatment, either abatacept, rituximab, or an anti-TNF agent), pneumonia was seen in 37%, cellulitis in 22%, urinary tract infections in 9% and bacteremia or sepsis in 7%. Hospitalized infection rates per 100 years were 4.4 (95% CI 3.1-6.4) for rituximab and 3.0 (95% CI 2.5-3.5) for anti-TNF agents 16 . In a study evaluating efficacy and safety of anti-TNF agents in sarcoidosis patients, Jamilloux et al found an infection rate of 36% among 132 patients 17 . In a systematic review and meta-analysis of small molecule JAK kinase inhibitors in RA patients, the incidence rate of serious infections among 5,888 patients taking tofacitinib 5mg twice daily was 1.97 (95% CI 1.41-2.68), and the incidence rate ratio when comparing to the placebo arm was 1.22 (95% CI 0.60-2.45) 18 .
Infection risk may also depend on dose of biologic therapy. A meta-analysis conducted by Leombruno et al reviewed 18 randomized trials with a total of 8808 patients with RA who were either randomized to anti-TNF agents (further divided into recommended dose vs high dose therapy), conventional synthetic disease modifying anti-rheumatic drugs (DMARDs), or placebo. High dose therapy was defined as the following: adalimumab > 40mg every 2 weeks, etanercept > 50mg weekly, and infliximab > 8mg/kg every 8 weeks. Over an average follow-up of 0.8 years, the authors did not find a statistically significant increase in infections in the synthetic DMARDs or placebo group compared to the recommended dose anti-TNF group. However, the high dose anti-TNF group had a two-fold increased risk of infections 19 . This is of particular importance in sarcoidosis, as high dose therapy is often used, in the absence of prospective randomized data. Another systematicic review and meta-analysis of anti-TNF use assessed the risk of infection in RA patients who were given standard dose anti-TNFs, high dose anti-TNFs, or control therapy. High dose anti-TNFs were defined as infliximab > 3mg/kg every 8 weeks and adalimumab > 40mg every other week. The authors found an OR of 2.3 (95% CI, 1.5-3.6) for the highdose anti-TNF group compared to the control group and an OR of 1.8 (95% CI, 1.1-3.1) for the standarddose group compared to the control group. However, when comparing the high-dose group to the standard-dose group, an OR of 1.4 was not found to be statistically significant (95% CI, 1.0-2.0, P = 0.07) 20 .
Adelzadeh et al completed a meta-analysis that evaluated the risk of herpes zoster in patients taking different biologic therapy (infliximab, adalimumab, etanercept, and ustekinumab) and found slightly higher rates of zosters in patients taking infliximab. Data for the other biologics showed varying rates, making the results inconclusive 21 . In the aforementioned systematic review and meta-analysis evaluating infection risk with tofacitinib, the incidence rate for developing herpes zoster was 2.51 (95% CI 1.87-3.30), but the incidence ratio rate when comparing to the placebo arm was no longer significant (1.38 with 95% CI 0.66-2.88) 18 . In a retrospective review of Medicare patients with RA, older patients tended to be at high risk of developing zoster regardless of biologic used, but the highest adjusted hazard ratio was seen among patients taking oral corticosteroids (> 7.5mg daily of prednisone or its equivalent) 22 .
Rituximab is also associated with increased infections, with serious infections encountered at rate of 3.76 per 100 patient years, although not all analyses reported an increased risk 23,24,25,26 . Because of its suppression of immunoglobulin production, there is an overall increased risk for viral infections. Rituximab has been shown to cause reactivation of herpes simplex virus, herpes zoster virus, and hepatitis B 27,28 . However, prolonged use of rituximab can lead to IgG depletion and neutropenia, and monitoring IgG levels on a regular basis is recommended. Immunoglobulin replacement therapy can be effective in reducing risk of infections in patients on prolonged rituximab therapy, but there are currently no guidelines on when and in which patients this should be done 29,30,31,32,33,34,35 .

Infections in Sarcoidosis
In sarcoidosis patients specifically, various infections have been described while on immunosuppressive therapies. Dureault et al examined infection rates in 585 patients, and reported 22 episodes of severe non-mycobacterial infections among 16 patients, and 14 mycobacterial infections among 14 patients 2 . Patients with severe infections were more likely to have been treated with ≥ 3 immunosuppressive agents. Although limited, current data suggests patients with sarcoidosis are at increased risk of infection regardless of immunosuppressant therapy. A retrospective review by Ungprasert et al found that patients with sarcoidosis had an increased incidence of community acquired infection requiring hospitalization compared to age-and sex-matched healthy controls (HR 2.00, 95% CI 1.14-2.84). Less than half of this cohort was on immunosuppressive therapy. Risk factors for infections included baseline diffusing capacity of the lung for carbon monoxide (DLCO) and baseline forced vital capacity (FVC), with a steady increase in infection rates with decreases in DLCO and FVC 1 . Further study is needed to further delineate infection risk in treatment-naïve sarcoid.

Opportunistic infections
Due to inherent and medication-induced immunosuppression, sarcoidosis patients have been shown to be at increased risk for opportunistic infections, albeit infrequently. Reported infections include Pneumocystis jirovecii pneumonia (PJP), Mycobacterial infection, Cryptococcus neoformans , and aspergillosis. Epidemiologic and geographic factors, as well as presence of parenchymal fibrosis, also play a part. Opportunistic infections have been observed in other autoimmune diseases in conjuncture with initiation of immunosuppressive medications. A large retrospective review identified opportunistic infections at an incidence rate of 0.045% , among patients who were newly started on either biologic or immunosuppressive therapy. Of the patients newly started on biologic therapy, the most commonly occurring infections were PJP (20%), nocardiosis (15%), tuberculosis (12.5%), histoplasmosis and non-tuberculosis mycobacteria (11.3% each), and salmonellosis (10%). The other opportunistic infections reported occurred in ≤ 5% of the cases 36 .
PJP is a commonly known opportunistic infection that affects HIV-positive patients as well as non-HIV, immunocompromised patients. In those without HIV, it tends to have a more severe course with rapidly progressive and fatal disease 37 . Several studies have reported the prevalence of PJP among patients with autoimmune disease to range from 0.18% to 1.2%, with the highest risk being among those on corticosteroid therapy, especially at doses > 20mg/day 38,39,40,41,42 . Other risk factors include older age and co-existing pulmonary disease 40 . PJP has been infrequently reported in sarcoidosis.
Mycobacterial infection has not often been reported in patients with sarcoidosis. As mycobacterial infection, especially tuberculosis, can present as granulomatous disease, it should be on the differential when assessing for sarcoidosis. There have been 27 reported cases of tuberculosis among sarcoidosis patients between 1976 and 2013, of which 74% were in patients being treated with corticosteroids. 43 . Fourteen non-tuberculosis mycobacterium cases were reported between 1977 and 2010, of which 71% were receiving corticosteroid therapy. A greater risk for tuberculosis than sarcoidosis itself is TNFalpha inhibitors, which are frequently used to treat sarcoidosis. This increased risk has been observed more commonly with infliximab and adalimumab than with etanercept 44,45,46 . Furthermore, TNF-alpha has been shown to play a part in the host defense against tuberculosis, and blockade of TNF-alpha can lead to reactivation of latent tuberculosis. A metaanalysis of 29 randomized clinical trials evaluating incidence of tuberculosis in patients on anti-TNF therapy identified 45 patients (0.57%) on anti-TNF therapy who developed tuberculosis, compared to only 3 of 3967 control patients who developed tuberculosis (p = 0.02) 47 . A systematic review of 40 randomized controlled trials with a total of 14,683 patients found an odds ratio of 24.8 for developing TB while on anti-TNF therapy (95% CI 2.4-133). When anti-TNF agents were combined with other immunosuppressive agents (methotrexate or azathioprine), the odds ratio increased to 54 (95% CI 5.3-88) 48 .
Fungal infections in patients with sarcoidosis has been sparsely reported. Baughman's study found 7 cases of fungal infection among 753 cases of sarcoidosis 49 . CrytpOsarc, a study completed by Bernard et al, identified 18 patients with cryptococcal infection and sarcoidosis and found that sarcoidosis accounted for 2.6% of the non-HIV associated cryptococcal infections 50 . One third of the identified patients were not on corticosteroids at the time of diagnosed infection, though presence of other immunosuppressants is not mentioned. Increased rates of aspergillosis have been documented among patients with chronic pulmonary fibrotic disease, and have been noted to occur more frequently in sarcoidosis than in other interstitial lung diseases 3 . Again, corticosteroids play an important role as a risk factor for development of aspergillosis as does mold exposure 2 .
Progressive multifocal leukoencephalopathy (PML) is more likely to occur in immunocompromised patients but has been reported in sarcoidosis patients not on immunosuppression. There are case reports of symptoms and magnetic resonance imaging (MRI) findings mistakenly attributed to neurosarcoidosis, leading to increased immunosuppression and worsening of symptoms 17,51,52 . The presentation of sarcoidosis-associated PML differs from neurosarcoidosis. In PML, cererbospinal fluid (CSF) is typically normal and MRI brain shows multifocal asymmetrical subcortical white matter lesions that are hypointense on T1, hyperintense on T2, and non-enhancing with contrast. In neurosarcoidosis, CSF frequently has pleocytosis and elevated protein but can be normal. MRI of the brain typically shows meningeal or parenchymal lesions with contrast enhancement. Definitive diagnosis requires JC virus DNA detection in the CSF by polymerase chain reaction or brain biopsy. JC virus may not be detected in CSF in early disease so it may require repeat lumbar puncture to diagnose. Brain biopsy can be considered if suspicion remains high 17,43 .
Herpes zoster is reported infrequently in patients with sarcoidosis, and likely occurs at the same rate as the general population 53,54 . There are reports of sarcoid granulomas occurring at the sites of healed zoster lesions 55,56,57 .

Recommendations for Vaccinations
As described, the dysregulated immune response underlying granuloma formation in sarcoidosis along with use of immunosuppressive therapies contributes to overall immune dysfunction. Despite the infection risk, there are no current guidelines on immunization practices in sarcoidosis patients. Although data describing infection risk in sarcoidosis is lacking, the recommendations for vaccinations in immunosuppressed patients are likely applicable to sarcoidosis patients. As sarcoidososis most commonly affects the lungs, vaccination should be considered in alignment with recommendations for chronic lung disease. Special consideration for vaccination should be taken in regards to use of immunosuppressive therapy and type of vaccine. Discussion with patients should also include possibly vaccinating household members and those who are regularly in close contact with the patient.
All new patients should be screened for their vaccination status and administer any appropriate immunizations prior to the start of immunosuppressive therapy 7 . Though patients with immune-mediated disease have been shown to have a comparable serologic response to vaccinations as those in the general population, immunosuppressive therapy can interfere with the immune response. This is most concerning with biologic therapy, especially rituximab, a B cell depletion therapy 58 . Patients treated with rituximab have been shown to have lower probability of immune response to various vaccines and absent antibody titers to influenza vaccines and pneumococcal vaccines 58,59,60 . In order to allow an adequate immune response, it would be best to wait two weeks after vaccinations to start immunosuppressive therapy 7 . If a patient is already receiving immunosuppressive therapy, therapy need not be held to administer inactivated vaccines. Though immunogenicity may be lower, there is still a protective response from the vaccinations.
However, when considering live vaccinations for patients on immunosuppressive medications, there should be careful thought to ensure benefits outweigh the risks. If possible, immunosuppressive therapy should be held 2-4 weeks prior to the administration of live vaccines, and the length of viremia should help determine when to restart immunosuppressive therapy. Special consideration should be given to patients receiving live vaccines while on rituximab; vaccinations should not be given until at least 5 months after the last dose of rituximab, and rituximab should not be re-dosed for at least one month after vaccinations 7 . Table 1 summarizes the list of vaccinations and Table 2 proposes the use of these vaccinations in patients with sarcoidosis.

Influenza
In sarcoidosis, as is the case with many other diseases, the presence of chronic pulmonary disease and impaired immune function likely predisposes to higher risk of complications, increased severity of disease and death from influenza 61 . The protective effect rendered by vaccination with modern influenza vaccines results from induction of antibody production against hemagglutinin (HA) or neuroaminidase antigens 62 .
Currently, the CDC recommends that any person 6 months of age or older should receive an influenza vaccination unless contraindicated because of severe allergy or other special considerations (e.g.:  patients who are unlikely to respond or who have received anti-B-cell antibodies within 6 months). Expressly, the CDC recommends that among the various types of influenza vaccines, adults 18 years of age and older receive 0.5mL of an age appropriate inactivated vaccine (trivalent or quadrivalent) or, alternatively, a recombinant quadrivalent vaccine. Notably, avoidance of live attenuated influenza vaccines in the immunocompromised individual is emphasized because of the risk of adverse events, though this is a weak recommendation with low quality of evidence 63,64 . Additionally, attention is brought to those patients 65 years of age and older given the decreased immune response to standard influenza vaccines as compared to healthy adults because of cellular senescence, and a recommendation is made which allows these individuals to receive a high-dose influenza vaccine which may provide greater immunogenicity 64,65 .
In sarcoidosis, specifically, there is paucity of data evaluating the degree of susceptibility to influenza, predisposition to disease flare after administration of influenza vaccine, and the robustness of antibody production to preventative levels against influenza after vaccination. A small prospective casecontrol study evaluated the serological response to influenza vaccination, and found no difference in serologic response to influenza vaccines, but interestingly, patients with sarcoidosis demonstrated a higher protection rate against the influenza B antigen after vaccination. Moreover, no signs of disease flares or major adverse events were observed in the sarcoidosis group after 6 months of follow-up 66 .
At the present, we recommend that immunosuppressive therapy should only be held if the risks do not risks do not outweigh the benefits. All patients without to vaccination should receive inactivated seasonal influenza vaccination yearly regardless of their therapy with a consideration for high-dose vaccination in those over 65 years of age.

Pneumococcus
Pneumococcal vaccines are typically indicated in adults over the age of 65. However, in immunocompromised patients, the CDC recommends vaccinations start at 19 years old 67 .
Regardless of age, patients should receive the 13-valent pneumococcal conjugate vaccine (PCV13 or Prevnar) vaccine first followed by the 23-valent polysaccharide vaccine (PPSV23 or Pneumovax) vaccine at least eight weeks later. Patients older than 65 years old should receive each vaccine only once (PCV13 and PPSV23). Patients less than 65 years old should have up to three PPSV23 vaccines no less than 5 years apart, with only one dose being given after a patient turns 65 years old 7,67 .
If the patient has already received PPSV23 first, the PCV13 should be given no sooner than one year after the PPSV23 vaccine. See Figure 1.

Tetanus, diphtheria, and pertussis (Tdap)
Tdap is typically completed as a series in childhood, and then is recommended every 10 years throughout adulthood. If a patient has not received any childhood Tdap vaccines, they should receive Tdap at 0, 1, and 6-12 months, and then a booster every 10 years 67 .

Zoster
The live zoster vaccine is not recommended in anyone who is immunosuppressed. As of 2020, the CDC does not yet have a recommendation regarding recombinant zoster vaccination (Shingrix) in immunocompromised adults 68 . The recombinant vaccine is given as a two-vaccine series, 2-6 months apart. If the second vaccine in the series is given too soon, it is recommended to repeat the dose at the appropriate interval. If the second vaccine is given too late, it is recommended to start over with the two-vaccine series 7,67 .
Patients who have already had a shingles infection or received the live zoster vaccine are still advised to get the recombinant zoster vaccine series 67 . Additionally, the recombinant vaccine is preferred over the live attenuated vaccine for all populations.

Hepatitis A and B
Hepatitis A (HepA) and hepatitis B (HepB) vaccines are recommended for those individuals at risk for exposure to the virus, but should also be given routinely for those who want protection. Risk factors for HepA include chronic liver disease, clotting factor disorders, men who have sex with men, drug use (including non-injection), homelessness, working with hepatitis A in research labs, close interaction with international adoptee within 60 days of arrival, and travel to country with endemic rates. Risk factors for HepB include hepatitis C Infection, chronic liver disease, infection with HIV, sexual exposure risk, current or prior injection drug use, percutaneous or mucosal risk of exposure to blood (including dialysis patients), and travel to countries with high endemic rates. Each vaccine is given as 2-3 dose series, depending on the vaccine 67 .

Other vaccinations
Vaccination for Measles / Mumps / Rubella (MMR), Yellow Fever and HPV should be followed per CDC guidelines. As the MMR vaccine is typically given to patients between the ages of 12 months and 12 years old, an adult patient should be considered vaccinated if there is presumptive evidence against immunity. This evidence includes written documentation of adequate vaccination, laboratory evidence of immunity, laboratory confirmation of measles, or birth before 1957. In those without presumptive evidence against immunity, measles immunoglobulin G (IgG) levels should be obtained. If the results are negative or equivocal, then the patient should be vaccinated or re-vaccinated. If vaccination is not possible, then the patient should be sent for second line diagnostic testing at the local health department 69 .

Tuberculosis
As TNF-alpha inhibitors can lead to reactivation of latent tuberculosis, it is recommended to screen all patients for tuberculosis exposure prior to initiation of biologics. This can be done either with a tuberculin skin test (TST) or with an interferon gamma release assay (IGRA). TST studies are less sensitive but highly specific (97.6%) for the diagnosis of tuberculosis among sarcoidosis patients 70 . However, as sarcoidosis has been associated with anergy, it is difficult to say if a negative TST in a sarcoidosis patient is a true negative. Therefore, IGRA may be more helpful. In a study by Gupta et al, patients with biopsy-proven sarcoidosis, pulmonary tuberculosis, and extra-pulmonary tuberculosis, as well as healthy controls, were prospectively enrolled to receive TST and IGRA. Patients with sarcoidosis reacted to the IGRA test more frequently than the TST, and not significantly less than in healthy controls 71 . As IGRA continues to be positive in sarcoidosis patients, it may be a better diagnostic tool for tuberculosis.
In patients with a positive TST or IGRA, TNFinhibitor therapy should only be started one month after initiation of prophylactic therapy (in cases of latent tuberculosis) or after the completion of therapy (in cases of active tuberculosis) 72 . Special consideration for anti-tuberculosis therapy should be given to patients with hepatic sarcoidosis or those on hepatoxic DMASD therapy.

Pneumocystis pneumonia (PJP)
As rates of PJP among non-HIV immunocompromised patients are low, there is no consistent data to help guide prophylaxis. . A retrospective review evaluating patients on high dose corticosteroid therapy (defined as prednisolone ≥ 30mg/day or its equivalent) with and without prophylactic therapy identified 30 cases of PJP, 29 of which were not receiving PJP prophylaxis 73 . Furthermore, a 2014 Cochrane review found a significantly reduced incidence of PJP in patients with acute leukemia or solid organ transplant who received prophylaxis by 85%. Trimethoprim-sulfamethoxazole was given thrice weekly or as a single daily dose, and the number needed to treat was 19 74 . Patients with risk factors (age older than 65 years, co-existing pulmonary disease, on corticosteroids) may benefit from prophylaxis 40 . The American Thoracic Society recommends considering prophylactic therapy for any patient who is receiving prednisone ≥ 20mg/day for ≥ 8 weeks, has an internal derangement of their immune system due to their disease, or is on a cytotoxic agent such as methotrexate or TNF-inhibitors 75 . Different regimens for prophylaxis are available (Table 3). Trimethoprim should be avoided in patients taking methotrexate as it may increase blood levels of methotrexate.

Herpes Simplex and Herpes Zoster
In patients who have a history of previous herpes simplex or zoster infection, consideration should be given for prophylactic therapy in order to prevent a flare precipitated by the initiation of DMASDs. In a Cochrane review of randomized clinical trials evaluating the efficacry of anti-virals in preventing herpes simplex infections in patients receiving cancer therapy, acyclovir was shown to be effective, with a risk ratio of 0.16 (95% CI 0.08-0.31) when compared to placebo. Further, valacyclovir was not found to be more efficacious that acyclovir 76 . According to guidelines put forth by the American Society of Clinical Oncology and the Infectious Diseases Society of America, prophylaxis with acyclovir should be considered in patients with profound neutropenia (defined as < 100 neutrophils per microliter) and seropositivity for herpes simplex 77 .

Conclusion
Infection prevention and vaccination in patients with sarcoidosis are of crucial importance. There is increased risk of infection associated with the use of immunomodulatory drugs used to treat sarcoidosis. Therefore the vaccination status should be evaluated in the initial patient workup. We propose that vaccination strategies should be implemented during stable disease and reassessed perodically during regular follow up.
The immune response to various vaccines in sarcoidosis patients is not well defined. Furthermore, the effectiveness of vaccines in patients with sarcoidosis to prevent life threatening infection requires additional research. In this review, we summarized the existing literature regarding infections in sarcoidosis patients. Furthermore we propose considering vaccination in this patient population, building on the experience from patients with other autoimmune diseases Future collaborative multi-center studies should help better understand the safety and efficacy of various vaccines in patients with sarcoidosis with and without immunomodulatory therapy. Even though the preliminary evidence is reassuring on the safety of vaccination in patients with sarcoidosis, there is a need for further studies regarding optimal vaccination strategies.
More longitudinal data is needed including large scale epidemiological studies in regard to the prevalence of various infections in sarcoidosis and the role of prophylactic therapy and vaccination in preventing such infections.
Efforts should be made to educate practicing physicians taking care of sarcoidosis patients, as well as patients, to pay special attention to infection prevention and vaccination. A personalized approach to infection prevention and vaccination would serve patients best.
This paper was reviewed and approved by the World Association of Sarcoidosis and Other Granulomatous disease (WASOG) executive committee.
There are no financial discolosures or conflicts of interest for any of the listed authors.