Prevention of Opportunistic Infections in HIV/AIDS

Utsav Shrestha; Usama Sadiq; Nilmarie Guzman; Sarosh Vaqar

Prevention of Opportunistic Infections in HIV/AIDS

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Continuing Education Activity

HIV/ AIDS patients with a low CD4 count have decreased humoral and cellular immunity, predisposing them to opportunistic infections. These diseases are associated with significant morbidity and mortality in patients with HIV/AIDS. This activity will highlight the prevalence and risk factors of common opportunistic infections in HIV/AIDS patients. It will proved a concise review for an interprofessional team of physicians, specialists, and nurses in the current guidelines for prophylactic antibiotic use and vaccinations against common opportunistic infections.

Objectives:

Explain the pathophysiology and risk factors of opportunistic infections.
Describe the role of antiviral therapy, vaccinations and immunizations in the prevention of opportunistic infections.
Identify the development of immune reconstitution syndrome after initiation of HAART.
Outline the common opportunistic infections in HIV patients, risk factors for exposure and prophylactic antibiotics.

Introduction

Opportunistic infections (OI) are a significant cause of morbidity and mortality in patients with HIV/AIDS. Although the incidence of OI has reduced since the introduction of highly active antiretroviral therapy (ART) in 1995, it continues to add to the burden of HIV-related hospitalizations and deaths in patients. This is particularly true in patients who have not received HAART therapy or who have been non-compliant to it.[1][2] These infections generally lack the virulence and pathogenicity to cause disease in immunocompetent hosts and are hence an uncommon phenomenon.[3]However, due to the immunodeficiency, the risk of OI in HIV/AIDS is substantially increased, particularly in the absence of ART and antimicrobial prophylaxis.

There is a progressive decrease in CD4+ counts in HIV/AIDS when left untreated. CD4+ cells play an important role in mounting an immune response against infections. These cells release cytokines that lead to the activation of antigen-presenting cells, phagocytic cells, natural killer cells, and cytotoxic T cells. They also support the conversion of B-lymphocytes into long-lived plasma cells and memory B cells. A decrease in CD4+ T cell count thus leads to a decline in both humoral and cell-mediated immunity. Ultimately it predisposes patients to a higher risk of contracting opportunistic diseases due to viruses, bacteria, fungi, and protozoa.[4][5][6][7][8] As the dogma of medicine is "Prevention is better than cure", preventing opportunistic infections in HIV/AIDS patients is paramount to seeing a decrease in both disease burden and associated mortality. In this review article, we discuss the methods of preventing opportunistic infections in HIV/AIDS patients.

Function

Strategies to prevent opportunistic infections in HIV/AIDS:

Prevention of opportunistic infections in HIV/AIDS involves a multidisciplinary approach that includes primary care physicians, infectious disease agents, and social workers for support. Early initiation of HAART remains the most efficient method for preventing OI.[9][10][11]Additional methods include the felicitous application of several strategies including vaccinations, screenings for co-infections, avoidance of exposures, patient education, and antibiotic prophylaxis.

1. Screening for co-infections:

It is highly recommended that patients with a newly diagnosed HIV infection be screened for the following infections, commonly found concurrently with HIV infection:

Disease	Screening method	Screening frequency
Screening for Sexually transmitted diseases:[12][13][14][15] Syphilis Chlamydia and gonorrhea Trichomonas (screening in women only)	RPR or VDRL test for syphilis. NAAT for chlamydia and gonorrhea, ideally from all urethra, rectum, and oral samples. Wet mount for Trichomonas infection following a per-vaginal exam.	At the time of the initial diagnosis of HIV and then annually. If patient high-risk sexual behavior (such as men having sex with men or promiscuous behavior), it is recommended that they get tested more frequently.
Latent Tuberculosis[16][17]	Tuberculin skin test or Interferon-gamma test.	At the time of diagnosis or initiation of ART. Then annually if there is a history of prior exposure to tuberculosis or ongoing risk of exposure (e.g. homelessness or incarcerated).
Hepatitis A and Hepatitis B[18][19][20]	Hepatitis A IgM, IgG antibody Hepatitis B surface antigen Ab (HBsAg), IgG HBsAg, IgM HBsAg, Hepatitis B core antigen.	At the time of diagnosis or initiation of ART. And after vaccination to evaluate for an immunogenic response.
Hepatitis C[21][22][23][24]	Hepatitis C antibody with reflex DNA PCR is positive.	At the time of diagnosis or initiation of ART. Then, annually for high-risk patients (e.g. Intravenous drug users).
Coccidioidomycosis[25][26]	IgG and IgM against coccidioides spp.	Annual screening is recommended in certain endemic states, such as California and Arizona.

2. Role of antimicrobial prophylaxis:

Antimicrobial prophylaxis, in addition to ART, is indicated in patients with severe immunosuppression and resultant increased risk of opportunistic infections. Low CD4 + cell count acts as a marker of the severity of an immunosuppressed state. [27][28][29]

Antimicrobial prophylaxis can be safely discontinued once CD4+ cell count is > 200 cells/microL for more than six months after the initiation of ART. The following table shows the common organisms that cause opportunistic disease in HIV/AIDS patients below certain thresholds of CD4 + cell count.[30][31][32]

Organism

Disease

CD4 count at risk

Prophylaxis

Mycobacterium tuberculin

Pulmonary or extrapulmonary TB

Any count, if the screening test is positive or patients have a prior history of active TB.

If the screening test is positive, the first step is to rule out an active disease with a chest X-ray. If negative, start Isoniazid for 9 months.

Coccidioides sp.

Coccidioidomycosis

< 250 cells/microL
And from endemic regions of southwestern United States

Fluconazole for patients with positive serological tests.

Pneumocystis jirovecii

Pneumocystis pneumonia

< 200 cells/microL

Trimethoprim-Sulfamethoxazole.
Alternate agents: Dapsone, atovaquone, or aerosolized pentamidine.

Toxoplasma

gondi

Toxoplasmosis

< 100 cells/microL

Trimethoprim-Sulfamethoxazole.
Alternate agents:

- Dapsone + pyrimethamine + leucovorin

- Atovaquone + pyrimethamine.

There is little or no evidence to suggest a clinical benefit of starting antimicrobial prophylaxis against the following organisms:

1. Histoplasma capsulated

2. Mycobacterium avium complex (MAC)

3. Bartonella spp

4. Cytomegalovirus (CMV)

5. Cryptosporidium

6. Candida spp.

These organisms have a low incidence in HIV/AIDS patients and there is potential for significant drug interactions with HAART therapy if prophylaxis is started concomitantly. Thus, the timely initiation of HAART and subsequent improvement in CD4 + cell count alone is thought to provide adequate prevention against disease.

3. Role of vaccinations:

The therapeutic efficacy or immunogenic potential of vaccines has not been fully established in HIV/AIDS patients. The decline in immune response in HIV/AIDS patients with low CD4+ cell counts poses a major hurdle in obtaining a robust and long-lasting protective benefit against disease.[33][34][35]Despite these limitations, vaccinations are strongly encouraged in this population given the potential benefit in alleviating the severity and mortality from a vaccine-preventable disease. In general, inactivated vaccines are generally preferred over live vaccines due to the potential risk of vaccine-related illness. If there is any doubt regarding immunogenicity or subsequent testing does not show an appropriate antibody response, it is revaccination is recommended once CD4+ cell count > 200 cells/microL has been achieved. [30][36][37]

The following vaccines are routinely recommended in HIV/AIDS patients:

Seasonal influenza vaccine inactivated form administered annually.
Tetanus, Diptheria, acellular pertussis (TdaP): Recommended in all patients 11 years or older who have not yet received it yet followed by Tetanus, Diptheria (Td) booster dose every 10 years.
Human papillomavirus (HPV): Generally administered during adolescent years of 11 -12 years, but in HIV patients, it is recommended up to 26 years of age. Administration of this vaccine even beyond 26 years of age has been recommended in patients with high-risk sexual behavior.
Pneumococcal vaccine: Patients older than 2 years old are recommended to get a Pneumococcal conjugate vaccine (PCV13 or Prevnar) with any CD4+ cell count followed by Pneumococcal polysaccharide vaccine (PPSV23 or Pneumovax) after at least 8 weeks. It is recommended that this booster be given after the CD4+ cell count improves to >200 cells/microL. A further dose of PPSV23 is recommended after 5 years of the first PPSV23 administration.
Hepatitis A and Hepatitis B vaccine: Administered to patients who are found to be non-immune during routine screening. It is recommended to check for an appropriate antibody response after one month of vaccine administration. If a poor response is seen, the administration of a vaccine after CD4+ cell count improves to >200 cells/microL is recommended.
Meningococcal vaccinations: Administration of meningococcal conjugate vaccine with serogroups A, C, W, Y is recommended in patients above the age of 2 months. In addition to this, the serogroup B vaccine is recommended in patients with asplenia, complement deficiency, and during meningococcal outbreaks involving serogroup B.

Certain vaccines are recommended when patients fulfill certain indications, such as:[31]

Haemophilus influenza b: Only indicated in children aged 5 to 8 years of age or in adults at risk of disseminated Hemophilus infections such as asplenia or complement deficiency.
Measles, Mumps, Rubella: For patients without severely immunocompromised state (CD4 count < 200cells/microL in adults or less than 15 % in children less than 5 years old), two doses of MMR vaccine 28 days apart is recommended if they do not have any evidence of previous immunity. For someone with a clear history of prior immunization, laboratory finding of an immune response, or birth before 1957 AD, vaccinations are not necessary.
Varicella vaccine: Recommended in patients born after 1979 and who do not have anti-varicella IgG or clearly documented history of receiving two doses of varicella vaccine when their CD4 count was >200 cells/microL.
Zoster vaccine: HIV patients 50 years or older should receive two doses of non-live recombinant Zoster vaccine (RZV), intramuscular, 8 weeks apart as per the US department of health and human services.

4. Minimizing the risk of exposure:

Opportunistic infections can be contracted by immunocompromised hosts in several ways:

Presence of high-risk environments to contract the disease (patients who contract Tuberculosis due to close proximity to other infected individuals e.g in prison or homelessness)
Presence of high-risk practices (e.g. Hepatitis B, Hepatitis C in patients using intravenous drugs, men who have sex with men, or people with multiple sexual partners).
Close proximity to certain vectors, who are carriers of the disease can also increase the risk of exposure and result in disease. For example, Crytococccas can be transmitted by pigeons and Toxoplasmosis from cat droppings.

It is understandable that certain risks of exposure such as being incarcerated or homeless might be difficult to remedy. However, patients should be counseled regarding avoidable exposures such as pets (cats, birds), high-risk sexual practice, and prevention of sexually transmitted diseases with the use of barrier contraceptives.

Issues of Concern

Immune Reconstitution Syndrome (IRIS)

Immune reconstitution inflammatory syndrome is a clinical phenomenon that occurs after the initiation of antiretroviral therapy. It represents a paradoxical worsening of preexisting infectious processes following improvement in immune response and a subsequent state of elevated inflammatory response. The preexisting infections can be subclinical (e.g. Toxoplasmosis) or previously treated infections (Tuberculosis). The clinical presentation depends on the location and severity of inflammation.[38][39][40][41][42]

IRIS has been found to occur in up to 30 % of HIV/AIDS patients receiving ART. Low CD4 cell counts or high HIV RNA load at the time of initiation of ART has been thought to be important risk factors for IRIS.[43][44][45]

There are no universally accepted diagnostic criteria for IRIS, but the presence of the following features is thought to be highly suggestive:[46][47][48]

Presence of AIDS with a low pretreatment CD4 count (often less than 100 cells/mm3). However, IRIS secondary to preexisting M. tuberculosis infection may occur in individuals with CD4 counts greater than 200 cells/mm3.
Patients should have no evidence of resistance to ART or lowered therapeutic efficacy due to drug interactions.
Temporal association initiation of ART and the onset of illness. There must be evidence of immunological response to antiretroviral therapy with improving CD4+ cell count.
Presence of clinical manifestations consistent with an inflammatory condition, such as:

CMV associated IRIS: painless floaters, blurred vision, ocular pain.
MAC associated IRIS: Fever and tender lymph node enlargement.
Cryptococcal infection-associated IRIS: fever, neck rigidity

5. Other causes of clinical deterioration such as drug allergies (e.g. with abacavir), new opportunistic infections must be considered and ruled out.

The most common pathogens that are commonly associated with IRIS are Mycobacterium tuberculosis, Mycobacterium avium complex, Cytomegalovirus, Cryptococcus neoforman, Pneumocystis jirovecii, Herpes simplex virus, Hepatitis B virus, Human herpesvirus 8.[39][49]A detailed explanation of pathophysiology and management of IRIS is beyond the scope of this review article. However, a crucial learning point regarding the management of IRIS is that it is directed towards the management of underlying opportunistic infection, and at no point should ART be stopped.

Clinical Significance

The timely introduction of ART to improved CD4+ counts is the most efficient method of minimizing the risk of opportunistic infections. The use of ART can however lead to IRIS due to inflammatory response once improvement of CD4+ cell count is seen and immune response has been achieved. The presentation of IRIS can be nonspecific and depends on the type of opportunistic infection, location, and severity of inflammatory response. Due to its nonspecific presentation, it can be hard to differentiate it from active infections (e.g hospital-acquired pneumonia), a progression of previously diagnosed opportunistic infections, or drug-related side effects. Continuation of ART and symptomatic management is the cornerstone of managing IRIS. The use of steroids is reserved for severe forms of IRIS. [50][51][52]

Enhancing Healthcare Team Outcomes

HIV patients who are untreated are prone to multiple opportunistic infections due to the progressive lowering of their CD4 + T cells. Because of the high morbidity and mortality of these infections, every attempt should be made that these patients have enough resources for early diagnosis of HIV, timely initiation of ART, regular follow up to ensure medication adherence.

These patients should be managed by an interprofessional team that includes an infectious disease specialist, internist, specialist nurse, pharmacists, and social workers. They also need close monitoring with regular lab work to evaluate for improvement of CD4+ cell count, assessment of medication-related side effects, and the emergence of opportunistic infections. Patients with HIV often face social stigma due to their infections. The team must additionally ensure adequate social and financial support, rehabilitation for intravenous drug abusers along with patient education regarding safe sex practices, and avoidance of high-risk behaviors.

Details

References

[1]

Palmisano L, Vella S. A brief history of antiretroviral therapy of HIV infection: success and challenges. Annali dell'Istituto superiore di sanita. 2011:47(1):44-8. doi: 10.4415/ANN_11_01_10. Epub [PubMed PMID: 21430338]

[2]

Esté JA, Cihlar T. Current status and challenges of antiretroviral research and therapy. Antiviral research. 2010 Jan:85(1):25-33. doi: 10.1016/j.antiviral.2009.10.007. Epub 2009 Dec 16 [PubMed PMID: 20018390]

[3]

Dropulic LK, Lederman HM. Overview of Infections in the Immunocompromised Host. Microbiology spectrum. 2016 Aug:4(4):. doi: 10.1128/microbiolspec.DMIH2-0026-2016. Epub [PubMed PMID: 27726779]

Level 3 (low-level) evidence

[4]

Ai JW, Ruan QL, Liu QH, Zhang WH. Updates on the risk factors for latent tuberculosis reactivation and their managements. Emerging microbes & infections. 2016 Feb 3:5(2):e10. doi: 10.1038/emi.2016.10. Epub 2016 Feb 3 [PubMed PMID: 26839146]

[5]

Vergis EN, Mellors JW. Natural history of HIV-1 infection. Infectious disease clinics of North America. 2000 Dec:14(4):809-25, v-vi [PubMed PMID: 11144640]

[6]

Alimonti JB, Ball TB, Fowke KR. Mechanisms of CD4+ T lymphocyte cell death in human immunodeficiency virus infection and AIDS. The Journal of general virology. 2003 Jul:84(Pt 7):1649-1661. doi: 10.1099/vir.0.19110-0. Epub [PubMed PMID: 12810858]

[7]

Achhra AC, Petoumenos K, Law MG. Relationship between CD4 cell count and serious long-term complications among HIV-positive individuals. Current opinion in HIV and AIDS. 2014 Jan:9(1):63-71. doi: 10.1097/COH.0000000000000017. Epub [PubMed PMID: 24275674]

[8]

Ford N, Meintjes G, Vitoria M, Greene G, Chiller T. The evolving role of CD4 cell counts in HIV care. Current opinion in HIV and AIDS. 2017 Mar:12(2):123-128. doi: 10.1097/COH.0000000000000348. Epub [PubMed PMID: 28059957]

Level 3 (low-level) evidence

[9]

Jain V, Hartogensis W, Bacchetti P, Hunt PW, Hatano H, Sinclair E, Epling L, Lee TH, Busch MP, McCune JM, Pilcher CD, Hecht FM, Deeks SG. Antiretroviral therapy initiated within 6 months of HIV infection is associated with lower T-cell activation and smaller HIV reservoir size. The Journal of infectious diseases. 2013 Oct 15:208(8):1202-11. doi: 10.1093/infdis/jit311. Epub 2013 Jul 12 [PubMed PMID: 23852127]

[10]

Badura R, Foxall RB, Ligeiro D, Rocha M, Godinho-Santos A, Trombetta AC, Sousa AE. Early ART in Acute HIV-1 Infection: Impact on the B-Cell Compartment. Frontiers in cellular and infection microbiology. 2020:10():347. doi: 10.3389/fcimb.2020.00347. Epub 2020 Jul 16 [PubMed PMID: 32766164]

[11]

Luzuriaga K, Tabak B, Garber M, Chen YH, Ziemniak C, McManus MM, Murray D, Strain MC, Richman DD, Chun TW, Cunningham CK, Persaud D. HIV type 1 (HIV-1) proviral reservoirs decay continuously under sustained virologic control in HIV-1-infected children who received early treatment. The Journal of infectious diseases. 2014 Nov 15:210(10):1529-38. doi: 10.1093/infdis/jiu297. Epub 2014 May 21 [PubMed PMID: 24850788]

[12]

Quilter L, Dhanireddy S, Marrazzo J. Prevention of Sexually Transmitted Diseases in HIV-Infected Individuals. Current HIV/AIDS reports. 2017 Apr:14(2):41-46. doi: 10.1007/s11904-017-0350-3. Epub [PubMed PMID: 28374281]

[13]

Cantor A, Nelson HD, Daeges M, Pappas M. Screening for Syphilis in Nonpregnant Adolescents and Adults: Systematic Review to Update the 2004 U.S. Preventive Services Task Force Recommendation. 2016 Jun:(): [PubMed PMID: 27336106]

[14]

Masha SC, Cools P, Sanders EJ, Vaneechoutte M, Crucitti T. Trichomonas vaginalis and HIV infection acquisition: a systematic review and meta-analysis. Sexually transmitted infections. 2019 Feb:95(1):36-42. doi: 10.1136/sextrans-2018-053713. Epub 2018 Oct 19 [PubMed PMID: 30341233]

Level 1 (high-level) evidence

[15]

Bochner AF, Baeten JM, Rustagi AS, Nakku-Joloba E, Lingappa JR, Mugo NR, Bukusi EA, Kapiga S, Delany-Moretlwe S, Celum C, Barnabas RV, Partners in Prevention HSV/HIV Transmission Study and Partners PrEP Study Teams. A cross-sectional analysis of Trichomonas vaginalis infection among heterosexual HIV-1 serodiscordant African couples. Sexually transmitted infections. 2017 Nov:93(7):520-529. doi: 10.1136/sextrans-2016-053034. Epub 2017 Apr 4 [PubMed PMID: 28377421]

[16]

Adams S, Ehrlich R, Baatjies R, Dendukuri N, Wang Z, Dheda K. Evaluating Latent Tuberculosis Infection Test Performance Using Latent Class Analysis in a TB and HIV Endemic Setting. International journal of environmental research and public health. 2019 Aug 14:16(16):. doi: 10.3390/ijerph16162912. Epub 2019 Aug 14 [PubMed PMID: 31416206]

[17]

Bruchfeld J, Correia-Neves M, Källenius G. Tuberculosis and HIV Coinfection. Cold Spring Harbor perspectives in medicine. 2015 Feb 26:5(7):a017871. doi: 10.1101/cshperspect.a017871. Epub 2015 Feb 26 [PubMed PMID: 25722472]

[18]

Mulkay JP. [Hepatitis B: screening and treatment]. Revue medicale de Bruxelles. 2012 Sep:33(4):215-22 [PubMed PMID: 23091924]

[19]

Abara WE, Qaseem A, Schillie S, McMahon BJ, Harris AM, High Value Care Task Force of the American College of Physicians and the Centers for Disease Control and Prevention, Abraham GM, Centor R, DeLong DM, Gantzer HE, Horwitch CA, Humphrey LL, Jokela JA, Li JMW, Lohr RH, López AM, McLean RM. Hepatitis B Vaccination, Screening, and Linkage to Care: Best Practice Advice From the American College of Physicians and the Centers for Disease Control and Prevention. Annals of internal medicine. 2017 Dec 5:167(11):794-804. doi: 10.7326/M17-1106. Epub 2017 Nov 21 [PubMed PMID: 29159414]

[20]

Jooste P, van Zyl A, Adland E, Daniels S, Hattingh L, Brits A, Wareing S, Goedhals D, Jeffery K, Andersson M, Goulder P, Matthews PC. Screening, characterisation and prevention of Hepatitis B virus (HBV) co-infection in HIV-positive children in South Africa. Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology. 2016 Dec:85():71-74. doi: 10.1016/j.jcv.2016.10.017. Epub 2016 Oct 31 [PubMed PMID: 27838494]

[21]

Easterbrook P, Johnson C, Figueroa C, Baggaley R. HIV and Hepatitis Testing: Global Progress, Challenges, and Future Directions. AIDS reviews. 2016 Jan-Mar:18(1):3-14 [PubMed PMID: 26991825]

Level 3 (low-level) evidence

[22]

Panneer N, Lontok E, Branson BM, Teo CG, Dan C, Parker M, Stekler JD, DeMaria A Jr, Miller V. HIV and hepatitis C virus infection in the United States: whom and how to test. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2014 Sep 15:59(6):875-82. doi: 10.1093/cid/ciu396. Epub 2014 May 27 [PubMed PMID: 24867787]

[23]

Kempf MC, Ott C, Wise JM, Footman AP, Araya BY, Hardy CM, Walker C, Latham C, Stockett R, Daniels G, Alexander M, Lanzi RG. Universal Screening for HIV and Hepatitis C Infection: A Community-Based Pilot Project. American journal of preventive medicine. 2018 Nov:55(5 Suppl 1):S112-S121. doi: 10.1016/j.amepre.2018.05.015. Epub [PubMed PMID: 30670196]

Level 3 (low-level) evidence

[24]

Terranova E, Tsoi B, Laraque F, Washburn K, Fuld J. Strengthening Screening for HIV, Hepatitis C, and STIs: An Innovative Partnership Between the Health Department and Community Health Centers in New York City. Public health reports (Washington, D.C. : 1974). 2016 Jan-Feb:131 Suppl 1(Suppl 1):5-10 [PubMed PMID: 26862225]

[25]

McNeil MM, Ampel NM. Opportunistic coccidioidomycosis in patients infected with human immunodeficiency virus: prevention issues and priorities. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 1995 Aug:21 Suppl 1():S111-3 [PubMed PMID: 8547498]

[26]

Masannat FY, Ampel NM. Coccidioidomycosis in patients with HIV-1 infection in the era of potent antiretroviral therapy. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2010 Jan 1:50(1):1-7. doi: 10.1086/648719. Epub [PubMed PMID: 19995218]

[27]

Brooks JT, Kaplan JE, Holmes KK, Benson C, Pau A, Masur H. HIV-associated opportunistic infections--going, going, but not gone: the continued need for prevention and treatment guidelines. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2009 Mar 1:48(5):609-11. doi: 10.1086/596756. Epub [PubMed PMID: 19191648]

[28]

Ledergerber B, Egger M, Erard V, Weber R, Hirschel B, Furrer H, Battegay M, Vernazza P, Bernasconi E, Opravil M, Kaufmann D, Sudre P, Francioli P, Telenti A. AIDS-related opportunistic illnesses occurring after initiation of potent antiretroviral therapy: the Swiss HIV Cohort Study. JAMA. 1999 Dec 15:282(23):2220-6 [PubMed PMID: 10605973]

[29]

Palella FJ Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, Aschman DJ, Holmberg SD. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. The New England journal of medicine. 1998 Mar 26:338(13):853-60 [PubMed PMID: 9516219]

[30]

Aberg JA, Gallant JE, Ghanem KG, Emmanuel P, Zingman BS, Horberg MA, Infectious Diseases Society of America. Primary care guidelines for the management of persons infected with HIV: 2013 update by the HIV medicine association of the Infectious Diseases Society of America. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2014 Jan:58(1):e1-34. doi: 10.1093/cid/cit665. Epub 2013 Nov 13 [PubMed PMID: 24235263]

[31]

Kaplan JE, Benson C, Holmes KK, Brooks JT, Pau A, Masur H, Centers for Disease Control and Prevention (CDC), National Institutes of Health, HIV Medicine Association of the Infectious Diseases Society of America. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports. 2009 Apr 10:58(RR-4):1-207; quiz CE1-4 [PubMed PMID: 19357635]

[32]

Kaplan JE, Masur H, Holmes KK, USPHS, Infectious Disease Society of America. Guidelines for preventing opportunistic infections among HIV-infected persons--2002. Recommendations of the U.S. Public Health Service and the Infectious Diseases Society of America. MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports. 2002 Jun 14:51(RR-8):1-52 [PubMed PMID: 12081007]

[33]

Ljungman P. Vaccination of immunocompromised patients. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases. 2012 Oct:18 Suppl 5():93-9. doi: 10.1111/j.1469-0691.2012.03971.x. Epub [PubMed PMID: 23051059]

[34]

Hechter RC, Qian L, Tartof SY, Sy LS, Klein NP, Weintraub E, Mercado C, Naleway A, McLean HQ, Jacobsen SJ. Vaccine safety in HIV-infected adults within the Vaccine Safety Datalink Project. Vaccine. 2019 May 31:37(25):3296-3302. doi: 10.1016/j.vaccine.2019.04.080. Epub 2019 May 4 [PubMed PMID: 31064675]

Level 2 (mid-level) evidence

[35]

Stone CA Jr, Rukasin CRF, Beachkofsky TM, Phillips EJ. Immune-mediated adverse reactions to vaccines. British journal of clinical pharmacology. 2019 Dec:85(12):2694-2706. doi: 10.1111/bcp.14112. Epub 2019 Nov 5 [PubMed PMID: 31472022]

[36]

Rubin LG, Levin MJ, Ljungman P, Davies EG, Avery R, Tomblyn M, Bousvaros A, Dhanireddy S, Sung L, Keyserling H, Kang I, Infectious Diseases Society of America. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2014 Feb:58(3):e44-100. doi: 10.1093/cid/cit684. Epub 2013 Dec 4 [PubMed PMID: 24311479]

Level 1 (high-level) evidence

[37]

Glesby MJ. Immunizations during HIV infection. Current opinion in infectious diseases. 1998 Feb:11(1):17-21 [PubMed PMID: 17033361]

Level 3 (low-level) evidence

[38]

Müller M, Wandel S, Colebunders R, Attia S, Furrer H, Egger M, IeDEA Southern and Central Africa. Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis. The Lancet. Infectious diseases. 2010 Apr:10(4):251-61. doi: 10.1016/S1473-3099(10)70026-8. Epub [PubMed PMID: 20334848]

[39]

Manzardo C, Guardo AC, Letang E, Plana M, Gatell JM, Miro JM. Opportunistic infections and immune reconstitution inflammatory syndrome in HIV-1-infected adults in the combined antiretroviral therapy era: a comprehensive review. Expert review of anti-infective therapy. 2015 Jun:13(6):751-67. doi: 10.1586/14787210.2015.1029917. Epub 2015 Apr 10 [PubMed PMID: 25860288]

Level 3 (low-level) evidence

[40]

Lai RP, Meintjes G, Wilkinson RJ. HIV-1 tuberculosis-associated immune reconstitution inflammatory syndrome. Seminars in immunopathology. 2016 Mar:38(2):185-98. doi: 10.1007/s00281-015-0532-2. Epub 2015 Sep 30 [PubMed PMID: 26423994]

[41]

Roade Tato L, Burgos Cibrian J, Curran Fábregas A, Navarro Mercadé J, Willekens R, Martín Gómez MT, Ribera Pascuet E, Falcó Ferrer V. Immune reconstitution inflammatory syndrome in HIV-infected patients with Pneumocystis jirovecii pneumonia. Enfermedades infecciosas y microbiologia clinica (English ed.). 2018 Dec:36(10):621-626. doi: 10.1016/j.eimc.2017.11.002. Epub 2017 Nov 26 [PubMed PMID: 29187293]

[42]

Gopal R, Rapaka RR, Kolls JK. Immune reconstitution inflammatory syndrome associated with pulmonary pathogens. European respiratory review : an official journal of the European Respiratory Society. 2017 Jan:26(143):. doi: 10.1183/16000617.0042-2016. Epub 2017 Jan 3 [PubMed PMID: 28049128]

[43]

Ratnam I, Chiu C, Kandala NB, Easterbrook PJ. Incidence and risk factors for immune reconstitution inflammatory syndrome in an ethnically diverse HIV type 1-infected cohort. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2006 Feb 1:42(3):418-27 [PubMed PMID: 16392092]

[44]

Manabe YC, Campbell JD, Sydnor E, Moore RD. Immune reconstitution inflammatory syndrome: risk factors and treatment implications. Journal of acquired immune deficiency syndromes (1999). 2007 Dec 1:46(4):456-62 [PubMed PMID: 18077835]

[45]

Grant PM, Komarow L, Andersen J, Sereti I, Pahwa S, Lederman MM, Eron J, Sanne I, Powderly W, Hogg E, Suckow C, Zolopa A. Risk factor analyses for immune reconstitution inflammatory syndrome in a randomized study of early vs. deferred ART during an opportunistic infection. PloS one. 2010 Jul 1:5(7):e11416. doi: 10.1371/journal.pone.0011416. Epub 2010 Jul 1 [PubMed PMID: 20617176]

Level 1 (high-level) evidence

[46]

Haddow LJ, Easterbrook PJ, Mosam A, Khanyile NG, Parboosing R, Moodley P, Moosa MY. Defining immune reconstitution inflammatory syndrome: evaluation of expert opinion versus 2 case definitions in a South African cohort. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2009 Nov 1:49(9):1424-32. doi: 10.1086/630208. Epub [PubMed PMID: 19788360]

Level 3 (low-level) evidence

[47]

Elston JW, Thaker H. Immune reconstitution inflammatory syndrome. International journal of STD & AIDS. 2009 Apr:20(4):221-4. doi: 10.1258/ijsa.2008.008449. Epub [PubMed PMID: 19304962]

[48]

Tappuni AR. Immune reconstitution inflammatory syndrome. Advances in dental research. 2011 Apr:23(1):90-6. doi: 10.1177/0022034511399915. Epub [PubMed PMID: 21441488]

[49]

Boulougoura A, Sereti I. HIV infection and immune activation: the role of coinfections. Current opinion in HIV and AIDS. 2016 Mar:11(2):191-200. doi: 10.1097/COH.0000000000000241. Epub [PubMed PMID: 26720550]

Level 3 (low-level) evidence

[50]

Meintjes G, Scriven J, Marais S. Management of the immune reconstitution inflammatory syndrome. Current HIV/AIDS reports. 2012 Sep:9(3):238-50. doi: 10.1007/s11904-012-0129-5. Epub [PubMed PMID: 22752438]

[51]

Beatty GW. Immune reconstitution inflammatory syndrome. Emergency medicine clinics of North America. 2010 May:28(2):393-407, Table of Contents. doi: 10.1016/j.emc.2010.01.004. Epub [PubMed PMID: 20413021]

[52]

Meintjes G, Stek C, Blumenthal L, Thienemann F, Schutz C, Buyze J, Ravinetto R, van Loen H, Nair A, Jackson A, Colebunders R, Maartens G, Wilkinson RJ, Lynen L, PredART Trial Team. Prednisone for the Prevention of Paradoxical Tuberculosis-Associated IRIS. The New England journal of medicine. 2018 Nov 15:379(20):1915-1925. doi: 10.1056/NEJMoa1800762. Epub [PubMed PMID: 30428290]