The Case


"I slept all day"


Patient presented 3 weeks ago to ED with fever and dyspnea and was found to be HIV positive with PCP pneumonia. He was started on treatment with Bactrim, prednisone and HAART.

He was feeling well since discharge, compliant with all medications until 2am the day prior when he took melatonin as a sleep aid. He then woke up 18 hours later. When he woke, patient reports feeling generally fatigued but has no specific complaints. Denies sick contacts, fevers/chills, increased cough, abdominal pain, nausea/vomiting/diarrhea, rash, headache, neck stiffness, dysuria, back pain.


PMH: as above, dx AIDS 3 weeks ago (CD4= 19, VL 1.16 million)
PSH: none
Meds: atovaquone (650mg bid), prednisone 20mg QD, Norvir (100mg QD), Darunavir (800mg QD), Truvado 1tab QD, melatonin (intermittent use)
SH: used to smoke, quit 16 years ago, social etoh, no IVDU, MSM

Physical Exam

T 103.9˚, HR 114, RR 16, BP 120/69 O2sat 98% on RA
GEN: nad, aox3, pleasant, well appearing
HEENT: eomi, perrl, no oral thrush, no nuchal rigidity
Cor: +s1, s2, regular but tachycardic
Pulm: decreased breath sounds L base otherwise clear
Abd: soft, nt, nd, +b.s.
Extr: +2 pulses b/l
Skin: no rash


VBG: 7.49/CO2 35.9 / Lac 1.6 (wnl)
CBC: 9.7 > 13.9
BMP: 135 | 4.2 | 100 | 23 | 10 | 0.7 < 112
LFT: AST 54 | ALT 34 | alkP 57 | TB 0.8 | DB 0.3 | TP 5.7 | Alb 3.1
Lipase: 60
UA: neg LE, neg nitrite
Blood cultures: pending



  1. What is your differential diagnosis for this patient’s presentation?

    Any immune compromised patient with fever should be concerning for sepsis. In this particular patient, there is no clear source; chest x-ray and urine were not helpful in isolating a source at this time. However, as the patient has recently had pneumocystis pneumonia (PCP/PJP), relapsed or persistent PCP/PJP should be considered. Other than sepsis, immune reconstitution inflammatory syndrome (IRIS) should also be included on the differential.

  2. What is the best initial management for this patient?

    In the ED, this patient should be treated like other septic patients with fluid resuscitation, broad-spectrum antibiotics, and antipyretics. Additionally, in this case, it would be appropriate to discuss the possibility of IRIS with the inpatient team.

More Info

Patient’s clinical course:

The patient was started on broad-spectrum antibiotics in ED and admitted. Overnight, the patient acutely decompensated with worsening dyspnea and desaturation. CT chest obtained the next day showed widespread ground-glass opacities with septal thickening affecting all 5 lobes consistent with clinical history of PCP/PJP pneumonia. Patient’s PCP/PJP regimen was then changed from PO atovaquone to IV clindamycin and primaquine, his prednisone dose increased to 40mg bid and broad-spectrum antibiotics discontinued incrementally. Patient improved on hospital day (HD) 4 and discharged on HD12. Final diagnosis at discharge was IRIS associated with PCP/PJP.

Other pertinent test results: patient’s sputum acid-fast bacilli (AFB) negative x5 (prior hospitalization), AFB negative on bronchoscopy but positive for pneumocystis (prior hospitalization), CMV IgM positive but negative for retinitis on ophthalmology exam, Cryptococcus ag negative, blood mycobacterium culture negative, legionella negative, mycoplasma negative, blood cultures negative x2, negative hepatitis BsAg, negative hepatitis C Ab.



While highly active antiretroviral therapy (HAART) has significantly decreased morbidity and mortality in patients with HIV, immune reconstitution inflammatory syndrome (IRIS) as a result of initiating HAART has become more widely recognized as it can contribute to increased morbidity and mortality in the most vulnerable populations2,6,8. IRIS, also known as immune reconstitution disease (IRD), occurs as an inflammatory manifestation that causes paradoxical clinical worsening of a patient with HIV after initiation of HAART. There are no universal diagnostic criteria for this condition, but the International Network for the Study of HIV Associated IRIS (INSHI) has developed 2 pathogens (TB and Cryptococcus) specific definitions1. The general principles derived from the pathogen specific definitions include: 1. The onset of symptoms must occur after initiation of HAART while timing may be different depending on the pathogen, 2. there must be the presence of an inflammatory condition either clinically or histologically, 3. no other alterative diagnosis exists to explain the current presentation such as medication non-compliance or another infectious process1.

There are two main categories of IRIS: paradoxical and unmasking1,7,9. Paradoxical IRIS presents as worsening of a pre-existing opportunistic infection that has been treated with adequate response prior to the initiation of HAART. The unmasking type of IRIS presents with an opportunistic infection that was not detected or suspected prior to the initiation of HAART1,7,9. In both presentations of IRIS, the inflammatory response to the opportunistic infection is above and beyond what is expected in the average HIV patient afflicted with a particular opportunistic infection1,2. While the pathogenesis of IRIS is not clearly delineated, it is hypothesized that dysfunction of the immune recovery leads to an excess inflammatory response detrimental to the host; The inadequately regulated immune system mounts an exaggerated reaction against persistent antigens in paradoxical IRIS and to viable pathogens in unmasking IRIS1-2,6.

IRIS is most likely associated with opportunistic infections that plague HIV patients with lower CD4 cell counts. In developing countries the most common opportunistic infections include TB and disseminated mycobacterium avium complex8. Other commonly associated opportunistic infections include CMV, Cryptococcus, PML, Kaposi’s sarcoma, and pneumocystitis4,6. The manifestations of IRIS differs depending on the associated opportunistic infection e.g. CMV associated IRIS commonly manifests as uveitis or retinitis whereas Cryptococcus associated IRIS often present as cryptococcal meningitis2,6,8,9. The incidence of pneumocystis associated IRIS, manifesting mainly in the pulmonary paradoxical form, appears to be lower than other opportunistic infections ranging from 2.2 to 20% of all IRIS presentations4,10. The reported incidence of IRIS has a wide range from 10% to 45%, which may reflect the lack of an universal definition for IRIS6-8,10. 

The timing in the development IRIS may also vary depending on the associated opportunistic disease, but most develop within 3 month of the initiation of HAART3-4,9. Pneumocystis associated IRIS seem to develop earlier with median of 15 days after HAART initiation compared to other opportunistic infections such as IRIS associated with Cryptococcus which develops at median of 9 weeks4. The underlying reason why some people will develop IRIS versus others will not is controversial and not completely understood. However, there is general consensus that low baseline CD4 cell count (especially CD4 count less than 50) is an independent risk factor for IRIS1,3,5-6,8-9.

In a recent meta-analysis of 54 cohort studies, Muller et al calculates that the overall mortality attributed to IRIS is 4.5% with the most significant increase in mortality attributed to a group of patients with cryptococcal meningitis associated IRIS6. This is consistent with prior studies showing that IRIS associated with central nervous system infections have higher mortality rates e.g. IRIS associated progressive multifocal leucoencephalopathy has been found to have morbidity and mortality rate as high as 50%2. Overall, IRIS can significantly hasten and increase mortality independent of baseline CD4 count making this an important entity to recognize8. 

Currently, no standardized guidelines exist for the management of IRIS. Because of the theorized pathogenesis of IRIS, it is largely accepted that corticosteroids can be used in severe cases of IRIS to decrease symptoms1-2,6,9. There is only one randomized control trial for the use of steroids in TB associated IRIS where patients received 4 weeks of prednisone taper shown to have improved symptoms and decreased length of hospitalization compared with placebo1. Unfortunately, the mortality benefit of corticosteroids is unknown1. More studies are required to define and treat this potentially dangerous diagnosis.



  1. Armstrong WS, The immune reconstitution inflammatory syndrome: a clinical update, Curr Infect Dis Rep, 2013 Rd;15(1):39-45.
  2. French MA, HIV/AIDS: Immune reconstitution inflammatory syndrome: a reappraisal, Clin Infect Dis, 2009 Jan;48(1):101-7.
  3. Manabe YC, Campbell JD, Sydnor E, Moore RD, Immune reconstitution inflammatory syndrome: risk factors and treatment implications, J Acquir Immune Defic Syndr, 2007 Dec;46(4):456-62.
  4. Mok HP, Hart E, Venkatesan P, Early development of immune reconstitution inflammatory syndrome related to Pneumocystitis pneumonia after antiretroviral therapy, Int J STD AIDS, 2014 Apr;25(5):373-7.
  5. Mori S, Polatino S, Estrada-Y-Martin RM, Pneumocystis-associated organizing pneumonia as a manifestation of immune reconstitution inflammatory syndrome in an HIV-infected individual with a normal CD4+ T-cell count following antiretroviral therapy, Int J STD AIDS, 2009 Sep;20(9):662-5.
  6. Muller 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, Lancet Infect Dis, 2010 Apr;10(4):251-61.
  7. Murdoch DM, Venter WD, Feidman C, Van Rie A, Incidence and risk factor for the immune reconstitution inflammatory syndrome in HIV patients in South Africa: a prospective study, AIDS, 2008 Mar;22(5):601-10.
  8. Novak RM, Richardson JT, Buchacz K, Chmiel JS, Durham MD, Palella FJ, Wendrow A, Wood K, Young B, Brooks JT, HIV Outpatient Study (HOPS) Investigators, AIDS, 2012 Mar;26(6):721-30.
  9. Sexton DJ, Pien BC, Immune reconstitution inflammatory syndrome, In: UpToDate, Bartlett JG (Ed), Uptodate, Waltham, MA (Accessed on January 3, 2016).
  10. Zolopa A, Andersen J, Powderly W, Sanchez A, Sanne I, Suchow C, Hogg E, Komarow L, Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial, PLoS One, 2009;4(5):e5575.