Prior to Question 19 from the first paper of 2015, this topic has never been examined in the written paper, but an entire chapter of Oh's Manual is dedicated to it. Also, the college at one stage did ask the candidate to "List the potential  causes of diffuse pulmonary infiltrates in a patient  with AIDS" (Question 9 from the first paper of 2003). Subsequently, in Question 20 from the second paper of 2018, they focused on IRIS (Immune Reconstitution Inflammatory Syndrome), a relatively rare complication of highly active antiretroviral therapy. 

Anyway, it seemed important to include a summary of it in the Required Reading section.

Unless otherwise stated, the information below is derived from Oh's Manual.

Recommended alternative sources for this topic could include the following:

Microbiology of HIV

  • A lentivirus (one of the Retroviridae)
  • Single-strand enveloped RNA virus, about 120nm in diameter (large for a virus)
  • Comes in 2 flavours: Type 1 and Type 2
    • Type 1 is the one which causes the majority of HIV infections
    • Type 2 is less infective and mainly confined to West Africa
  • Inside the host cell, the viral RNA is reverse-transcribed into DNA by a viral reverse transcriptase enzyme.
  • Proviral DNA is then integrated into the host DNA by a viral integrase enzyme.
  • Proviral DNA is transcribed into RNA when the cell is activated, resulting in the assembly of new viral particles.

Chronology of infection and complications

Oh's chapter has a graph very similar to this.

For those who don't like colourful graphs, here is a boring grey table:

Chronological Course of HIV Infection

Stage

CD4 count per μL

Characteristic features

Incubation

normal (1000) none

Seroconversion:

1-4 weeks post exposure

1000-500
  • Fever
  • Lymphadenopathy
  • Headache
  • Photophobia
  • Fatigue
  • Myalgia

Early disease

1000-500
  • GBM
  • Chronic demyelinating neuropathy
  • Idiopathic thrombocytopenia
  • Reiter’s syndrome
  • Polymyositis
  • Sjogren’s syndrome
  • Bell’s palsy

Intermediate disease

500-200
  • Tinea, onychomycosis
  • Gingvitis
  • Seborrhoeic dermatitis
  • Herpes zoster
  • Tuberculosis (pulmonary)
  • Sinusitis
  • Kaposi’s sarcoma
  • Non-Hodgkins lymphoma
  • Primary CNS lymphoma

Advanced disease

under 200
  • Oral candidiasis
  • Herpes simplex
  • Cryptococcus
  • Mycobacterium avium
  • Cytomegalovirus
  • Toxoplasma
  • Tuberculosis (extrapulmonary)

Issues related to chronic HIV infection are all very interesting, but largely irrelevant to the ICU environment. The choice of antiretroviral drugs and chronic disease monitoring will not interest the pragmatic intensivist, and the CICM candidate cannot be expected to have anything more than a workmanlike understanding of these issues. They are presented below with little detail.

Diagnosis

  • Definitive diagnosis rests on finding anti-HIV antibodies.
  • During seroconversion, these may take several weeks to develop.
  • Most patients have positive antibodies by 3 months.

Monitoring

  • PCR detection of viral nucleic acid
  • Useful in prognostication and in assessing treatment response
  • Stable patients are tested every 3-4 months

Issues of interest to the intensivist

In other words, as if answering Question 19 from the first paper of 2015, "what relevant information about the patient’s HIV disease would you elicit from the history, examination and investigations to assist management?" 

The college answer has been remixed with some additional suggestions.

History

Prognosis-defining features:

  • duration of disease
  • AIDS-defining illnesses
  • IV drug use
  • Malignancy
  • Weight loss
  • Compliance with meds
  • PJP prophylaxis
  • Side effects of the ART

Examination

  • Nutritional state
  • Stigmata of IVDU
  • oral candida
  • Oral heres simplex
  • Cardiovascular disease
  • Respiratory disease (eg. COPD)
     

Investigations

  • CD4 count
  • viral load
  • historical nadir
  • CXR (for TB, PJP)
  • ECG (accelerated atheroma)
  • ART drug resistances
     

Commencement or continuation of antiretroviral therapy during a critical illness

Question 19 from the first paper of 2015 also wants us to "discuss the issues associated with the administration of antiretroviral therapy in the Intensive Care Unit"

  • If they are already on antiretroviral drugs, those should continue.
  • However:
    • None are parenteral.
    • Many of them won't get absorbed properly (all are capsule drugs)
    • Alkalinised stomach content will not permit adequate absorption
    • Feeds need to be paused for the administration of many of them, leading to sub-optimal nutrition.
    • Metabolism and clearance will be altered
    • Some will interact with ICU medications (eg. protease inhibitors potentiate the effects of midazolam)
  • If they are not on antiretroviral drugs, and are admitted for some non-HIV related problem, then one can safely defer starting them until after the critical illness has resolved.
  • They may not know they have HIV. Up to 40% of patients admitted to ICU with a complication of HIV don't know they are infected.
  • If they are admitted with an infectious complication of untreated HIV, then antiretroviral drugs should be started as early as possible (it seems to result in less AIDS progression and decreased mortality with no increase in adverse events)
  • Exceptions to this rue are cryptococcal meningitis and TB meningitis, because:
    • Drug interactions are prohibitive.
    • A severe inflammatory syndrome (Immune Reconstituion Inflammatory Syndrome, IRIS) can develop.

Freakish side-effects of antiretroviral therapy

These drugs are far from benign:

  • All of them are hepatotoxic
  • Didanosine and stavudine cause pancreatitis
  • NRTIs cause lactic acidosis
  • Tenofovir and indinavir are nephrotoxic
  • Nevirapine causes Stevens-Johnson syndrome

Opportunistic infections:

Pneumocystis:

  • Prophylactic co-trimoxazole if the CD count is less than 200
  • IV co-trimoxazole or pentamidine
  • Steroid therapy and lung-protective ventilation for PJ pneumonia

Cryptococcus neoformans meningitis:

  • Neck stiffness is often minimal or absent
  • Test for cyptococcal antigen
  • IV amphotericin plus flucytosine, followed by suppressive fluconazole

Toxoplasma encephalitis:

  • Characteristic ring-enhancing lesions on CT
  • Serology (toxoplasma antibodies) is always present
  • Oral pyrimethamine, together with either intravenous sulfadiazine or clindamycin

Differential diagnosis of a space occupying intracranial lesion in a patient with advanced HIV:

  • Primary CNS lymphoma (EBV antigen)
  • Toxoplasmosis
  • Tuberculosis
  • Bacterial brain abscess
  • Cryptococcal brain abscess

A systematic approach to the complications of HIV in an ICU patient

One day, a CICM fellowship question may ask the candidate to discuss the issues related to the management of a critically ill patient with advanced HIV infection. A systematic approach would be called for. One might even be invited to tabulate one's answer.

Airway:

  • Intubation can be problematic, owing to the increased risk of VAP.
  • Compared to patients with normal CD counts, patients with a CD count under 200 have a significantly higher mortality associated with invasive ventilation, and end up ventilated for much longer, which has led some authors to suggest that they should not be offered intubation.

Respiratory issues:

  • Consider unusual pathogens as the cause of pneumonia (eg.Pneumocystis, Mycobacterium avium complex, tuberculosis)
  • Use lung-protective ventilation

Circulatory issues:

  • Dilated cardiomyopathy may be present ( a late complication of AIDS)
  • Acute coronary syndromes are much more common among AIDS patients
  • Autoimmune vasculitis affecting the coronaries is also common
  • Autonomic neuropathy may be present, complicating their shock state

Central Nervous System problems

  • Delirium in these patients is common
  • Meningitis (especially with Cryptococcus) may not present with meningism
  • Consider the following differentials for CNS disease:
    • Viral (herpes) meningitis
    • Subacute encephalitis
    • Herpes simplex encephalitis
    • Multifocal leukoencephalopathy
    • HIV-related dementia and neurocognitive impairment.

Endocrine and electrolyte derangement

  • Lactic acidosis may be due to NRTIs rather than shock
  • Hyperlipidaemia and insulin resistance develop as a result of antiretroviral therapy
  • The cortisol levels may be abnormally high; conversely they may be hypoadrenal.
  • Electrolytes may be wildly deranged due to chronic diarrhoea
  • Refeeding syndrome may occur due to premorbid malnutrition

Renal impairment

  • Involvement of renal system may be due to:
    • Nephrotoxic effects of anti-retroviral drugs causing acute renal failure
    • Chronic effects of HIV infection leading to end stage renal disease.

Gastrointestinal complications:

  • Autonomic neuropathy may contribute to ileus and slow gastric emptying
  • Oesophageal candidiasis results in an increased risk of bleeding from even minor oesophageal instrumentation
  • Chronic diarrhoea due to CMV or Cryptosporidium may be present.
  • Bowel perforation occurs more easily due to chronic colitis

Haematological problems

  • Either as a result of infection or as a consequence of antiretroviral therapy, these patients may have a host of haematological abnormalities:
    • Thrombocytopenia
    • Anaemia
    • Neutropenia
    • Coagulopathy
  • Viral load tends to increase in HIV patients receiving blood transfusion (due to transfusion-associated immunomodulation) and they should be transfused sparingly.

 

Immune Reconstitution Inflammatory Syndrome (IRIS)

This is the exuberant inflammatory response which develops within days or weeks of the commencement of antiretroviral therapy. The immune system, awakening from its stunned state, finds the body overrun by the likes of Pneumocystis, and reacts violently. A more formal definition is asked for in Question 20 from the second paper of 2018, where the model answer characterises it as:

"a collection of inflammatory disorders associated with paradoxical worsening of pre-existing infectious process following initiation of antiretroviral therapy primarily in HIV-infected patients"

"Paradoxical worsening of an existing infection or disease process" is also the description given to this disease state by Sharma & Soneja (2011). In fact, there does not appear to be an agreed-upon gold standard of definition in the literature. Suggested definitions (French et al, 2004; Robertson et al, 2006) generally require some combination of the following features:

  • Temporal relationship with antiretroviral treatment
  • Worsening of inflammation
  • Symptoms not explained by new infection or worsening of a previous infection
  • Increase in CD4 count or decrease in HIV RNA copies

Obviously such HIV-centric definitions do not take into account the fact that IRIS can occur in several other conditions (eg. with tuberculosis).

Pathogenesis of IRIS is well-described in the IRIS article from UpToDate, from which the college answer to Question 20 from the second paper of 2018 appears to draw most of its inspirations.  For the purposes of regurgitating a point-form summary of what happens, the causes of IRS can be summarised thus:

  • The loss of CD-4 TH cells results  in a diminished immune response against a variety of antigens
  • As a consequence, with a very low CD4 cell count there may be infections with opportunistic pathogens which are sub-clinical and unrecognised
  • As HAART is started, HIV viral load rapidly decreases by as much as 90%  (as HIV has a short 1-4 day half life) and CD4 counts increase (over 3-6 weeks)
  • As CD4 counts increase, antigen-specific immune response pathways are restored
  • Thus, clinically silent opportunistic infections suddenly become clinically apparent as the immune response to them returns to normal
  • This typically manifests as inflammation of the locally affected tissues, or potentially as systemic inflammatory response resembling septic shock.

Risk factors for IRS  (according to Shellburn et al, 2005include:

  • Low CD4 counts at baseline
  • High HIV viral load at baseline
  • Highly active antiretroviral therapy (HAART)
  • Rapid drop of HIV RNA counts (i.e. vigorous response to HAART)
  • Infection with characteristic agents:
    • M. tuberculosis
    • M. avium complex
    • C. neoformans
    • P. jirovecii
    • VZV
    • HSV
    • CMV
    • Hepatitis viruses

Differential diagnosis (From Beshuizen et al, 2009):

  • Treatment failure of ART
  • Failure of treatment of an opportunistic infection
  • An alternative opportunistic infection.
  • Drug interactions
  • Drug toxicity

Clinical manifestations may include:

  • ARDS
  • Worsening of Pneumocystis pneumonia
  • Vasodilated shock
  • Fevers and rigors
  • Worsening of progressive multifocal leukoencephalopathy
  • Worsening of CNS tuberculosis infection (or pulmonary, for that matter)
  • Worsening of CMV retinitis and uveitis
  • Exacerbation (or de novo emergence) of VZV encephalitis
  • Worsening of cryptococcal meningitis (rising ICP)
  • Enlargement of CNS lesions due to M.tuberculosis
  • Worsening liver function due to IRIS reaction against Hep B or Hep C
  • Typically, features develop rapidly (within 90 days) of commencing HAART.

Management of IRIS (ffrom Konishi et al, 2010)

  • Major management principles
    • Continue HAART 
    • Aggressively treat the opportunistic infection against which the reconstitution response has developed
    • Wait: most of the time, IRIS resolves over days or weeks
  • Specific therapy
    • NSAIDs
    • Corticosteroids (0.5-1.0mg/kg/day of prednisolone)
    • Infliximab, anti-TNF-α monoclonal antibody (Richaud et al, 2015)
    • Adalimumab, another kind of anti-TNF-α monoclonal antibody (Lwin et al, 2018)
  • Supportive therapy
    • Vasopressors, lung-protective ventilation, ICP management, FASTHUG
  • Worst case scenario
    • Interrupt HAART therapy

References

Oh's Manual:  Chapter 68  (pp. 710) HIV  and  acquired  immunodeficiency  syndrome  by Alexander  A  Padiglione  and  Steve  McGloughlin

Zolopa, Andrew R., et al. "Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial." PloS one 4.5 (2009): e5575.

Huang, Laurence, et al. "Intensive care of patients with HIV infection." New England Journal of Medicine 355.2 (2006): 173-181.

Murdoch, David M., et al. "Immune reconstitution inflammatory syndrome (IRIS): review of common infectious manifestations and treatment options."AIDS research and therapy 4.1 (2007): 9.

Bajwa, Sukhminder Jit Singh, and Ashish Kulshrestha. "The potential anesthetic threats, challenges and intensive care considerations in patients with HIV infection.Journal of pharmacy & bioallied sciences 5.1 (2013): 10.

Duggal, Abhijit, et al. "OUTCOMES OF HIV PATIENTS REQUIRING INVASIVE MECHANICAL VENTILATION AS COMPARED TO PATIENTS WITH AIDS." CHEST Journal 136.4_MeetingAbstracts (2009): 115S-a.

Mayer, Kenneth H., and Martyn A. French. "Immune reconstitution inflammatory syndrome: a reappraisal." Clinical Infectious Diseases 48.1 (2009): 101-107.

Sharma, Surendra K., and Manish Soneja. "HIV & immune reconstitution inflammatory syndrome (IRIS)." The Indian journal of medical research 134.6 (2011): 866.

French, Martyn A., Patricia Price, and Shelley F. Stone. "Immune restoration disease after antiretroviral therapy." Aids18.12 (2004): 1615-1627.

Robertson, Jaime, et al. "Immune reconstitution syndrome in HIV: validating a case definition and identifying clinical predictors in persons initiating antiretroviral therapy.Clinical infectious diseases 42.11 (2006): 1639-1646.

Shelburne, Samuel A., et al. "Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy." AIDS 19.4 (2005): 399-406.

Beishuizen, S. J., and S. E. Geerlings. "Immune reconstitution inflammatory syndrome: immunopathogenesis, risk factors, diagnosis, treatment and prevention." Neth J Med 67.10 (2009): 327-331.

Konishi, M., K. Uno, and E. Yoshimoto. "Management of immune reconstitution inflammatory syndrome." Nihon rinsho. Japanese journal of clinical medicine 68.3 (2010): 508-511.

Richaud, Clémence, et al. "Anti-tumor necrosis factor monoclonal antibody for steroid-dependent TB-IRIS in AIDS." Aids 29.9 (2015): 1117-1119.

Lwin, Nilar, Michael Boyle, and Joshua S. Davis. "Adalimumab for corticosteroid and infliximab-resistant immune reconstitution inflammatory syndrome in the setting of TB/HIV coinfection." Open forum infectious diseases. Vol. 5. No. 2. US: Oxford University Press, 2018.