Immune suppression and immunodeficiency syndromes

Because an entire chapter of Oh's Manual is dedicated to this topic, in 2015, when the author was preparing for another (second? third?) attempt at his Part Two exam, it seemed important to include a summary of it in the Required Reading section, in case the college somehow eventually got around to asking about it. Considering how often this is seen in clinical practice, it is remarkable that an SAQ did not come along until Question 13 from the first paper of 2020. In that question, the examiners were interested in the changes to antibiotic choices which might be expected in the setting of immunosuppression, and how one would manage the immunosuppression if the patient has an active infection. The topic was raised again twice in the second paper of 2023: as Question 7, where candidates were expected to produce a list of infectious complications at different stages following solid organ transplantation, and as Question 20, where they had to give a lot of detail about the pharmacology of immunosuppressants.

Unless otherwise stated, the information below is derived from Oh's Manual. The main reason for this is that the college specifically referenced it in their answer to Question 7 from the first paper of 2023, mentioning the two chapters on solid organ transplantation (Liver transplantation and Heart and lung transplantation in the 8th edition).  For those without freegan access to The Manual or similar textbooks there really is no single resource to cover this topic. Satisfactory alternatives include the Google Books version of Stiehm's Immune Deficiencies (1156 pages!) and this 2009 update from the Journal of Allergy and Clinical Immunology. Unfortunately, for most people, the fastest revision strategy is to get Oh's Manual. 

Immunodeficiency disorders can also be divided into primary and secondary; primary being disorders where the immune system components are defective due to some sort of disabling mutation. An excellent summary table is available in Armstrong (1991):

Defective neutrophils or neutropenia

What makes them defective? Neutropenia is neutropenia, and having too few of them makes you rather defenceless, but it is also possible to be functionally neutropenic with normal neutrophil numbers. For instance, let us take the example of the chemotherapy patient whose counts never quite recover from their last cycle. The concerned haematologist gives them some filgrastim and becomes rather less concerned when their WCC returns to normal, but are they really protected? G-CSF produces a sort of "emergency" haematopoiesis and sends a bunch of immature neutrophil stem cell precursors into the circulation. Once there, these cells are sufficiently neutrophil-like that they are able to fool the automated cell counter, but upon closer scrutiny they perform few of the normal neutrophil fuinctions, have greatly impaired chemotaxis, and are basically incapable of the normal oxidative burst (Thunström et al, 2018).

Anyway. The following list of possible causes may come in useful one day.   If one needed to dig deeper for some reason, one would find gold in the free article by Lakshman & Finn (2001).

Causes of Neutropenia or Neutrophil Dysfunction

Neutropenia	Impaired neutrophil function
Decreased neutrophil production Aplastic anaemia, MDS Radiation poisoning Nutrient deficiency (eg. B12) Congential disorders Increased neutrophil destruction Haemodialysis or plasmapheresis Sequestration Hypersplenism Drug-induced bone marrow suppression: Arsenic Chemotherapy Clozapine Chlorpromazine Phenytoin Chloramphenicol	Congenital defects Chronic granulomatous disease (CGD) Numerous rare disorders Acquired defects NIDDM Vitamin C deficiency Hypothermia Immature neutrophils GM-CSF Drug-induced neutrophil dysfunction Corticosteroids Pantoprazole Propofol Thiopentone

Characteristic infections in neuropenic or neutrophil-defective patients are mainly infections by extracellular pathogens:

• Recurrent bacterial infections
• Recurrent fungal infections (particularly abscesses in solid organs)
• Oral and periodontal disease is common
• They may have severe superinfected eczema
• Wound healing is severely delayed
• Systemic infections with catalase-positive organisms:
  • Staphylococcus aureus
  • Serratia
  • Aspergillus
  • Burkholderia cepacia
  • Nocardia

Laboratory investigations to explore the extent of their neutrophil defect include:

• Neutrophil count
• Nitroblue tetrazolium reduction test (tests oxidative killing)
• Neutrophil migration tests
• Bacteria or Candida killing assay

Defective T- lymphocytes

A CICM Part II candidate's revision of this primary-level topic could safely be limited to Chapter 8 from the 5th edition of Immunobiology: The Immune System in Health and Disease by Janeway et al (2001), which happens to be free.  Without entering a protracted digression into immunology which the author only pretends to half-understand, it would suffice to say that T-lymphocytes play a roll in cell-mediated immunity as well as the coordination of humoural immunity. Their main targets are viruses and virus-infected cells (which end up being destroyed by effector T-cells). T-helper cells are also instrumental in activating blissfully unaware macrophages which harbour intracellular parasites such as M.tuberculosis and M.leprae. T_H2 cells also participate in humoural immunity by activating naive antigen-specific B cells to produce antibodies in response to more "classical" pathogens such as Gram-stainable bacteria and protozoa.

Causes of T-Lymphocyte Deficiency or Dysfunction

Lymphocytopenia	Impaired T-cell function
Decreased production Aplastic anaemia, MDS Radiation poisoning Nutrient deficiency (eg. B12) Congential disorders Di George syndrome Increased destruction Haemodialysis or plasmapheresis HIV/AIDS Sequestration Hypersplenism Recent viral infection Drug-induced bone marrow suppression: Chemotherapy Corticosteroids	Congenital defects Chronic mucocoutaneous candidiasis APECED syndrome Di George syndrome Acquired defects End-stage renal failure Thymectomy T-cell lymphoma Immature lymphocytes GM-CSF Drug-induced lymphocyte dysfunction Essentially any drugs used to prevent solid organ rejection: Calcineurin inhibitors (Tacrolimus and cyclosporin) Mycophenolate and azathioprine

Characteristic infections in a patient with T-cell problems resembles the so-called AIDS-defining group of disease, i.e. mainly infections by intracellular pathogens and colonising opportunists:

• Recurrent viral diseases:

  • HSV, VZV, EBV, CMV
• Recurrent bacterial diseases:
  • Listeria
  • Salmonella
  • Shigella
• Fungal infections:
  • Candida
  • Cryptococcus
  • Aspergillus
• Protozoal infections:
  • Toxoplasma
  • Pneumocystis

Laboratory investigations:  

• T-cell subset count (CD4, CD8 counts)
• Cytokine assays
• Delayed-type hypersensitivity (DTH) skin test responses to antigens

Defective antibodies

A problem with the B-lymphocyte population would lead to a scenario where antibody-mediated immunity would fail to control the pathogen population which it is meant to control. Antibody-mediated immunity covers all the sort of stuff you would normally expect to become immune to over the course of living a normal life (for example, encapsulated organisms which cause pneumonia and meningitis), commensural flora normaly kept at basy by mucosal IgA,  as well as a bunch of organisms which one might summarise as "Victorian-era killers" against which virtually everybody today is usually vaccinated. The best article to look at this sort of thing is actually these papers by Nixon et al (2017) and Looney et al (2008), which are all about the infectious complications of rituximab. This makes logical sense because rituximab is a directed antibody which causes the death of all your B-cells, flushing your humoural immunity down the toilet. 

Causes of Failure in Humoural Immunity

Decreased antibody production	Defects of antibody function
Congenital: X-linked agammaglobulinaemia hyper-IgM immunodeficiency syndrome Common variable immunodeficiency (CVID) Acquired: B-cell leukaemia Aplastic anaemia, MDS Radiation poisoning Asplenia Phenytoin	Congenital defects Rare isotype or light chain deficiencies Acquired defects NIDDM (impaired Fc fragment function) Drug-induced immunoglobulin synthesis failure Corticosteroids Mycophenolate and azathioprine (indirectly) Drugs which are specifically directed against B-cells: Rituximab

 

Characteristic infections would mainly be recurrent bacterial infection, particularly by encapsulated organisms:

• Streptococcus pneumoniae
• Neisseria meningitides
• Haemophilus influenzae
• Salmonella typhi
• Klebsiella pneumonia
• Group B streptococci (S.agalactae, etc)

Infections you'd never expect because normally everybody has good humoural immunity against them:

• Pneumocystis
• Parvovirus

Reactivation of dormant enemies:

• Hepatitis B and C
• CMV
• EBV

Laboratory investigations would include:

• Peripheral B-cell count
• IgG subclasses (serum levels)
• Assessment of antibody response to immunization, eg. polysaccharide antigens and protein antigens.

Defective complement

Complement, the most basic immune system ("established in the common ancestor of eumetazoa more than 500 million years ago"), can occasionally break down spontaneously as the conseqence of depletion by plasmapheresis or sepsis. Bacteria and fungi are then free to run rampant. 

Causes of Complement Deficiency

Congential complement deficiency	Acquired complement deficiency
Congenital deficiency of C3 ( severe recurrent pyogenic infections) Deficiency of MAC components is more common (recurrent meningococcal infections) Deficiency of classical pathway components (C1, C2, C4) (recurrent meningococcal infections)	Plasmapheresis Haemodialysis Persistent bacterial infections, causing depletion Cirrhosis SLE Overwhelming sepsis Drugs targeting complement, eg. eculizumab

Characteristic infections: generally speaking, bacterial infections dominate the spectrum:

• Streptococcus pneumoniae
• Neisseria meningitides
• Moraxella
• Acinetobacter

Laboratory investigations:

• Complement levels
• Functional assay of the classical pathway (CH50)
• Functional assay of the alternative pathway

Post-splenectomy state

The post-splenectomy state is another form of immunodeficiency, and clinically it looks a lot like a failure of humoural immunity. This has come up in the exams a lot, and therefore merits its own summary page.

Broadened antibiotic choices in immunosuppressed patients

Question 13 from the first paper of 2020 gave the candidates a patient who has been taking steroids and antirejection drugs for renal transplant. Now, he presents with what sounds like some sort of pneumonia; "pulmonary infiltrates" to be precise. And the transplant is apparently not doing so well either. "Justify what empirical antimicrobial treatment you would commence", the examiners cackled sadistically.  

The exact drug choices are obviously going to be difficult to discuss, because they will depend to a considerable degree on the local microbiome and the previous infections of this obviously infection-prone patient. Did they grow Pseudomonas or Prevotella last time they were in hospital? Clearly, the college could not possibly have wanted any specific drug choices or drug doses. Instead, some sort of basic fundamental principles were being asked for, right?

Well. Turns out, there is not a lot out there. An excellent article by Armstrong (1991), though dated, reveals why that might be. Though it is a thorough review of the subject, the auther was unable to discuss the principles here in terms of generalities, and was basically limited to listing pathogens and suggested drug cocktails to manage them individually. That's also good (his Table 3 was so useful that it's reproduced above but it does not have any advantage over, say, a subscription to the Sanford Guide mobile app. There is a suitable UpToDate article to turn to, which also has some 

Anyway. What trends can we derive from this, that could be compiled into a guide for management, rather than a list of recipes? 

• Start broad. Narrow spectrum agents designed for immunocompetent hosts in the community will fail to cover the spectrum of bugs which tend to infect the defenseless lung. Ergo, it is reasonable to use broad spectrum monotherapy to begin with. As one can see, there is a lot of Enterobacteriaceae in the list of pathogens above. Third generation cephalosporins may be ineffective. Moreover, whetever you culture will just be the faster grower on that specific agar, and whatever is actually causing he disease is going to go unnoticed. Also multiple infections processes could be taking place simultaneously. The early use of agents like piperacillin/tazobactam and carbapenems is therefore justified.
• Start early. The presence of culture and sensitivity data is to be viewed as some sort of rare gift rather than an essential part of antimicrobial therapy. Of the cultures collected from severely neutropenic patiens, very few will produce any positive results. Thus, empiric antibiotics need to be commenced early, without waiting for clarifying data like cultures and imaging. When you see that halo sign on the CT, you will be pleased that you started empirical voriconazole.
• Specific host defence failures have specific pathogen patterns (see above).
• Consider the unusual suspects:
  • Fungi
  • PJP
  • CMV and HSV
  • Tuberculosis

Timing of infections in the solid organ transplant recipient

The Oh's Manual chapters on solid organ transplantation referenced by the examiners in their answer to uestion 7 from the first paper of 2023 consist of Chapter 101 (Liver transplantation) and Chapter 102 (Heart and lung transplantation) in the 8th edition. Unfortunately, they do not seem to contain enough information to answer this question. There is only this table in the liver chapter, as well as some scattered ideas, which would be difficult to knit together into a coherent answer. Fortunately, there is an excellent UpToDate entry on this subject, which spares the reader an hour of digging through Oh's. Plus there is an excellent narrative review by Fishman (2017) and a 2020 summary of some Swiss data by van Delden. To summarise these works:

Relative risk of infection in the transplant recipient, and reasons:

• Early: high risk, mainly because of the surgery and its complications, as well as the pre-existing infectious burden of both the donor and the recipient.
  • During this period immunosuppressive treatment has been commenced and the recipient is immunocompromised
  • The fact that they have recently had some fairly major surgery exposes them to post-operative infectious complications (anastomotic leaks, line site infections, etc)
  • They may also be suffering chronic or clinically silent infections (which then reactivate, eg. CMV and TB)
  • The donor may have passed along infectious agents in the actual transplant (for example, hepatitis B virus in the donated liver)
  • However: there are also protective factors:
    • The patient retains some residual humoral immunity
    • There are usually post-op antibiotics in use
    • The patient is usually in a controlled environment (i.e. ICU or hospital), carefully monitored and protected from transmission by reverse barrier practices
• Intermediate:  greatest risk, because:
  • During this period the immunosuppression is maximal:
  • Residual humoral immunity has dissipated
  • Opportunistic pathogens with long incubation periods have had time to emerge 
  • Pathogens picked up during the stay in hospital (eg. resistant organisms, C.difficile, etc) now re-emerge as problematic
  • Graft rejection may be occurring, requiring higher levels of immunosuppression
• Late:  lowest risk, because during this period the immunosuppression is minimised:
  • Satisfactory graft function will at this stage permit a decrease in the dose of immunosuppression
  • The recipients will mostly be exposed to community acquired pathogens, which are lower in virulence

Potential pathogens and sites of infection:

• Early
  • From the donor: viruses (eg. HIV), toxoplasmosis, hepatitis
  • From the recipient: HSV, TB, CMV reactivation
  • From the surgery: anastomotic leaks, surgical wound infections
  • Hospital acquired: VRE, MRSA, VAP, Aspergillus, bloodstream infections (eg. CLABSI)
• Intermediate
  • Opportunistic pathogens 
    • Bacteria: TB (lung, brain)
    • Fungi: Pneumocystis (lung), Cryptococcus (lung, brain)
    • Parasites: strongyloidiasis, toxoplasmosis
    • Viruses: HSV, CMV, EBV, BK virus, hepatitis viruses
  • Community-acquired pathogens
    • viruses (influenza, RSV, etc)
    • urinary tract infections
• Late
  • Community-acquired pathogens
    • Standard viruses (influenza, RSV, etc)
    • Listeria (meningitis)
    • Legionella and S.pneumoniae

Prophylaxis 

• Early
  • Bactrim (covers PJP Listeria and toxoplasmosis)
  • Fluconazole or posaconazole (covers Aspergillus and Candida)
  • Valganciclovir (covers CMV)
  • Perioperative surgical site prophylaxis (cephazolin, vancomycin or clindamycin if MRSA-colonised)
• Intermediate
  • ​​​​​​​Bactrim (covers PJP Listeria and toxoplasmosis)
  • Valganciclovir or letermovir (covers CMV)
• Late
  • ​​​​​​​Vaccination vs. influenza, pneumococcus, other community-based pathogens