This chapter deals with the management of sepsis in somebody without an immune system. The bone marrow transplant recipient is a good model of such a situation. Question 11 from the first paper of 2014 uses the bone marrow transplant as a backdrop for some sort of infectious-asounding diarrhoea.

The four stages of bone marrow transplantation


There are 4 well recognised risk periods in the population of BMT recipients. They follow a predictable time pattern. This is a timetable of the most common infectious complications one encounters on their road to new bone marrow.

timetable of infections post bone marrow transplant

Pathogens in the immunocompromised host

An immunocompetent host typically suffers sepsis at the hands of known, familiar enemies:

  • E. coli
  • Pseudomonas aeruginosa
  • Klebsiella
  • Streptococci
  • Staphylococci

An immunocompromised neutropenic host has much more to offer to a bacterium with ambition. There is a list of organisms which one needs to consider in addition to the above.

Pathogens to Keep Mindful of in the Immunocompromised Host
  • Pneumocystis jirovecii
  • Herpes simplex virus (HSV)
  • Varicella zoster virus (VZV)
  • Serratia marcescens
  • Enterobacter cloacae
  • Enterococcus sp.
  • Streptococcus pneumoniae
  • Candida sp.
  • Aspergillus sp.
  • Cytomegalovirus
  • Nocardia sp.
  • Legionella sp.
  • Listeria monocytogenes
  • Cryptococcus
  • Toxoplasma gondii
  • Strongyloides stercorales
  • Clostridium difficile

The Investigations

The CICM exam candidate should be able to not only regurgitate these, but produce some sort of rationale as to why they are being ordered.

Investigation of Sepsis in the Immunocompromised Host

Blood

  • Blood cultures (x 2 or 3)
  • Hickman catheter cultures
  • Aspergillus galactomannan
  • Atypical mycobacteria serology

Urine

  • Urine culture
  • Streptococcal urinary antigen
  • Legionella urinary antigen

Sputum

  • Sputum culture (or BAL)
  • Acid-fast bacilli

CSF

  • HSV PCR
  • VZV PCR
  • CMV PCR
  • Aspergillus PCR
  • Cryptococcal antigen
  • Acid-fast bacilli
  • Toxoplasma PCR

Stool

  • C. difficile toxin
  • Stool culture
  • Ova, cysts, parasites

Think about...

  • Mucositis in general
  • Line tips (eg. PICC)
  • Teeth and gums
  • Ears and sinuses (Mucor!)
  • Heart valves
  • Bile duct / gall bladder
  • The prostate

The neutropenic broadside: empiric therapy for fever of unknown origin

This is not a recipe, but rather a list of options.

The Neutropenia Arsenal of the Anxious Intensivist
  • Vancomycin -to cover beta-lactam resistant gram-positives
  • Meropenem - to cover gram-negatives like Pseudomonas and the anaerobes, as well as to work synergistically with vancomycin
  • Caspofungin - to cover candida species which might be resistant to fluconazole, such as Candida glabrata
    • Voriconazole might be substituted if pulmonary infection is suspected (where caspofungin doesnt penetrate very well)
    • Amphotericin might be substitited if one wishes to cover even more broadly, eg. for Zygomycetes or Cryptococcus
  • Ganciclovir - to cover cytomegalovirus
  • Trimethoprim/sulfamethoxazole - to cover P.jirovecii

It is of course possible to unitelligently give all the antibiotics.

More skill is required to determine which are the appropriate ones.

The Sanford Guide, in its recommendations regarding the high-risk neutropenic patient, suggests the following cocktail:

  • Vancomycin
  • Meropenem or Cefepime
  • an echinocandin (eg. Caspofungin)
  • Voriconazole if fever persists and the patient has had a good amount of anti-candida prophylaxis.

If CNS involvement is suspected:

  • Vancomycin -to cover beta-lactam resistant gram-positives
  • Ampicillin - to cover Listeria
  • Ceftriaxone - to cover Strep pneumoniae
  • Amphotericin - to cover Cryptococcus
  • Trimethoprim/sulfamethoxazole - to cover P.jirovecii

If diarrhoea is present

  • Metronidazole-to cover C.difficile

NIV instead of intubation


A good NEJM article has suggested that intermittent NIV for these people is a better option than intubation, or standard high flow oxygen via Venturi mask. Specifically, the group randomised to NIV were less likely to die in the ICU. The inclusion criteria in this study were a respiratory rate of over 30, evidence of pulmonary infiltrates, fever and the deterioration of gas exchange beyond a PaO2/FiO2 ratio of 200. The use of NIV very early in these patients (i.e. as soon as they met these criteria) was associated with a massive decrease in the in-ICU death rate (from 69% to 38%). Indeed the only deaths that occurred were in the patients who progressed to intubation; and the incidence of sinusitis and pneumonia were higher in the group who did not receive NIV.

Some might argue that the patients who ended up intubated had a more severe pulmonary sepsis and this skews the data. Perhaps that is true.  But everyone who got VAP died in this study.  Other data has demonstrated that the advantage of NIV in patients with respiratory failure rests on the decrease in the incidence of VAP. Ergo, to avoid VAP is to avoid a significant proportion of ICU mortality in the immunocompromised population.

Shall we admit this person to the ICU?


The evidence demonstrates that ICU doctors and haem/onc doctors frequently disagree as to who belongs in the ICU and who doesn’t. One specific study has asked us to broaden our admission policy, given that only 78.7% of the BMT patients we consider “too well” to benefit from ICU will survive at 30 days. There appears to be good reason to err on the side of caution; common sense suggests that some of these people will benefit from 1:1 nursing and regular intensivist attention and thus may survive longer; other will be palliated in a more controlled environment, and will suffer less in their final hours.

The family conference


The prognosis is grim; that much is clear at even the resident level. But let us take a closer look at the data. The same study that suggested we admit more people has demonstrated that BMT patients we actually subject to ICU did even worse than the patients whom we judge to be “to well”; of these people only 54.2% survive at 30 days. Another study summarises the findings of many reports, and comes up with a figure of 65% for 30-day mortality, in ICU or after discharge from it. The allogenic patients tend to do poorly at 100 days (5-10% survival) in comparison to autologous transplant recipients. Additionally, it seems multi-organ system failure in this group is associated with a 100% in-ICU mortality. In a meta-analysis of 2653 patients, the strongest independent predictors for 1-year mortality were mechanical ventilation and hemodialysis. In  a study by Soubani et al, nobody with an admission lactate over 6 had survived.

References

I had to give a talk on this subject at one stage in 2014, which was probably of fairly poor quality.

An excellent resource for this topic are the chapters in Oh's Manual dealing with severe sepsis (ch 61, by A Raffaele de Gaudio) and with the immunocompromised host (ch 59, by Steve Wesselingh and Martyn A H French).

An older, yet similarly respectable source is Shoemaker (2005);

Chapter 155 (Infections in the immunocompromised patient) by Andrew Githaiga, Magdaline Ndirangu and David L. Paterson covers this topic with great detail.

The Surviving Sepsis Campaign has these published guidelines to peruse; they have thir own problems.

There is a particularly useful UpToDate article on this topic, available only to UpToDate customers and their friends.

Leather HL, Wingard JR. Infections following hematopoietic stem cell transplantation. Infect Dis Clin North Am. Jun 2001;15(2):483-520.

Thiéry G, Azoulay E, Darmon M, Ciroldi M, De Miranda S, Lévy V, Fieux F, Moreau D, Le Gall JR, Schlemmer B. Outcome of cancer patients considered for intensive care unit admission: a hospital-wide prospective study. J Clin Oncol. 2005 Jul 1;23(19):4406-13.

Hilbert, Gilles, et al. "Noninvasive ventilation in immunosuppressed patients with pulmonary infiltrates, fever, and acute respiratory failure." New England Journal of Medicine 344.7 (2001): 481-487.

Antonelli M, Conti G, Rocco M, et al. A comparison of noninvasive positive-pressure ventilation and conventional mechanical ventilation in patients with acute respiratory failure. N Engl J Med 1998;339:429-435

Afessa, Bekele, and Elie Azoulay. "Critical care of the hematopoietic stem cell transplant recipient." Critical care clinics 26.1 (2010): 133.

Soubani AO, Kseibi E, Bander JJ, et al. Outcome and prognostic factors of hematopoietic stem cell transplantation recipients admitted to a medical ICU. Chest 2004;126(5):1604–11.

Scales, Damon C., et al. "Intensive care outcomes in bone marrow transplant recipients: a population-based cohort analysis." Crit Care 12.3 (2008): R77.