Collateral Damage

"I'll be your mess, you be mine,
That was the deal that we had signed,
I bought a hazmat suit to clean up your waste,
Gas masks, gloves, to keep us safe,
But now I'm alone in an empty room,
Staring down at immaculate doom."
     -Where she went; Gayle Forman

In our material world,  Effect can't be divorced from side effect. And the end result is, not always, the calculated balance beween these two, at least in sociopolitical world.

Intervention in clinical medicine also embraces this truth, but awareness, measures of prevention and effective treatment can decrease the severity of side effect.

●Immune Restoration Disease (IRD) or Immune Reconstitution Inflammatory Syndrome  (IRIS):
Restoration of immune response against living or dead opportunistic pathogen causes immunopathological lesion in tissues infected by that pathogen. First described in HIV infected patients, where commencing antiretroviral therapy (ART) may cause paradoxical worsening of opportunistic infection or unmasking of a subclinical infection.

Infections commonly associated with IRD are M.tuberculosis, Mycobacterium  avium complex, Mycobacerium leprae, BCG, Cryptococcus, Pneumocystis jiruveci, Cytomegalovirus, JC polyomavirus, Herpes virus, Varicella zoster virus, Hepatitis B and C viruses.

IRD against mycobacerial antigen may unmask M. tuberculosis infection that was unrecognised before ART was started. Consequently higher rates of tuberculosis are observed during first 3 months of ART in countries with rates of endemic tuberculosis.

The most common identified risk factor for IRD are CD4+ T cell count  less than 50 and high pathogen load. In other words starting ART before severe CD4+ T cell count depletion occurs, is a means of preventing IRD.

Initiation of treatment of opportunistic infection, to decrease microbial burden, before starting ART, will decrease the risk of IRD. Steroids are effective in treating IRD.
ART should be ceased only in severe IRD, particularly when it is life threatening.

IRD has also been reported after withdrawl  of immunosuppression in patients who are negative for HIV. Few examples are IRD following withdrawl of TNF blockade in rheumatoid arthritis and crohn's disease, natalizumab in multiple sclerosis, and in solid organ transplant patients.

New insight into pathogenesis of IRD, from animal models have suggested that, in the settings of T cell deficiency, innate and adaptive immune responses are temporarily uncoupled. Macrophages require two signals to become fully activated, first comes from the recognition of microorganisms through pattern recognition receptors, and second comes from CD4+T cell help. In T cell deficiency, macrophages are primed by microbial pathogen, but don't receive help of CD4+ T cells to become fully activated. Once T cells are restored, there is fulminant activation of primed macrophages in the tissues. This leads to sudden spike in inflammation  and tissue damage that outpaces host repair mechanism, resulting in IRD pathophysiology.

●Cytokine Release Syndrome (CRS): symptoms complex associated with the use cytotoxic chemotherapy especially monoclonal antibodies (mAbs) like anti CD3 (OKT3), anti CD52 (alemtuzumab), anti CD20 (rituximab)and CD28 super agonist (TGN 1412). CRS manifests when large number of lymphocytes (B cells, T cells, natural killer cells) and or myloid cells (macrophages, dendritic cells and monocytes) become activated and release inflammatory cytokines. Symptoms typically begins within minutes to hours after starting infusion, and varies from fever, chills, headache, myalgia to pulmonary oedema, shock, DIC and multi organ failure, mimicking sepsis.

Hence infection must be considered in all patients presenting with CRS symptoms and empirical antibiotic are started after sending appropriate cultures.

Treatment consists of immunosuppressive agents. Tocilizumab, an anti human IL6R mAb. Tocilizumab prevents IL6 binding to IL6R and inhibits inflammatory cascade. Steroids are also effective but are considered second line therapy.

●Differentiation Syndrome or Retinoic acid Syndrome: A form of Cytokine Release Syndrome in patients with acute promyelocytic leukemia(APML) undergoing induction chemotherapy with all trans retinoic acid (ATRA) and or arsenic trioxide.

●Tumour Lysis Syndrome (TLS): Abrupt release of large amounts of cellular components into systemic circulation, as a result of massive break down of tumour cells, after initiation of chemotherapy for highly aggressive hematological malignancies. It manifests clinically as cardiac arrhythmia, paresthesia, muscle cramps, tetany, seizure, acute kidney injury and biochemically as hyperkalemia,  hyperphosphatemia, hyperuricemia, hypocalcemia and renal tubular deposition of calcium phosphate and uric acid crystals.

Prevention and treatment consists of good hydration, urine alkalinization, allopurinol, rasburicase and renal replacement therapy.

Urine alkanization has potential disadvantage of promoting calcium phosphate precipitation and deposition in kidney. Therefore it should be used only in patients with metabolic acidosis.  Urine alkalinization is not used in patients receiving rasburicase.

Rasburicase is recombinant urate oxidase, which catalyses uric acid to more water soluble allantoin.