Immunocompromised state refers to the inability of an individual to mount an adequate immune response towards an infection.

This effectively means problems in innate or adaptive immunity

In practice it also includes non immune conditions like trauma and severe burns

Causes of immunocompromised state 1.Neoplastic - hematological malignancies 2.Organ transplant recipients 3.Autoimmune diseases 4.Immunodeficiency syndromes congenital acquired

Causes of immune compromise in Malignancy 1.Reduction in phagocytic cells specifically neutrophilis hence acute response to infection is lost 2.Functional deficiency without change in number 3.Monocytes and macrophages These cells collaborate with helper T cells against intracellular pathogen such as mycobacteria, fungi and parasites. 4.Quantitative defects in humoral factors - Circulating IgG and IgM antibodies, secretory IgA antibodies, and components of the complement cascade

Host Defect Impaired phagocytic function

Phagocyte mobilization Neutropenia Impaired cell-mediated immunity Decreased antibody levels

Disease Acute leukemia

Lazy leukocyte syndrome Aplastic anemia Acute leukemia Hodgkin's disease Multiple myeloma Chronic lymphocytic leukemia

Organ transplant recipients Issues involved

Hematopoietic stem cell transplant Underlying disease (e.g., hematologic malignancies) Cytotoxic conditioning therapy ( total body irradiation) Prophylaxis and treatment of graftversus-host disease (e.g., corticosteroids, calcineurin inhibitors, antimetabolites, TNF- antagonists) Defects in primary and secondary humoral and cellular immunity. Defects in phagocytic cell quantity and function Bone marrow suppression. Defects in primary and secondary humoral and cellular immunity Defective function in phagocytic cells and dysfunction of primary and secondar humoral and cellular immunity

Solid organ Underlying disease (e.g., diabetes, end-stage liver transplantation disease) (SOT)

Organ dysfunction and miscellaneous immune dysfunction

Induction therapies (e.g., corticosteroids, antilymphocyte globulin, splenectomy, anti-IL-2 Ab, anti-CD52 Ab, calcineurin inhibitors

Depletion and impairment in primary and secondary cellular and humoral immunity
Breach in mucosal barriers. Defects in organ function.

Surgical intervention and altered anatomy

Acute and chronic rejection prophylaxis and treatment (e.g.,corticosteroids, calcineurin inhibitors, antimetabolites and alkylating agents, plasmapheresis, antithymocyte globulin)

Defective function in phagocytic cells, primary and secondary humoral and cellular immunity

Treatment of collagen vascular and autoimmune diseases

Anti-inflammatory and immunosuppressive agents (corticosteroids, nonsteroidal antiinflammatory drugs, calcineurin inhibitors, sirolimus, mycophenol ate mofetil) Antimetabolite and alkylating agents

Defective function in phagocytic cells, primary and secondary humoral and cellular immunity

Bone marrow suppression, defects in primary and secondary humoral and cellular immunity

Biologic immune response Defective function in primary modifiers (e.g., and secondary humoral and antithymocyte cellular immunity globulin, monoclonal antibodies to B and T cells, anticytokine therapies, T-cell costimulation blockers)

Approach to the Compromised Patient

Fever in a compromised patient - ominous development, Fever with neutropenia( <1000/mm3 ) The risk for bacterial infection increases proportionally with the decline in neutrophil count. The most common definition of significant neutropenia is a level lower than 500 cells/mm3, Profound neutropenia - neutrophil concentration less than 100 cells/mm3. The risk for documented bacteremia is at least 20% in patients with profound neutropenia.

Approach to fever Fever should trigger a prompt and thorough bedside evaluation of the patient Examination of the head and neck - Evidence of central nervous system (CNS) infection Oropharynx and respiratory tract - Evidence of pharyngitis and gum inflammation and the anterior and posterior aspects of the lungs for evidence of an abnormality in breathing or an airway abnormality. Palpation of the abdomen and the costovertebral angles, auscultation of the abdomen for quality of bowel movements should be undertaken Perirectal area and pelvic examination in a female patient is mandatory Intravenous or intra-arterial catheter should be carefully examined

CNS Infections Presentation - Brain abscess or meningitis

Pathogen Involved 1.Listeria monocytogenes 2.Encapsulated bacteria such as pneumococci and staphylococci can cause metastatic CNS disease and meningitis 3.Cryptococcus neoformans 4.Candida, Aspergillus 5.Herpes simplex, Cytomegalovirus, and Epstein-Barr virus, 6.Infection of the CSF with HIV-1 can cause CNS reactive pleocytosis. 7.Reactivated or quiescent CNS syphilis Non Infectious Drug-related toxicities, e.g., Carbapenem-related seizures PRES

SinoPulmonary Bacterial Infections Pneumonia Cough, shortness of breath, chest pain, and hypoxia. Computed axial tomography early in course of disease Pneumococci and Haemophilus influenzae can cause lobar or diffuse pneumonia. Gram-negative bacilli can cause pneumonia of a necrotizing type in severely neutropenic patients. Ventilatory support - risk of secondary gram-negative bacillary pneumonia or staphylococcal pneumonia. Legionella pneumophila Tuberculosis M.tuberculosis Nontuberculous mycobacteria such as Mycobacterium avium

Fungal Infections of Respiratory tract Blastomycosis, coccidioidomycosis, and histoplasmosis Acute pneumonia Candida - uncommon primary lung pathogens. Pneumocystis (now referred to as P. jiroveci) has been reclassified as a fungus on the basis of DNA sequencing interstitial pattern of lung infiltration consolidation pulmonary nodules. Aspergillus, Zygomycetes, chest pain hemoptysis. Aspergillus infection can spread through the pulmonary vasculature leading to pulmonary infarction.

Viral Infections Difficult to diagnose in immunocompromised patients. Measles Varicella-zoster Respiratory Syncytial Virus Adenoviruses Reactivated Cytomegalovirus Non infectious Drug-related pulmonary toxicities Pneumonitis (sirolimus) Diffuse alveolar damage Bronchiolitis obliterans syndromes

Gastrointestinal Infections Diarrheal Syndromes Salmonella Shigella Campylobacter Clostridium difficile Should be suspected in patients who had received a course of antibiotics as long as a month previously. Isospora belli and Cryptosporidium - Impairments in cell-mediated immunity. Microsporidians. Giardia lamblia - hypogammaglobulinemia.

Esophagitis Candida mucosal overgrowth in the mouth and esophagus. Herpes simplex virus and cytomegalovirus - esophagitis. In severely neutropenic patients Pseudomonas aeruginosa - mucositis/pharyngitis.
Non Infectious Drug-related toxicities, e.g., MMF

Cutaneous Syndromes Infectious Ascending streptococcal or staphylococcal cellulitis Metastatic abscesses - Staphylococcus aureus Necrotizing vasculitis - P. aeruginosa infections Aspergillus and Candida - metastatic cutaneous lesions.
Non infectious Drug eruptions GVHD Sweets syndrome

APPROACH TO FEVER DURING CHEMOTHERAPY-INDUCED NEUTROPENIA PAST AND CURRENT CLINICAL CONSIDERATIONS What is the type and duration of immunologic deficiency? Does the patient have any organ dysfunction that would predispose to particular infection? Does the patient have any unique environmental or epidemiologic exposures? What are the patients prior infections and colonizing organisms? What are the current and recently administered antimicrobial agents? Are there any specific presenting signs or symptoms that suggest a particular type of infection or syndrome

MULTINATIONAL ASSOCIATION OF SUPPORTIVE CARE IN CANCER (MASCC) RISK SCORING INDEX FOR IDENTIFICATION OF LOW-RISK PATIENTS WITH FEBRILE NEUTROPENIA CHARACTERISTIC SCORE Extent of illness No symptoms 5 Mild symptoms 5 Moderate symptoms 3 No hypotension 5 No chronic obstructive lung disease 4 Solid tumor or no fungal infection 4 No dehydration 3 Outpatient at onset of fever 3 Age < 60 yr 2
POINTS > 21 low risk less than 5 % risk of complications

Investigations Gram stain of body fluids, exudates,or aspirates. Complete blood count with differential, serum creatinine, and screening liver function. Chest radiograph Routine urinalysis. Computed Tomography (CT) - persistent fever especially in the presence of airway symptoms.

Noninfectious cause of fever Hematoma Drug reactions Transfusion reactions Pulmonary emboli Splenic infarcts Underlying malignancy.

Persistent fever The possibility of infection caused by nonbacterial pathogens Fungi (especially Candida and Aspergillus species) Widespread adoption of routine antifungal empirical therapies in the setting of fever that persists more than 4 to 7 days. Azole drugs, echinocandins and polyenes.

Fever (temperature 38.3 C) + Neutropenia (<500 neutrophils/mm3)

Low risk Vancomycin not needed Two drugs Aminoglycoside + AntipseudomonaI penicillin Cefepime Ceftazidime or Carbapenem

High risk

Oral CiprofIoxacin + Amoxicillinclavulanate (adults only) or Expandedspectrum quinolone

IV

Vancomycin needed

Monotherapy Cefepime Ceftazidime Antipseudomonal penicillin or Carbapenem

Vancomycin + Vancomycin + Cefepime, ceftazidime, or carbapenem aminoglycoside

Reassess after 3-5 days

Susceptible to capsulated bacteria Risk of systemic pneumococcal disease 75 % Functional splenectomy in sickle cell disease Prevention of infection Vaccination (preferably before splenectomy) Prophylactic antibiotics Pen V or amoxycillin

Conclusion Infections are a major cause of mortality in immunocompromised hosts. The approach to fever and suspected infection requires knowledge of specific risks inherent to the type and duration of immunodeficiency Diagnostic diligence Tailored therapeutics