Approach to the patients with fever BEHESHTI UNIVERSITY

Approach to the patients with fever BEHESHTI UNIVERSITY OF MEDICAL SCIENCES Yadegarynia, D. MPH January 11, 2006

Overview • • Clinical approach to the patients with fever Differential diagnosis Fever with underlying diseases Fever with nonspecific laboratory findings Fever in the neutropenic cancer patients Current epidemiology/ spectrum Empirical antibiotic therapy

Case report 1 • A 65 years old Afghanian male presented to the hospital with history of fever and lower abdominal pain. He was admitted to the hospital and appendectomy was performed. Three days after the operation, he complained of fever, shaking chills, and headache. • After blood culture, treatment with Ceftriaxone was initiated. On the fourth day, he developed a change in his mental status. ID consultation was requested.

• Laboratory findings: • WBC 12000 mm 3 (Neutrophil 60%, Lymphocyte 25%, Band 15%) • Chest X- Ray normal • Urine analysis: 2+ blood, 2+ albumin, 60 RBC, 5 WBC • Elevated AST, ALT • Blood culture negative • Diagnostic clues: Ø Traveler from Afghanistan Ø Fever and shaking chills Ø Abdominal surgery Ø Confusion Ø Bandemia

How to approach this patient? 1. Fever with focal signs and symptoms (confusion and fever) ? 2. Fever and shaking chills? 3. Post operative fever ? 4. Fever in returning traveler ? 5. Fever with CNS sign in returning traveler ?

What is the DDx? 1. Emergency treatable diseases 2. Non-emergency treatable diseases 3. Non-emergency non-treatable diseases

Laboratory diagnosis • Lumbar puncture and CT of the brain were negative • Peripheral blood smear shows: • Treatment with Quinine was initiated.

• Repeated peripheral blood smear shows: • Pathological report doesn’t show appendicitis.

FEVER in the ER • Fever is part of the presenting complaint in 6% of all adult (ages 18 -65) visits. 10% to 15% of all elderly (>65 years old) visits and 20% to 40% of all pediatric visits to the ER.

Approach to the patients with fever Key factors are: • • • Age Height of temperature Severity of illness Presence of a focus of infection White cell count

Age (neonates and young infants) • May not have the characteristic signs of serious infection • Localizing features may be absent • Can deteriorate rapidly • May be infected with organisms from the birth canal

Height of Fever( > o 40 ) • The sensitivity of hyperpyrexia to detect serious bacterial infection in young infants is only 21% and the specificity is 97% (Neto 2000) [Level III-2].

Clinical Assessment Severity of illness (toxicity) • The sensitivity of a “toxic appearance” in detecting serious bacterial infection varied from 11% to 100% in different studies (Neto 2000) [Level I].

Toxic appearance Clinical presentation • • • High grade fever Lethargy Evidence of poor perfusion Cyanosis Hypoventilation or hyperventilation Tachycardia

While blood cell count • A total white cell count >15× 109/L has only 31 - 52% sensitivity in predicting serious bacterial infection [level III- 2 evidence, Neto 2000]

Identifying Lukocytosis (elderly) • There is a high probability of underlying bacterial infection in and older person whose WBC count is elevated if they have a high percentage of Neutrophils or they show an elevated total band count. • Only 60% of elderly patients with bacteraemia present with leukocytosis (Evidence- based Steven Levenson 2004) • An elevated WBC, therefore is reasonably specific but not sensitive for infection.

Approach to the patient with fever • • • Fever and age Fever pattern Duration of fever Fever in returning travelers Pattern syndrome Fever with underlying diseases Fever with nonspecific signs Fever with focal signs & symptoms Fever of unknown origin Fever with nonspecific laboratory finding

Fever Pattern A. Degree • High grade fever • Low grade fever B. Fever chart • Remittent • Intermittent • Relapsing • Sustained • Double Quotidian • Reversed Diurnal Gradient

High grade fever • • • Flu Meningitis & Encephalitis Sepsis Malaria Infective endocarditis MDR typhoid fever Pneumonia Viral hemorrhagic fever TSS Leptospirosis Juvenile Rheumatoid arthritis Neuroleptic Malignant Syndrome

Relapsing fever • • Malaria Rat bite fever (3 - 5 days) Charcot’s intermittent fever Relapsing fever (Borrelia 2 -3 weeks) FMF Cyclic Neutropenia (21 days) Pel Ebstein Fever (Hodgkins, Brucellosis 710 days)

Sustained fever • • • Lobar pneumonia (pneumococcal) Rickettsial diseases Drug fever Typhoid fever CNS damage

Fever pattern • In general, correlation between fever pattern and specific disease is weak, notable exceptions are relapsing fever and sustained fever.

Fever and shaking chills • • Pneumonia Sepsis Malaria Absceses Legionaires disease Pylonephritis Bacterial endocarditis Filariasis

Fever and age Age Category Infection pattern 0 -7 days Newborn Early onset- sepsis, torch 8 - 30 days Newborn Late onset- sepsis, nursery infection 1 - 3 months Young infant Late onset- sepsis 3 - 24 months Infant Primary bacteremia, meningitis, UTI, virus 2 - 5 years Preschool Meningitis, Pneumococcal infection, systemic haemophilus infection, viral infection 6 - 12 years Primary school Mycoplasma, strep- pharingitis, viral hepatitis, UTI, viral infection 13 - 20 years Teen age Infectious mononucleosis, Mycoplasma, viral infection, STD, UTI >65 years Elderly UTI, Pneumonia, viral infection , sepsis

Fever & Age Clinical approach • Depends on age of child. • First month of life: greatest risk of invasive bacterial disease. • Clinical examination notoriously unreliable under 3 month of age. • Full sepsis evaluation for febrile infants less than 3 month. • Admit all febrile infants <1 month.

Duration of fever • Fever lasting for more than 4 - 7 days is rarely due to self limiting viral illness and needs investigation.

Duration of fever • Fever lasting for more than 2 weeks indicated serious underlying problem and needs thorough investigation.

Fever <4 - 7 days Viral signs & symptoms Focal signs & symptoms Symptomatic management Management No Focal, No viral signs & symptoms General Danger signs No general danger signs • CBC- FBS Refer to Hospital • Urine analysis • Chest X-Ray • Blood culture Symptomatic management

Fever >4 - 7 days Focal signs & symptoms No Focal, No viral signs & symptoms Diagnosis CBC+ FBS+ Urine analysis+ Blood culture Chest X- Ray+ Serological test+ ESR Management Refer No diagnosis Diagnosis CT+ Echo Management Diagnosis No diagnosis

Fever in returning travelers • The number of travelers at risk for febrile illness is significant. More than 500 million people cross international borders each year, more than 45 million of these travelers are U. S. citizens half of whom visit tropical or developing countries, it is reported that up to 5 - 10 % of all international will consult a physician upon their return.

Typical incubation periods for infectious diseases in the returned travelers < 21 days >21 days Trypanosomiasis Dehgue fever Japanease encephalitis Leptospirosis Malaria Meningococcemia Nontyphoidal salmonellosis Plague Typhoid fever Typhus Viral hemorrhagic fever Yellow fever HIV Schistosomiasis Amoebic liver abscess Borreliosis Brucellosis Leishmaniasis Malaria Rabies TB Viral hepatitis Trypanosomiasis

Fever with underlying diseases • • • Fever in the Neutropenic cancer patients Fever in the Diabetic patients Fever in the Alcoholic patients Fever in intravenous drug users Fever in the HIV infected patients Fever in the patients with splenectomy

Fever with underlying diseases Fever in the alcoholic patients • • • Alcohol withdrawal Delirium tremens Hepatitis Pancreatitis Subarachnoid hemorrhage Pneumonia (aspiration) TB Spontaneous bacterial peritonitis (cirrhosis) Vibrio vulnificus sepsis Spontaneous bacteraemia

Fever with underlying diseases life threatening infectious associated with diabetes • Rhinocerebral mucoromycosis • Malignant otitis externa • Emphysematous cholecystitis • Emphysematous pyelonephritis • Necrotizing fasciitis • Sepsis

Fever with underlying disease Fever in the intravenous drug users • HIV • • Viral hepatitis Infective endocarditis Pneumonia Cellulites at injection sites Tetanus Septic pulmonary emboli TB Pyrogenic reaction

Fever Of Unknown Origin • Physicians should repeatedly interview and examine the patients and review laboratory test results and imaging studies • In two pediatric series, abnormal physical findings where reported to have contributed to the diagnosis in 60% of causes of FUO, in the half of these the abnormalities where detected only after repeated examination

Evaluation Of FUO In adults • Thorough history (travel, exposure, drug, sexual contact) • Screen as usual (CBC/diff, ESR, LFT, BCs, PPD, consider TSH, ANA, ANCA, HIV) • Site directed • No clear site (Abd/pelvic CT scan) • ESR elevation and anemia or age>65 TABx • LFTs elevation or hepatomegalia liver Bx • Pancytopenia, high Ca++ BM Bx

Fever With Nonspecific Laboratory Finding Leukocytosis , Neutrophilia & Bandemia • • Sever sepsis Sever pneumonia Meningitis Infective endocardaitis Some time complicated sever viral infection Hemorrhagic fever viruses Toxic shock syndrome Sever abdominal infection

Fever with Nonspecific laboratory finding WBC>50 -100000 mm 3 • Leukemia • Myeloproliferative disorders

Fever with Nonspecific laboratory finding Fever with lymphocytosis (lymphosite count greater • • than 4000/mcl) Pertusis Mononucleosis Cytomegalovirus infection RSV Viral hepatitis Chronic lymphocytic leukemia HIV TB

Fever with Nonspecific laboratory finding Fever and monocytosis ( > 950 mcl) • • • Infective endocarditis TB Brucellosis Solid tumor Hodgkin’s diseases I. B. D Rockymountain spotted fever Monocytic leukemia Syphilis Sarcoidosis Malaria

Fever with Nonspecific laboratory finding Bandemia With Normal WBC • • Sever typhoid fever Malaria Sever Viral Infection Hemorrhagic Fever Viruses

Fever with Nonspecific laboratory finding Fever with Leukopenia • • Malaria TB Brucellusis Typhoid Fever Kala-azar Sever sepsis Viral infection

Fever with Nonspecific laboratory Finding ESR • Erythrocyte sedimentation rate determination is a commonly performed laboratory test with a time-honored role, however the usefulness of this test has decreased as a new method of evaluating diseases have been developed. • The test remains helpful in the specific diagnosis of a few conditions including temporal arteritis, polymyalgia rheumatica and possibly rheumatoid arthritis and multiple myeloma

Fever With Nonspecific Laboratory Finding Fever and ESR > 100 mm/hr • • • Sepsis Abscess TB Osteomyelitis Infective endocarditis Kala azar Lymphoma Leukemia Collagen vascular diseases Multiple myeloma Subacute thyroiditis

Fever With Nonspecific Signs • • Fever and splenomegaly Fever and anemia Fever and abdominal mass Fever and hepatomegalia

Fever With Focal Signs and Symptoms • Fever with gastrointestinal signs and symptoms Ø Fever with diarrhea Ø Fever with constipation Ø Fever with abdominal pain Ø Fever with abdominal mass • Fever with CNS signs and symptoms • Fever with lower respiratory signs and symptoms • Fever and rash

Fever Without Focal signs • • Documented fever Duration 2 -3 weeks No localizing signs Normal urine analysis

Case Report 2 • A 24 -year-old man with newly diagnosed AML presented to the ER with fever (>40 o. C) and neutropenia. He had received therapy with idarubicin and a high dose of cytarabine 7 days previously and was discharged with ciprofloxacin prophylaxis. A central venous catheter had recently been implanted.

Case Report 2 • At examination, the patient had moderate mucositis and appeared to be fatigued. The central venous catheter site was not inflamed. • The patient was admitted to the hospital and was given a β-lactam plus an amino glycoside antibiotic. He appeared to be stable.

Case Report 2 • 36 hr later, he developed a high fever and hypotension. • He was then transferred to the intensive care unit (ICU) and died within 48 hr.

Diagnostic Clues : • • • Underlying malignancy (AML) High grade fever Idarubicin+ cytarabine Moderate mucositis Ciprofloxacin prophylaxis Neutropenia

Case Report 2 • Potential choices for initial therapy for the case patient would include broad-spectrum iv therapy with agents such as piperacillintazobactam, ticarcillin-clavulanate, cefepime, or imipenem, given either as monotherapy or in combination with vancomycin, amikacin, or both. • Outpatient therapy would not be advised for this patient because of his underlying cancer and unwell appearance.

Cause : • Vancomycin-resistant enterococci (rarely) • P. aeruginosa (less likely) • Acinetobacter and Stenotrophomonas species (rarely) • Viridans streptococcus (toxic shock-like syndrome) • Diagnosis: The diagnosis was sepsis and toxic shock due to viridans streptococcus.

Approach to Patients with Febrile Neutropenia • Infection is the most common complication of chemo therapy- induced neutropenia. Bacterial infections predominate during the early stages of a neutropenic episode whereas invasive fungal infections tend to occur later.

Approach to Patients with febrile Neutropenia Definition • Fever: fever has been defined as an oral temperature of ≥ 38. 3 o. C or a temperature of ≥ 38. 0 o. C for ≥ 1 hr. • Neutropenia: Neutropenia is defined as an absolute neutrophil count of either <500 cells/mm 3 or <1000 cells/mm 3 with a predictable decline to <500 cells/mm 3 in 2448 hr. Ø Duration of Neutropenia is important determination of the risk of infection

Current Spectrum of Bacterial Infections in patients with Neutropenia • The pattern of bacterial infections and antimicrobial susceptibility has changed significantly during the past 20 - 30 yrs. Ø The prevalence of gram- negative organisms decresed. 1 Ø prevalence of gram- positive organisms increased. 1 Ø Despite a decline in the frequency of gramnegative infection, there has been an increase in the proportion of such infections caused by nonfermentative gram- negative bacilli. 2 1 Yadegarynia, 2 Yadegarynia, D. et al. CID, 2003: 37, 1145. D. et al. Diagnostic Microbiology and Infectious Disease, 51 (2005) 215218

Polymicrobial infection in Neutropenic Patients • Approximately 80% have gram- negative component • 30 - 35%- multiple gram- negative species • P aeruginosa- most common GNR isolated from polymicrobial infections (4555%) Elting et al. Medicine. 1986; 65; 218 -225; Adachi et al. Presented at: American Society of Microbiology; Oct. 19 - 23; 2003, Lake Tahoe, Nev. Abstract 4.

Bacterial infections in patients with solid tumors and hematologic malignancies. Type of bacterial infection Percentage of infections in patients With solid tumors With hematologic malignancies Gram positive 42 47 Gram negative 27 30 31 23 Single organism (monomicrobial) Polymicrobial Data are from Yadegarynia et al. [15]. CID 2005: 40 (suppl 4) S 247.

Gram-Positive Pathogens in Neutropenic Patients Organism (n= 487) % Frequency Comment Coagulase- negative staphylococci 52 77% methicillin resistance Staphylococcus aureus 20 29% methicillinresistant Staphylococcus aureus (MRSA) Enterococcus spp 10 56% of E faecium were VRE Viridans group stretoccoci 5 MIC ≥ 0. 12 in 27% Wisplinghoff et al. Clin Infect Dis. 2003; 36: 1103 - 1110.

Common sites of infection in patients with cancer No. (%) of infections Type of infection In patients with hematological malignancy In patients with solid tumor Pneumonia 93 (38) 99 (26) Bloodstream 88 (35) 74 (20) Urinary Tract 27 (11) 85 (22) Skin and soft tissue 17 (6) 65 (17) Gastrointestinal 16 (6) 38 (10) Other 12 (4) 17 (5) 253 (100) 378 (100) Total Data are from Yadegarynia, D. et al. CID 2003: 37 1144.

Scoring system for determining the risk of serious medical complication with the febrile neutropenia. Clinical Characteristics Weight No symptoms (or mild) 5 Moderate symptoms 3 No hypotension 5 No COPD 4 Solid tumor/ no fungal infection 4 No dehydration 3 Outpatient at fever onset 3 Age <60 years 2 Note. Score of ≥ 21 predicts a <5% risk for sever complication Klostersky. CID 2004: 39.

Management of the Febrile Neutropenic Patient • Prompt administration of empiric, broadspectrum antibiotics therapy based on local epidemiology and susceptibility/ resistance patterns is essential • Conduct risk assessment (identify low-risk patients) • Consider pervious infection/ therapy/ prophylaxis • Combination regimens/ monotherapy • Treatment setting (hospital/ outpatient) • Route of administration (parenteral, oral)

Clinical Assessment • Symptoms and signs of inflammation may be minimal or absent in the severely neutropenic patients. • History and examination • Look for inflammation/ infection at the following sites and sample as appropriate: mouth-gums , pharynx, sinuses, upper gastrointestinal, lung, perineum, skin lesion genito-urinary , vascular sites, bone marrow aspiration sites, diarrhea.

Fever + Neutropenia Low risk Oral High risk Vancomycin not needed Iv Monotherapy Ciprofloxacin + Amoxicillinclavulanate ·Cefepime, ·Ceftazindime, or ·Carbapenem Two Drugs Aminoglycoside + ·Antipseudomonal penicillin, ·Cefepime, ·Ceftazidime, or ·Carbapenem Reassess after 3 - 5 days Vancomycin needed Vancomycin + Cefepime, ceftazidime, or carbapenem ± aminoglycoside

Afebrile within first 3 -5 days of treatment No etiology identified Low risk Change to: ciprofloxacin + amoxicillin-clavulanate (adult) or cefixime (child) Discharge Etiology identified High risk Continue same antibiotics Adjust to most appropriate treatment

Fever and Neutropenia: Duration of Therapy • The single most important determinate of successful discontinuation of antibiotics is the neutrophil count. • Therapy can be stopped if Ø No infection identified Ø Neutrophil count ≥ 500 for 2 days Ø Patients afebrile for ≥ 48 hr • If patient afebrile but still neutropenic Ø Continue therapy until ANC >500 Ø Stop therapy and monitor closely

Persistent fever during first 3 - 5 days of treatment: no etiology Reassess patient on days 3 - 5 Continue initial antibiotics If no change in patient’s condition (consider stopping vancomycin) Change antibiotics Antifungal drug, with or without antibiotic change ·If progressive disease, ·If criteria for vancomycin are met If febrile through days 5 -7 and resolution of neutropenia is not imminent

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