Fevers without localizing Features

 

Common Early Infections.

           

Bacterial:       Septicemia, Respiratory infections, GIT infections, and UG infections.

 

Viral:               High-grade fever, especially in children. The syndrome is mostly self-limiting and untreatable. The importance for establishing the specific diagnosis is therefore small. However the differentiation between viral and other causes of febrile illness is on the other hand is of critical importance.

Parasites.        Malaria, Amoebiasis, which may be liver abcess or hepatitis.

Fevers associated with Animal Eposures: Brucellosis, Q Fever, Leptospriosis, and Cat Scratch disease. By history and examination try to identify the system involved in fever and so try to localize the infection pathology in a specific system. If unable to focus the fever to anyone system then try to adopt following approach.

 

Causes:       Viral Fevers: Examine the throat. Think of Infectitous mononucleosus and other mononucleosis syndromes.

·        Enteric Fever

·        Malaria

·        Infections with rare or atypical organisms.

Think of seasonal causes of fever

           

Early summer                                      = R T I, G I T, Viral

            Early winter    & Late Winter             = R T I

Peak summer                                      = Water and Food born diseases through flies. Incidence of Viral fevers and Malaria is low.

Short Duration Fevers with Rash, On next page

 

Fevers with Lymphadenopathy

 

v     Viral:         Measles, Rubella, Hepatitis B, and Mononucleosis Syndromes.

v     Bacterial:  Scarlet Fever,Brucellosis,Leptospirosis,Tuberculosis,Syphilis,Lyme Disease

 

Preliminary Investigations.

 

 CBC with ESR    Leukocytosis usually indicates increased neutrophils, which in turn means pyogenic infections. Usual sources are

 

·        Urinary infections

·        Respiratory tract infections like Pneumonia.

·        Dysentry.

Normal Count:           Enteric fever, Malaria, and viral infections.

Leukopenia                Most common cause is Enteric fever.

ESR                            Non specific.

DLC                            Atypical Lymphocytes point towards mononucleosis syndromes (EBV, CMV, and Toxoplasma Gondii)

 

(2) Urine Examination

 

It is a part of routine physical examination of all patients. Women may be having U T their fever and I may not accompany any symptoms of UTI.Significant Pyuria should be treated. Significance depends upon culture results of urine. All urine samples having more than 5-10 pus cells /HPF should be followed with culture on a centrifuged specimen of urine. The presence of WBC cast in infected urine indicates the presence of Pyelonepheritis.Significance is followings.

 

Bacterial Counts of                > 100,000,00                           = Infection.

                                                < 100,000-100,000,00            = Contamination

                                                < 100,000                                = Normal.

A hazard in interpreting the results of urine culture is that if the sample is allowed at room temperature for few hours before planting on culture plates, bacteria can multiply. This results in spuriously high bacterial counts. For this reason urine samples for culture should not be collected from catherter bags. Specimens that are not planted immediately should be refrigerated.

 

(1) X ray Chest

 

Patient with Pneumonia and other respiratory diseases may have normal X Ray in the early days. Patients with abnormal X-ray may not have active infection. So interpretation of Xray findings has to be in the perspective of possible D/D.If there is a cavity; it usually means active infection. (Tuberculosis).

 

(2) Slide for Malarial Parasite.

 

Before giving antimalarials to problematic pyrexic patients sample for slide should be taken. Best time is during rigors. Thick films (Presence or absence of M Parasite) and thin films (for the species involved) must be examined. Serological tests for diagnosis of Malaria are not routinely available.

 

(4) Blood Cultures

 

In all problematic pyrexic patients it is better to take sample for blood culture before starting any antibiotic. Best time to take sample is during fever. For Typhoid fever culture is best examined during first week but continue to be positive with decreasing frequency in 2^nd and 3^rd week.

 

(5) Widal test:                        It is of little value. It becomes positive during second week.

 

(6) Ultra sound Examination of Abdomen and Pelvis:         It can be done where abdominal visceral or pelvic pathology is suspected.

 

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Management of Acute Fevers.

 

§         Clue about etiology is present in history, examination or in investigations. Find it.

§         Always use time test medicines.

§         Steroids should be avoided unless there is a diagnosis of specific (for steroids) condition.

 

Antibiotics.

·        Quinolones should be avoided in children due to risk of arthropathy.

·        Quinolones are not good antibiotic for R T Is.

·        Use broad-spectrum penicillin derivates if diagnosis is not clear. Amoxicillin, Ampicillin.

·        Chloramphenical should be used with proper supervision and monitoring due to risk of aplastic anaemia.

·        Use Tetracycline groups for G I T infections.

·        Use Penicillin derivatives and sulpha drugs for U T I.

 

Antipyretics.

·        Avoid excessive dose of paracetamol as it may lead to hypotension due to sweating in-patients of enteric fever.

·        Aspirin may cause ulcerations.

·        Antipyretics should be given SOS.

·        Antipyretics will only work if temperature is below 102 F.If it is above it sponging will help. For sponging cold water is not essential. Bath with tap water may be enough. Sponges should be rubbed and changed often.

·        Antipyretics mask the symptoms of fever and pattern of fever.

·        In children avoid Aspirin and Salicylates due to risk of Reye’s syndrome. Paracetamol and other NSAIDs may be used.

 

Antimalarials

 

I prefer Artemethar, especially in resistant cases. Dose is 2 caps bid on first day then 2 cap OD for next 4 days. Halfan is also effective but it can prolong the QT interval in many patients. I use Basoquin and Fansidar in children.

F.U.O

 

Essentials of Definition

 

v     High-grade fever: >101 F.

v     Duration of  more than 3 weeks

v     Undiagnosed inspite of all investigation after 3 days in hospital or after three outpatient visits. Improvements in non-invasive diagnosic testing have resulted in newly proposed categories.

 

(A new definition may be in order. It may be like this. Duration = one week, 3 visits to the physician, Undiagnosed = inspite of intensive investigations.)

 

Categories of F.U.O

 

1.    Classic FUO:                     For which common etiologies are infections, malignancy, inflammatory diseases, and drug fever.

 

2.    Neutropenic FUO:             TLC equal to or less than 500/cmm. Perianal and periodontal infections, Candidemia, Aspergillosis as major causes.

 

3.    HIV associated FUO:        Mycobacterium avium, complex infections, Tuberculosis, Non-Hodgkin lymphoma, drug fever and CMV are important etiologies.

4.      Nosocomical FUO:            Septic Thrombophlebitis, Clostridial difficile colitis and drug fever are major diagnostic possibilities.

 

The evaluation of an FUO remains among the most challanging problems facing the physician. The majority of illnesses that cause FUO are treatable, making pursuit of the diagnosis particularly rewarding. There is no substitute for meticulous history and physical examination. These should be repeated frequently. This may jar an important historical clue or important physical finding. These clues may direct to the next series of diagnostic studies.

 

Diagnosis                if there is no response to the therapy, patient is taking, then reassess the situation. One essential step is that takes the history again. Examine thoroughy again. Consider following possibilities.

 

v     Autoimmune/Collagen /Connective Tissue diseases.

v     Malignancies.

v     Chronic Infections.

v     Granulomatous diseases

v     Drug fever

v     Factitious fevers.

 

Fevers of Autoimmune Disorders

 

 

Following tests are quite sensitive to indicate the presence of this group of disorders. But these are non-specific as far as individual diseases are concerned.

 

¨      ESR

¨      RA factor

¨      ANA antibodies (Against Nucleus Antibodies).

 

v     If RA factor and ANA are negative then there is no collagen disease.

v     If one of these two is positive and other one is negative then there is 70-80 % chance of Connective tissue disease.

v     If both are positive then there is definite connective tissue disease.

ESR             this is non-specificIt measures acute phase response. It is significantly raised (> 100) in following diseases.

¨      Connective Tissue Disease

¨      Lymphoreticular Disease.

¨      Malignancy of solid organ

¨      Chronic infections.

 

Although ESR lacks specificity, It is particularly useful in following the treatment of patients with Polymylgia Rheumatica and Tepmoral Arteritis.

CRP(C reactive Protein):                     Like ESR it is a non-specific marker for inflamatory diseases like Rheumatic fever, Rheumatic Artheritis and other collagen diseases. It is an acute phase reactant like Fibrinogen and is more accurate than ESR but also more expensive.

Specific Antibodies for certain diseases.

SLE                                         Anti double stranded DNA (Anti ds DNA). Disease can

Presents with PUO, Artheritis, Kidney CNS involvement and skin rashes.

Sjoggren’s Syndrome                         anti SSA (Anti-Ro) and Anti SSB (Anti-LA)

Mixed Connective Tissue Disease:              Anti Ribonucleoprotein.

Scleroderma:                                                  Anti-Tropoisomerase 1

Autoimmune Hepatitis:                                  Anti LKM-1 antibodies.

Rheumatoid Arthritis:            Diagnosis depends upon clinically defined major and minor criteria. RA factor is non-specific. It is positive in 80 % of acute cases of Rh.Artheritis.

 

Malignancies

 

When looking up for malignancies in the background of PUO, two groups are relevant.

(1) Haematopoitic (Blood):

 

Lymphoreticular:       Lymphoma, Non hodgekin lymphoma, and Lymphatic leukemia.

 

Myeloproliferative:   hence associated with spleenomegaly. Chronic myeloid leukomia, Polycythemia, Myelofibrosis, Essential Thrombocytopenia.

 

Investigations for this group are

§         CBC with ESR

§         Peripheral blood film

§         Bone marrow Biopsy & aspiration.

 

(2) Visceral malignancies:     Hepatic, Colonic and Renal Carcinoma and malignancies of other solid organs may be associated.       Investigations for this group are USG and Scans and other relative tests.

 

Biochemical markers for malignancies.

 

Alpha-Fetoprotein                              For primary liver malignancies.

Prostate Specific Antigen (PSA)       For Prostate malignancy

Carcingen Embryonic Antigen          for Colon, especially for recurrence.

Alkaline Phosphatase                                    For metastatic bone tumors & for Liver Tumors.

Hypercalcaemia                                 Parathyroid

CA-125                                               Carcinoma of Ovary.

 

 

Chronic Infections

Common among these is Abcesses (Intra abdominal), endovascular infections, Osteomyelitis, UTI and RTI.One very important one are pulmonary and extrapulmonary Tuberculosis.Problem arises in atypical cases. Following tests may help.

 

PCR or DNA of MTB.Only positive result is important. It is specific for TB.This can be done on sputum, blood, stool, urine, or other easily obtainable fluids. Cost is Rs 2000.

Montoux, Mycodot, and ESR are non-specific tests.

 

Montoux test can be false negative due to wrong inoculation or wrong dose or use of steroids and other immunosuppressive drugs, which reduce immunity. All sensitivity and diagnostic tests are done intradermal.subcutaneous route is for therapeutic administeration of drugs.

Measurement of Mountoux Test.     It should be measured in a transverse line and give it a number by adding erythema and induration.

            Upto 5 mms = Negative, 5-10 mms    = Borderline,  > 10 mms    = Positive.

Negative Mountoux is more important if technique is correct. If with right technique and dose it is negative then consider Sarcoidosis, HIV or Lymphoma in differential diagnosis. Patients with disseminated Tuberculosis will also have a negative test.bone marrow or liver biopsy often reveal granulomas and culture of these sites are positive in 50-90 % of patients with disseminated Tuberculosis.

 

Abdominal Tuberculosis           Four possible patterns.

A.   Intestinal Involvement

   Hyperplastic type:             Common in Ileocaecal region. Subacute obstruction may be the symptom.

   Ulcerative Type.                 Presents with diarrhoea and blood per rectum.

B.   Peritoneal Tuberculosis               Presents with Ascites.

C.   Lympadenitis                                Usually mesenteric. More common in children.

D.     Live and Biliary Passages.          Alkaline Phosphatase is raised. ALT is normal. Biopsy of a granuloma may be definitive in diagnosis.

 

Investigations for Abdominal Tuberculosis.             USG and Biopsy through USG, Barium Meal Studies, Ascitic Tap, FNA (Fine needle Aspirate)/Liver Biopsy.

 

Typhoid Fever

 

The word Typhoid means mental dullness or cloudiness.

Common Presentations.

§         Fever:                   Stepladder pattern. This pattern means two types of variations. First it gradually reaches its peak. Secondly there is also gradual increase in temperature from morning to evening. It reaches its peak during second week. It more or less remains constant & continous.

§         Abdominal symptoms(Pain,Diarrhoea,Constipation,Nausea/Vomiting)

§         Headache, Weakness, Prostration, Lethargy, lassitude.

§         Central coating of tongue and relative bradycardia has no diagnostic value.

§         Rose spots:                                  At the end of first week.

§         Hepatosplenomegaly:     

§         Toxic Features:                Irritability, Confusion, Drowziness,Delirium.

 

Complications Third week is the week of complications.

 

Intestinal Haemorrhage:       With the onset of haemorrhage temerature usually settles down but patient goes into shock.

Intestinal Perforation.

 

CNS Complications

§         Menengism                      All features of menengitis but CSF are normal.

§         Menengitis                       CSF is abnormal. Conscious level is usually normal.

§         Encephalitis          Chief abnormalities, as compared with menengitis, are behavioural abnormalities like defective memory, changed concious level etc.

§         Optic Neuritis

§         Deafness

 

Complications of other systems.

 

Parotitis                      results in excessive salivation.

Chest                          Myocarditis, Pneumonia, Bronchitis

Abdomen                    Hepatitis.In typhoid jaundice occurs at the peak of fever in contrast to viral hepatitis where juandice appears when fever is usually normal. Another feature is rise in SGOT levels, more than that of SGPT. (Opposite of viral hepatitis).

                                    Cholecystitis

                                    Pancreatitis

Kidneys                      Pyelonepheritis

Bones & Joints          Arthritis, Osteomyelitis

Thrombophlebitis

DIC

Carrier state or Relapses.

Relapse is more common usually within 2 weeks of typhoid therapy. It occurs more commonly in those who are treated with antibiotics as compared to untreated patients. It may be due to decreased immunity caused by use of drugs. Prolonged use of drugs does not prevent relapse.

Carrier State persists in 1-4 % of patients. These continue to excrete the organisms, usually in stools or in urine, one year after fever.

 

Pathogenesis:        Salmonella species, causing enteric fever, are humopathogenic. So one case means there is at least another one (Carrier) case in the house or community. Proper search should be made to trace and treat him.

 

Investigations for Typhoid.

 

First Week:

CBC:                                        It may show leukopenia.if leukocytosis is present in a definite case of Typhoid it may be an indicator for pyogenic complication.

Blood Culture:             Preferably before the use of antibiotics. Othewise 48 hours after cessation of antibiotic.

Second Week

Widal test:                               One test is of no value. Rising titres, especially against O antigen withen 3-4 days is significant in those patients who have not been vaccinated against Typhoid.Titres positive in 160 dilution is supportive for diagnosis. Effective antibiotics can blunt the rise in titres H-agglutinins persist. High after previous infections or vaccination so it is of little value.

Third Week                             

Urine Culture.                          Negative culture will not rule out, but positive will confirm the diagnosis.

Bone Marrow Culture             it is positive at any time, not affected by use of antibiotics.

Typhidot Test                          it is non-specific.

Elisa Tests                               Ideal Tubex, Eliza test for different antigens. These are coming in the market. These will be more specific.

 

Management of Typhoid Fever:

§         Anything which reduces gastric acidity will increase the chances of typhoidal infection as acid kills the germs. Other major risk factors include malnutrition, malignancy (particularly lymphomas, leukemias, sicle sick anaemia and other defects in cellular and humoral immunity.

§         Patients suffering from Typhoid fever should have normal diet. There is no role of avoidance of wheat or meat.

 

Primary Drugs.

§         Chloramphenical

§         Amoxicillin

§         Co-trimoxazole

Chloramphenical is more specific. If it is going to be effective than withen 48 hours there should be some relief and patient should become afebrile withen 5 days. Resistance of all above-mentioned drugs has been documented in 50-60 % of patients in 1987.This is labelled as multi drug resistant typhoid.

 

Second Line Drugs.

 

Quinolones                             Good efficacy. All are effective. More clinical trials have been conducted with Ciprofloxacin.These should be avoided below 17 years of age. Contraindicated in pregnancy.

 

Third Generation Cephalosporins.                These can be used if resistance to quinolones is suspected.

            Ceftriaxone                   1-2 gms/day, Parenterally

            Cefaprazone                 //                      //

            Cefotaxime                   //                      //

            Cefixime                       20 mgs/kg        Oral

§         In pregnancy, Renal failure, and hepatic failure, Amoxicillin should be prefered.

§         Third generation cephalosporins are relatively contraindicated in pregnancy.

 

Vaccination against Typhoid Fever

 

Oral and multidose parenteral vaccines are available. The minimum age for oral vaccine is 2 years and for parenteral, Vicps, is 6 months. For whole cell vaccines minimum age is 6 years. These oral and parenteral vaccines have similar efficacy for the first year but cumulative of whole cell parenteral vaccine is better than the oral and Vicps parenteral vaccine. Whole cell vaccine is associated with much higher incidence of side effects.16 % of patients receiving whole cell vaccine develop fever as compared to 1-2 % of those receiving any one of other two types.

Vaccination is recommended in the followings.

 

Persons travelling to developing counteries who will have prolonged exposures to contaminated food and water or close contact with indigenous population in rural areas?

Persons with intimate or household contact with a chronic carrier.

Laboratory workers who frequently work with S.typhi.

 

Efficacy:           Heat inactivated vaccine maintains its efficacy for five years while oral one for 4 years and parenteral Vicps for 2 years.