1.

Causes of fever

TB
Tuberculosis lesions often occur without pyrexia. On the other hand, the occurrence of some degree of fever
without any apparent cause may be the sole evidence of such disease, especially the miliary form. Pulmonary
tuberculosis is almost invariably pyrexial, but in an earlier stage there are often long periods of apyrexia even
when the tuberculous process is active, with brief febrile spells. Tuberculous disease of the joints may be
apyrexial unless secondarily infected. Glandular tuberculosis is less likely to be pyrexial when the nodes
involved are cervical or bronchial than when the mesenteric and other abdominal nodes are caseous and
softening (‘tabes mesenterica’), when there may be – and usually is – prolonged pyrexia. The diagnosis may be
easy if there is ascites in a child or if there are palpable abdominal masses, but it may be difficult in the absence
of lumps and ascites in a condition of ill-health with pyrexia and with vague abdominal pains, which may be
mistaken for some other non-tuberculous abdominal disease. The patient is usually young, and in European
countries may be an immigrant. The presence of enlarged cervical lymph nodes supports this diagnosis.

SLE
Systemic lupus erythematosus may for many months present as pyrexia, often accompanied by skin rashes
and symptoms relating to locomotor and other tissues. The high erythrocyte sedimentation rate and joint pains
may lead to confusion with rheumatoid arthritis.

Malignancy
Lymphomas of different types, including Hodgkin’s disease, may be associated with prolonged fever, although
not confined to it. Lymphosarcoma may be associated with prolonged pyrexia, as may carcinoma, particularly if
associated with sepsis, as is seen not infrequently in the bronchus and large intestine. Infection is not
necessary for pyrexia to be present; high fevers are occasionally seen in primary and secondary carcinoma
where no sepsis exists, and a low-grade pyrexia is common. Particularly likely to be accompanied by prolonged
pyrexia are hypernephroma, hepatoma, secondary carcinoma in the liver and widespread metastatic disease.

2. Antibiotics - EDWIN
Classifications of antibiotics (Mode of action)
- inhibits/ destroys:
1.Cell wall
β-lactam antibiotics are bactericidal, binds to transpeptidase/PBP, inhibit the synthesis of the peptidoglycan layer of
cell walls of Gram-positive bacteria.

2.Cell membrane
Bactericidal, binds to lipopolysaccharide (LPS) in the cytoplasmic outer cell membrane of Gram-negative bacteria,
disrupting both the outer and inner membranes, altering membrane permeability.

3.DNA / RNA synthesis

● DNA gyrase - Bacteriostatic, binds to the topoisomerase IV, inhibiting DNA replication
● DNA directed RNA polymerase - Bacteriostatic/Bactericidal (depending on the susceptibility of
the bacteria and the concentration of the drug), inhibits DNA-dependent RNA polymerase,
leading to a suppression of RNA synthesis and cell death.

4.Protein synthesis
● 50s ribosomal subunit
● 30s ribosomal subunit
● t-RNA - binds to bacterial isoleucyl-tRNA synthetase, an enzyme which promotes the conversion
of isoleucine and tRNA to isoleucyl-tRNA,inhibiting bacterial protein and RNA synthesis.

5.Folic acid metabolism

binds to dihydrofolate reductase and inhibits the reduction of dihydrofolic acid (DHF) to tetrahydrofolic acid
(THF). THF is an essential precursor in the thymidine ( precursor of pyrimidine) synthesis.

Adverse Reactions of Penicillins (related to trigger)

- Skin rash ( ampicillin )
- Interstitial nephritis ( also in cephalosporins )

Broad Spectrum antibiotics

- Aminoglycosides (except for streptomycin)
- Ampicillin
- Amoxicillin
- Amoxicillin/clavulanic acid (Augmentin)
- Carbapenems (e.g. imipenem)
- Piperacillin/tazobactam
- Quinolones (e.g. ciprofloxacin)
 - Tetracyclines
- Chloramphenicol
- Ticarcillin
- Trimethoprim/sulfamethoxazole (Bactrim)

3. ATT
According to Gomes et al, a sample is called diagnostic when Z-N stain and/or culture is positive, suggestive
when there is granulomatous inflammation, and inconclusive when there is nonspecific inflammation or isolated
giant cell or blood elements. According to Das et al,17 when AFB is positive in a smear containing epithelioid
granuloma and/or necrosis, it is diagnostic of a tuberculous lesion. When AFB is negative in the presence of
epithelioid granuloma in a developing country like India, it is considered a granulomatous lesion likely to be of
tuberculous etiology, and culture for mycobacterium is advised. When the smear contains only necrotic material
with or without inflammatory cells and AFB is negative, it is advisable to exclude TB by mycobacterium culture
and even by a therapeutic trial, if needed. In such a situation, the demonstration of mycobacterial antigen by
immunocytochemistry may be of use.

EMPIRICAL THERAPY
IN PUO Tuberculosis, particularly extra pulmonary tuberculosis, has emerged as the most common final
diagnosis in patients presenting with FUO in most Indian studies. Sharma et al, in a combined prospective and
retrospective study of 150 cases of FUO, found that infections, particularly tuberculosis, were the most common
cause of FUO (50%). 28 Another group of investigators found tuberculosis as the cause of FUO in 26 of 121
patients (21.5%) in a prospective study. A recent study involving 60 patients with FUO who met the strict
revised criteria established by Petersdorf found extra pulmonary tuberculosis to be the most common cause of
FUO. All the patients tested CHAPTER 7 negative for human immunodeficiency virus (HIV). 39 Extra pulmonary
tuberculosis, particularly tuberculous mediastinal adenopathy, was the final diagnosis in 27 (45%) patients.
Tuberculosis was the single most common in most PUO series. 4 This strongly supports the view that the
institution of empirical antituberculous therapy is justified in any patient of PUO where no specific diagnosis is
evident after a reasonable diagnostic work-up.

4. Causes of Cervical Lymphadenopathy

I

Cervical lymphadenopathy

Cervical lymphadenopathy is a common problem in children. Cervical nodes drain the tongue, external ear,
parotid gland, and deeper structures of the neck, including the larynx, thyroid, and trachea. Inflammation or
direct infection of these areas causes subsequent engorgement and hyperplasia of their respective node
groups. Adenopathy is most common in cervical nodes in children and is usually related to infectious
aetiologies. Lymphadenopathy posterior to the sternocleidomastoid is typically a more ominous finding, with a
higher risk of serious underlying disease.

● Infectious etiologies
1. Cervical adenopathy is a common feature of many viral infections. Infectious mononucleosis
often manifests with posterior and anterior cervical adenopathy. Firm tender nodes that are not
warm or erythematous characterize this lymph node enlargement. Other viral causes of
cervical lymphadenopathy include adenovirus, herpesvirus, coxsackievirus, and CMV. In herpes
gingivostomatitis, impressive submandibular and submental adenopathy reflects the amount of
oral involvement.
2. Bacterial infections cause cervical adenopathy by causing the draining nodes to respond to local
infection or by the infection localizing within the node itself as a lymphadenitis. Bacterial infection
often results in enlarged lymph nodes that are warm, erythematous, and tender. Localized
cervical lymphadenitis typically begins as enlarged, tender, and then fluctuant nodes. The
appropriate management of a suppurative lymph node includes both antibiotics and incision and
drainage. Antibiotic therapy should always include coverage for Staphylococcus aureus and
Streptococcus pyogenes.
3. In patients with cervical adenopathy, determine whether the patient has had recent or ongoing
sore throat or ear pain. Examine the oropharynx, paying special attention to the posterior
pharynx and the dentition. The classic manifestation of group A streptococcal pharyngitis is sore
throat, fever, and anterior cervical lymphadenopathy. Other streptococcal infections causing
cervical adenopathy include otitis media, impetigo, and cellulitis.
4. Atypical mycobacteria cause subacute cervical lymphadenitis, with nodes that are large and
indurated but not tender. The only definitive cure is removal of the infected node. [16]
 5. Mycobacterium tuberculosis may manifest with a suppurative lymph node identical to that of
atypical mycobacterium. Intradermal skin testing may be equivocal. A biopsy may be necessary
to establish the diagnosis.
6. Catscratch disease, caused by Bartonella henselae, presents with subacute lymphadenopathy
often in the cervical region. The disease develops after the infected pet (usually a kitten)
inoculates the host, usually through a scratch. Approximately 30 days later, fever, headache, and
malaise develop, along with adenopathy that is often tender. Several lymph node chains may be
involved. Suppurative
7. Adenopathy occurs in 10-35% of patients. Antibiotic therapy has not been shown to shorten the
course.

· Noninfectious etiologies

1. Malignant childhood tumors develop in the head and neck region in one quarter of cases. In the
first 6 years of life, neuroblastoma, leukemia, non-Hodgkin lymphoma, and rhabdomyosarcoma
(in order of decreasing frequency) are most common in the head and neck region. In children
older than 6 years, Hodgkin disease and non-Hodgkin lymphoma both predominate. Children
with Hodgkin disease present with cervical adenopathy in 80-90% of cases as opposed to 40%
of those with non-Hodgkin lymphoma.
2. Kawasaki disease is an important cause of cervical adenopathy. These children have fever for at
least 5 days, and cervical lymphadenopathy is one of the 5 diagnostic criteria (of which 4 are
necessary to establish the diagnosis).

5. Red Rash on leg

Skin Lesions
Macules and patches - Flat areas of discoloration without change in texture
Papules and plaques - Elevated, palpable
Vesicles and Bullae - fluid-filled spaces
Pustules - vesicle or bullae containing pus
Nodule - solid, rounded skin lesion

Disease/Etiology Clinical Findings

Viral

Cytomegalovirus Erythematous macules and papules

in diffuse distribution. Skin or
mucosal ulcerations are possible.
 Mononucleosis Morbilliform rash spreads over entire
body

Rubella Rose-pink macules in cephalocaudal

spread, and clears in 2-3 days in the
same manner.
posterior auricular/occipital
lymphadenopathy.

Roseola Erythematous, blanchable, macules,

and papules. Periorbital edema is a
common association. Rash
appearing after fever defervescence
is key finding.

Hand, Foot, Mouth Disease Macules progress to vesicles on red

base on the hands and feet
(especially on palms and soles) and
oral mucosa

No Confirmed Etiology

Kawasaki’s Disease (1) fever >5 days, (2) palmoplantar

urticarial erythema/desquamation,
(3) conjunctivitis, (4) strawberry
tongue/red fissured, crusted lips, (5)
cervical lymphadenopathy. A
polymorphous rash on the trunk and
extremities usually occurs
presenting as a maculopapular,
targetoid or scarlet fever-like rash
with accentuation in body fold areas.
"Atypical" cases more commonly
diagnosed

Multiple Etiologies

Serum-sickness like Reaction Targetoid or annular to polycyclic

(SSLR) erythematous plaques. Violaceous
Cefaclor most common cause. center of plaques very characteristic
Amoxicillin, griseofulvin also
described, among others

6.Cause of Acute Renal Failure

Acute kidney injury
Acute kidney injury (AKI), previously called acute renal failure (ARF),[1][2] is an abrupt loss of kidney function
that develops within 7 days.[3]
Its causes are numerous. Generally it occurs because of damage to the kidney tissue caused by decreased
kidney blood flow (kidney ischemia) from any cause (e.g., low blood pressure), exposure to substances harmful
to the kidney, an inflammatory process in the kidney, or an obstruction of the urinary tract that impedes the flow
of urine. AKI is diagnosed on the basis of characteristic laboratory findings, such as elevated blood urea
nitrogen and creatinine, or inability of the kidneys to produce sufficient amounts of urine.

AKI may lead to a number of complications, including metabolic acidosis, high potassium levels, uremia,
changes in body fluid balance, and effects on other organ systems, including death. People who have
experienced AKI may have an increased risk of chronic kidney disease in the future. Management includes
treatment of the underlying cause and supportive care, such as renal replacement therapy.

The clinical picture is often dominated by the underlying cause.The symptoms of acute kidney injury result from
the various disturbances of kidney function that are associated with the disease. Accumulation of urea and
other nitrogen-containing substances in the bloodstream lead to a number of symptoms, such as fatigue, loss of
appetite, headache, nausea and vomiting.[4] Marked increases in the potassium level can lead to abnormal
heart rhythms, which can be severe and life-threatening.[5] Fluid balance is frequently affected, though blood
pressure can be high, low or normal.[6]

Pain in the flanks may be encountered in some conditions (such as clotting of the kidneys' blood vessels or
inflammation of the kidney); this is the result of stretching of the fibrous tissue capsule surrounding the
kidney.[7] If the kidney injury is the result of dehydration, there may be thirst as well as evidence of fluid
depletion on physical examination.[7] Physical examination may also provide other clues as to the underlying
cause of the kidney problem, such as a rash in interstitial nephritis (or vasculitis) and a palpable bladder in
obstructive nephropathy.[7]

Prerenal
Prerenal causes of AKI ("pre-renal azotemia") are those that decrease effective blood flow to the kidney and
cause a decrease in the glomerular filtration rate (GFR). Both kidneys need to be affected as one kidney is still
more than adequate for normal kidney function. Notable causes of prerenal AKI include low blood volume (e.g.,
dehydration), low blood pressure, heart failure (leading to cardiorenal syndrome), liver cirrhosis and local
changes to the blood vessels supplying the kidney. The latter include renal artery stenosis, or the narrowing of
the renal artery which supplies the kidney with blood, and renal vein thrombosis, which is the formation of a
blood clot in the renal vein that drains blood from the kidney.

Intrinsic
Intrinsic AKI refers to disease processes which directly damage the kidney itself. Intrinsic AKI can be due to one
or more of the kidney's structures including the glomeruli, kidney tubules, or the interstitium. Common causes of
each are glomerulonephritis, acute tubular necrosis (ATN), and acute interstitial nephritis (AIN), respectively.
Other causes of intrinsic AKI are rhabdomyolysis and tumor lysis syndrome.[8] Certain medication classes such
as calcineurin inhibitors (e.g., tacrolimus) can also directly damage the tubular cells of the kidney and result in a
form of intrinsic AKI.

Postrenal
Postrenal AKI refers to acute kidney injury caused by disease states downstream of the kidney and most often
occurs as a consequence of urinary tract obstruction. This may be related to benign prostatic hyperplasia,
kidney stones, obstructed urinary catheter, bladder stones, or cancer of the bladder, ureters, or prostate.

7. Cause of DIC
● Always secondary condition
● Abnormal response to tissue damage and shows complex interaction between inflammatory and
coagulation pathways
○ Normal response to tissue damage is a contained generation of thrombin (initiated by tissue
factor release) at the site of injury, mediated by complexing of tissue factor and activated factor
VII on the damaged endothelium
○ Thrombin is necessary to control hemostasis. It balances the procoagulant and anticoagulant
activities by activating the conversion of fibrinogen to fibrin and activating the protein C
anticoagulant regulatory pathway.
○ Loss of controlled thrombin generation and homeostatic balance is common in DIC
○ Thus uncontrolled generation of thrombin intrinsic pathway activation through the release of
tissue factor by damaged or hypoxic endothelium → coagulation factor consumption and
increase fibrin deposition and breakdown.
○ Blood clots forms throughout the body blocking small blood vessels. These blood clots can reduce
or block blood flow through the blood vessels, which can damage the body's organs.As clotting
factors and platelets are used up, bleeding may occur.
■ Severe infection and sepsis are most common causes of DIC >50% of cases. E.g. TB
■ Trauma: serious tissue injury and burns cause endothelial damage and release of tissue
factor. E.g. burns, hyperthermia, rhabdomyolysis, extensive surgery.
■ Organ destruction: DIC is seen in severe pancreatitis
■ Severe immunological reactions/autoimmune: e.g. after transfusions with ABO
incompatible blood cells, transplant rejection, SLE)
■ Malignancy (acute preomyelocytic leukemia)
■ Severe allergic or toxic reactions (e.g. snake venom)
● Patient given platelet replacement

8. Need for Cryoprecipitate

Cryoprecipitate is a frozen blood product prepared from blood plasma. To create cryoprecipitate, fresh frozen
plasma is centrifuged and the precipitate is collected.
● Fibrinogen
● Factor VIII
● von Willebrand factor
● Factor XIII
Indications for giving cryoprecipitate include:
● Haemophilia – Used for emergency back up when factor concentrates are not available.
● von Willebrand disease – Not currently recommended unless last reserve. ddAVP is first line, followed
by factor concentrates.
 ● Hypofibrinogenaemia (low fibrinogen levels), as can occur with massive transfusions
● Afibrinogenemia
● Bleeding from excessive anticoagulation – Fresh frozen plasma contains most of the coagulation
factors and is an alternative choice when anticoagulation has to be reversed quickly.
● Massive haemorrhage – RBCs and volume expanders are preferred therapies.
● Disseminated intravascular coagulation
● Uremic bleeding tendency

9. Fever of Unknown Origin - Epidemiology

Fever of unknown origin (FUO), pyrexia of unknown origin (PUO) or febris e causa ignota (febris E.C.I.) refers to a
condition in which the patient has an elevated temperature (fever) but despite investigations by a physician no
explanation has been found.
Unexplained fevers are worrisome to patients and clinicians, but most persistent fevers are diagnosed, and
often within one week of hospital evaluation or 3 outpatient visits.
Most fevers that persist beyond this period are caused by common conditions presenting uncommonly.
Hundreds of conditions may cause FUO. While infections remain a significant cause, most FUOs in the
developed world are caused by noninfectious inflammatory disorders, with malignancy a much smaller percentage.
Infection is likely to evolve with increased global travel and use of immunomodulating drugs.
The differential diagnoses of FUO depend on and continue to evolve based on regional factors, exposures,
and available diagnostic tools.
A significant percentage of FUO cases are caused by miscellaneous conditions, and there is no standard
algorithm for evaluating FUO. The approach to diagnostic study is best guided by ongoing assessment for historical,
physical, and basic laboratory clues. Following clues and beginning with the least invasive evaluation avoids
unnecessary harm and cost to the patient.
Physical examination in FUO should pay special attention to skin, eyes, lymph nodes, liver, and spleen.
It is reassuring that most cases of FUO that remain undiagnosed despite intensive evaluations have a good
long-term prognosis and resolve within a year.
A prospective review of FUO in 290 subjects between 1990 and 1999 found noninfectious inflammatory diseases in
35.2% of cases, infections in 29.7%, miscellaneous causes in 19.8%, and malignancies in 15.1%. Most were
diagnosed within 3 visits or 3 hospital days. the rate of unknown causes is higher in this report than in prior
estimates, with 33.8% remaining undiagnosed beyond 7 days.
A final diagnosis was established early in 67 patients (23.1%), intermediate in 38 (13.1%), and late in 87 (30.0%). In
the remaining 98 (33.8%), no diagnosis was made. The cause of the fever remained obscure in 50 (47.6%) of 105
patients with episodic fever vs 48 (25.9%) of 185 patients with continuous fever (P<.001). Among the 192 patients
with a final diagnosis, noninfectious inflammatory diseases represented the most prevalent diagnostic category
(35.4%), surpassing infections (29.7%), miscellaneous causes (19.8%), and malignancies (15.1%).
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