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UNEXPLAINED UNEXPLAINED FEVER — AN APPROACH TO DEFINING THE AETIOLOGY

The cause of an unexplained fever needs to be found before treatment can be started.

Patients at all levels of the health care system will often have a fever on initial presentation. The cause may be obvious; most will have a simple viral upper respiratory tract (URTI) and others will have pointing to the site and aeti- ology of the fever. Sometimes, however, a patient will present with fever without obvious localising clinical features. A systemat- ic approach is needed to elucidate the cause of the fever in these situations, in which the cause of the fever is often a common dis- ease with an uncommon presentation, rather than a rarity.

In this article, we suggest 10 questions that should be asked when an adult patient has an unexplained fever on initial presen- GRAEME MEINTJES KEVIN REBE tation. This article is not intended to deal with the separate, but MB ChB, MRCP (UK), FCP (SA) MB ChB, FCP (SA) related, issue of a fever of unknown origin (FUO), which is Senior Registrar Senior Registrar defined as documented fever of > 38.3°C for more than 3 weeks Infectious Diseases Unit Infectious Diseases Unit with no established diagnosis despite appropriate investigation University of Cape Town University of Cape Town for 1 week.1 Consultant Consultant 1. IS THERE A FOCUS OF BACTERIAL SEPSIS? Department of Medicine Department of Medicine

GF Jooste Hospital GF Jooste Hospital A thorough history and examination and directed special investi- Manenberg Manenberg gations will usually elucidate a focus of bacterial sepsis. Particular attention should be paid to focal and Dr Meintjes’ research inter- Dr Rebe’s research interests (e.g. pleuritic, renal angle, over sinuses), purulent secretions (e.g. sputum, nasal discharge, dysentery, vaginal discharge) and other ests include immune recon- include Pneumocystis features of acute inflammation (e.g. erythema, swelling, limitation stitution inflammatory syn- carinii pneumonia. of movement of a joint). Other specific symptoms (such as tachyp- dromes, delay in TB diag- noea in the case of pneumonia) will point to an organ system. A nosis and . checklist of sites of bacterial sepsis is given in Table I.

Investigations should be directed by the suspected site of sepsis, but if bacterial sepsis is suspected without an obvious site, the initial investigations should include a chest X-ray, urine Dipstix, urine microscopy and culture, and .

In elderly or immunosuppressed patients, for example diabetics, HIV-positive patients, those on and alcoholics, the clinical signs of bacterial sepsis may be subtle. These patients may even fail to mount a febrile response. An example is the eld- erly patient with pneumonia presenting with confusion, but with- out a cough, and with minimal fever. Tachypnoea is often the major clue to the diagnosis in this scenario. Another example is the diabetic patient with a renal presenting with constitu-

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Table I. Sites of bacterial infection tional symptoms and weight loss but minimal urinary tract symptoms.

Diverticulitis and diverticular Upper respiratory tract are an easily missed cause of fever in Tonsillitis elderly patients. Clinicians should be alerted by a history of rectal bleeding Otitis media or loose bowel motions, evidence of Retropharyngeal abscess rectal bleeding on examination, and Lower respiratory tract lower abdominal pain and tenderness. Bronchitis Pneumonia Always look for stigmata of infective Empyema , particularly in patients Lung abscess with a murmur or who are known to Abdominal have valvular or congenital heart dis- ease, or a prosthetic valve. The exami- Appendicitis nation should include urine Dipstix. and diverticular abscess Blood cultures and echocardiography are indicated if the diagnosis is enter- Other intra-abdominal collection (e.g. subphrenic abscess) tained. Peritonitis Urinary tract 2. IS THIS PATIENT SEPTICAEMIC? Renal abscess There is no single clinical sign to warn Perineum that a patient is septicaemic, but clues Ischiorectal abscess include hypotension, poor peripheral Skin and soft tissue perfusion, confusion, marked tachycar- Cellulitis dia and tachypnoea (representing Erysipelas metabolic acidosis) in the absence of Soft-tissue abscess including psoas abscess pneumonia. Immediate hospital refer- Central nervous system ral and admission is advised. Meningitis Brain abscess Two important causes of septicaemia Extradural abscess are: Cardiovascular Salmonella septicaemia Septic The classic syndrome associated with Arteritis and mycotic salmonella infection is enteric fever. Septic thrombus This is an acute illness that initially Pelvic presents with fever, and Pelvic inflammatory disease abdominal pain. Other signs may Prostatitis include a relative bradycardia and Musculoskeletal splenomegaly. The syndrome is usually Septic arthritis due to infection with Salmonella typhi, but may also be caused by other sal- Pyomyositis monella species such as S. paratyphi Dental and shigella or campylobacter. Prostheses and grafts The fever is initially remitting but Sepsis of vascular grafts, joint prostheses, artificial valves, intravascular becomes sustained. Diarrhoea and lines, etc. constipation are both described. The Surgical wound majority of patients with enteric fever will have some disturbance of gastro- intestinal function. Rose spots occur in 2-46% of patients, but may be diffi- cult to see in patients with dark skin.

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Definitive diagnosis is made by cultur- will be suffering from unrelated and then be requested for confirmation. ing the organism, with the highest simple diseases such as a viral URTI, Certain diseases also have a predilec- yield from blood cultures early in the but it is important to exclude travel- tion for specific organ systems (e.g. course of the disease. Stool and urine acquired diseases that are serious, viral ), and clinical findings cultures may become positive only treatable, or might require isolation. may guide investigation and manage- later, and their yield is under 50%. A ment.4 decreased leukocyte count is a useful The first diagnosis to consider in any pointer. The Widal test is of limited patient who has been travelling is 4. IS THERE A ? 2 value in diagnosis. . This requires a detailed his- In any patient who has a rash with a tory of their travel itinerary, concen- fever, the aetiology must initially be Studies from sub-Saharan Africa look- trating on destinations and duration of assumed to be infectious or drug-relat- ing at bacteraemia in HIV-positive travel, as well as airport lay-overs, as ed. The rash may be a clue to a spe- patients admitted with a fever have ‘airport-acquired’ malaria is not cific diagnosis. shown that salmonella species are unheard of. The travel history should commonly isolated. Non-typhi salmo- include domestic travel to malarial Considerations in the patient with nella bacteraemia is an AIDS-defining areas of South Africa. Always ask fever and a rash include: illness. about chemoprophylaxis for malaria, • drug exposure in the last month as well as any self-treatment with anti- • travel and outdoor exposure It is also important to consider shigella malarials or antibiotics. Smears for • occupational exposure or campylobacter colitis if there is a malaria should be sent (Fig.1) and • animal exposure short history of fever with abdominal antigen testing is also useful. If the • possibility of sexually transmitted cramps, even in the absence of diar- diagnosis is strongly suspected, repeat infection. rhoea, as these features may precede smears should be sent if the initial one the diarrhoea or dysentery. is negative. Clues to the diagnosis When considering a rash, the follow- include splenomegaly and thrombocy- ing factors are important: Staphylococcal septicaemia topenia. It is also worth remembering • timing of the rash Staphylococcus aureus septicaemia that cases of malaria do rarely occur • type of skin lesions may present in the absence of a clini- outside endemic malaria areas without • distribution cally identifiable source (up to 58% of a history of travel, and are probably • progression cases of community-acquired S. related to the transportation of the • associated clinical findings (e.g. 3 aureus). The most common identified mosquito vector to the non-endemic meningism). source is skin sepsis. A quarter of area. patients with community-acquired A few important examples of diseases staphylococcal septicaemia are diabet- causing fever and a rash are cited ic. Intravenous drug abuse and the use below.5 of intravenous indwelling catheters increase the risk of staphylococcal Meningococcus septicaemia and endocarditis. Rash occurs in 50 - 90% of patients with fulminant disease. The rash Common presenting features are begins as small irregular petechiae, , sweats, rigors and confusion. which may coalesce to form palpable Staphylococcal septicaemia tends to purpura, which often have a gun result in seeding out of infection, giv- metal-grey colour. They may occur ing rise to endocarditis, septic arthri- Fig. 1. Smear showing Plasmodium anywhere on the body. A Gram stain tis, abscesses, osteitis and meningitis. falciparum infection. from a deroofed skin lesion frequently Community-acquired staphylococcal reveals the causative organism. septicaemia carries a mortality of Once malaria has been excluded the 35%. Management includes aggres- following approach may be useful: Tick bite fever sive antibiotic therapy and surgical • consider the incubation period of Rash is a hallmark of this disease. drainage of sites of metastatic infec- common pathogens (Table II) Initially the rash is maculopapular and tion. • consider the patient's travel history, then becomes more petechial. It specifically duration and destina- occurs classically 4 - 6 days after the tion bite. History of tick exposure is impor- 3. IS THERE A HISTORY OF • consider the likely pathogens that tant, as the onset of the rash may be RECENT TRAVEL? occur at the destinations visited. delayed. The rash typically begins on the extremities, often around the wrists The list of tropical diseases that can These factors can then be combined to or ankles and affects the palms and cause fever is extensive. Many find a ‘best fit’ differential diagnosis soles. It then spreads to involve the patients with a travel history and fever and appropriate investigations can

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Table II. Travel-related pathogens classified according to incu- Consented HIV testing with pre- and bation period post-test counselling is indicated if these features are present, or an HIV- related opportunistic infection (e.g. Long (> 2 weeks) Short (< 2 weeks) Pneumocystis carinii pneumonia (PCP)) Malaria Arboviral infections is suspected. Viral haemorrhagic fevers Viral hepatitis Enteric bacteria and viruses The common causes of fever in HIV- Amoebae and worms Rickettsia positive patients are outlined in Table HIV Plague III. Schistosomiasis Seafood poisoning Filariasis Pneumonia The work-up of a fever in an HIV-posi- Influenza tive patient may include: a chest X-ray, Trypanosomiasis Anthrax blood cultures (including TB and fun- gal blood cultures), urine and sputum for TB, lymph node fine needle aspira- trunk, often sparing the face. papular erythematous eruption involv- tion biopsy (FNAB), abdominal and Headache occurs in over 90% of ing the trunk and extremities including cardiac ultrasound, bone marrow cases. palms and soles. Other features are biopsy (especially if patient is pancy- constitutional (including fever), condy- topenic), serum cryptococcal latex Toxic shock syndrome lomata lata and generalised lym- agglutination test (CLAT) and lumbar This syndrome may occur following phadenopathy. puncture. colonisation or localised infection with toxin-producing S. aureus. Patients 5. IS THE PATIENT HIV- Patients with advanced HIV infection may present severely ill, with an acute POSITIVE? may present with a fever within 3 febrile illness, hypotension, and symp- The aetiological possibilities are obvi- months of starting antiretroviral thera- toms and signs of multi-organ involve- ously wider if a patient has HIV infec- py, owing to development of an ment. A generalised erythematous tion. If the patient's HIV status is not immune reconstitution syndrome. This reaction occurs due to staphylococcal known, clinical features that suggest is an overexuberant immune response toxin production. The rash is a diffuse HIV infection should be sought — the to an infection that was clinically erythroderma with desquamation most common clinical pointers are occult while the patient was profound- occurring 1 - 2 weeks after the onset generalised , signifi- ly immunosuppressed. Immune recon- of the illness. It is important to look for cant wasting, oral , oral stitution syndromes may develop in the site of localised infection (e.g. car- hairy leukoplakia, shingles (old or cur- relation to most of the infections listed buncle or retained tampon). rent), molluscum contagiosum, fungal in Table III. Immune reconstitution syn- infections, Kaposi's , papular drome may also manifest as a para- Other infections due to staphylococcal pruritic eruption or post-inflammatory doxical deterioration with fever in a and streptococcal infection may also scarring. present with a rash. Examples include staphylococcal scalded skin syndrome, Table III. Common causes of a fever in HIV-positive patients6 impetigo, cellulitis and erysipelas.

Bacterial endocarditis This diagnosis may be suggested by a CD4 > 200 variety of skin lesions. These include Bacterial pneumonia Osler's nodes, Janeway lesions and Upper respiratory tract infection splinter haemorrhages. Pulmonary tuberculosis (PTB) CD4 < 200 Viral exanthems PTB and extrapulmonary TB Many viral illnesses are associated PCP with rash. They classically produce a Cryptococcosis, maculopapular rash. Included in this (CMV) group are all the common childhood Mycobacterium avium-intracellulare viruses such as rubella, measles and Salmonella non-typhi roseola. Secondary Rash is the most characteristic finding in secondary syphilis. It is classically a Note: HIV itself can cause fever (as part of seroconversion or of the HIV wasting syndrome).

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condition for which the patient is on Differential diagnosis is acute EBV or treatment, typically TB. cytomegalovirus (CMV), but these are rare in adults, as most acquire immuni- 6. COULD THIS BE AN HIV ty after childhood infection. SEROCONVERSION ILLNESS?

This is obviously a common cause of The diagnosis is confirmed with either fever in South Africa today. Features p24 antigen or viral RNA testing and can be nonspecific, and HIV serocon- subsequently HIV antibody testing. version is probably often misdiag- Antibody tests become positive 22 - 27 nosed as a viral URTI or infectious days after infection and once symp- mononucleosis due to Epstein Barr toms have subsided. Fig. 2. Chest radiograph appearance virus (EBV) infection. Between 40% of miliary TB. 7. COULD THIS BE TB? and 90% of new HIV-1 infections are constitutional (92%), respiratory associated with symptomatic illness. The diagnosis of TB is invariably con- (72%), neurological (25%) and The presence of generalised lym- sidered when there is a history of abdominal (21%). The median symp- phadenopathy, orogenital ulceration chronic cough or haemoptysis, togeth- tom duration of miliary TB in HIV-nega- and a morbiliform or fine maculopapu- er with , and tive individuals when they are admit- lar rash (mainly involving the trunk) weight loss. However, TB may not ted to a tertiary care facility is 4 should alert the clinician. It is impor- always present with respiratory fea- weeks (range 1 - 52 weeks).8 tant to note that the rash may be mini- tures. In patients with advanced HIV mal, especially in dark-skinned individ- (CD4 < 200) cavitation in the lung 8. COULD THIS BE THE PRE- uals, the nodes small and other fea- may not occur, and dissemination and ICTERIC PHASE OF VIRAL tures absent, making fever the predom- extrapulmonary TB are more common HEPATITIS? inant sign. than in HIV-negative patients. The pres- entation of TB in these patients may be Acute viral hepatitis is most often a The importance of diagnosing acute atypical, with constitutional and non- self-limiting febrile illness. Many dif- HIV lies in the opportunity to prevent pulmonary symptoms predominating. ferent hepatitis viruses have been iso- further infection through appropriate For example, if the patient has abdom- lated, and early in their course there is counselling. The common clinical fea- inal TB, this may present with abdomi- little to differentiate them clinically. tures are listed in Table IV. It is also nal pain and fever. The presentation of viral hepatitis is important to remember that because variable and ranges from asympto- patients develop transient profound In addition, miliary TB may affect HIV- matic infection to fulminant liver fail- lymphopenia during seroconversion, it negative individuals, especially those ure. is possible that they may develop who are immunosuppressed for anoth- opportunistic infections such as oral er reason such as alcoholism. Miliary The illness is divided into four phases: thrush or even PCP during this time. TB in this context will usually give a • incubation phase distinctive appearance on a chest • pre-icteric phase Symptoms tend to occur days to weeks radiograph (CXR) (Fig. 2), but the CXR • icteric phase after the infection. The acute illness may be clear initially (in 22% in a • convalescence. may persist from a few days to 10 series at Groote Schuur Hospital the weeks, but in most subsides within 2 CXR did not reveal miliary nodules). Importantly, the patient feels well dur- weeks. Common symptoms of miliary TB are ing incubation. The pre-icteric phase often presents as a flu-like illness with Table IV. Clinical features of HIV seroconversion illness7 , , , and fever. Fever rarely persists into the icteric phase and thus jaundice with a high fever is not characteristic Fever > 80 - 90 % of viral hepatitis. Fever is also not an > 70 - 90% invariable feature of viral hepatitis Rash (usually maculopapular) > 40 - 80% prodromes. Headache 32 - 70% Lymphadenopathy 40 - 70% When this diagnosis is considered, a Pharyngitis 50 - 70% careful history should be obtained to or arthralgia 50 - 70% determine possible exposure. Oral ulcers 10 - 20% Supportive clinical features such as Genital ulcers 5 - 15% right upper quadrant tenderness may Aseptic meningitis 24% be useful. The diagnosis is confirmed by serological tests.

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9. DOES THIS PATIENT HAVE Many commonly used drugs (especial- IN A NUTSHELL CHRONIC LIVER DISEASE? ly antibiotics) can cause a drug fever. Diagnosis of a drug fever is confirmed A thorough history and examination Patients with chronic liver disease and by resolution of the fever within 3 - 4 will often elucidate a focus of bac- excessive alcohol intake are immuno- days of stopping the drug, and recur- terial sepsis. suppressed and this may mask the site rence of fever on rechallenge. Even of sepsis causing fever. These patients The signs and site of bacterial sep- medication that a patient has taken for are at increased risk of both bacterial sis may be masked in elderly and years may cause a drug fever. and fungal infections. One of the immunocompromised patients. most common causes of sepsis is spon- The commonest malignancies to pres- Clues to a septicaemic illness are taneous bacterial peritonitis (SBP). ent with fever are Hodgkin's and other hypotension, poor peripheral perfu- This may occur in the absence of clini- . Others to consider are sion, confusion, marked tachycar- cally identifiable ascites, and signs of , leukaemia and cer- dia and tachypnoea in the absence peritonism are usually absent. When tain solid tumours (e.g. renal cell car- of pneumonia. present, ascites should be tapped and cinoma and atrial myxoma). sent for analysis to confirm or exclude The most important community- SBP. acquired septicaemic illnesses to Inflammatory bowel disease may pres- consider are: staphylococcal, sal- ent with fever prior to the onset of gas- 10. COULD THE CAUSE OF monella, meningococcal and septi- trointestinal symptoms. THIS FEVER BE NON- caemia secondary to pneumonia or INFECTIVE? pyelonephritis. Finally, other rare infective causes of The list of non-infective causes of fever fever to consider are , Q The presence of a rash may point is extensive. The important categories fever, , amoebic liver to a specific aetiology such as tick are listed in Table V. abscess and pseudomembranous coli- bite fever or meningococcaemia. tis. Pseudomembranous colitis occurs An important cause of fever in elderly A history of recent travel to a after antibiotic exposure and may ini- malaria area should be sought. patients is . Patients tially present with fever and abdomi- typically present with symptoms of nal pain prior to diarrhoea. In HIV-positive patients the diagnos- , unilateral tic possibilities are wider, and headache and fever. Other - References available on request. include pulmonary and extrapul- tous diseases such as and monary TB, cryptococcosis and Wegener's granulomatosis may also PCP. present with fever. HIV seroconversion illness is fre- quently missed. Signs that suggest it 1 Table V. Categories of non-infective causes of fever are a morbiliform rash, orogenital ulcers and generalised lym- phadenopathy.

Connective tissue and granulomatous diseases The most important diagnoses not Drugs to miss initially are: the septicaemic Malignancy illnesses mentioned above, malaria, Deep-vein thrombosis (DVT) or (PE) a pus collection, infective endo- Haematoma carditis, thrombotic thrombocy- topenic purpura and acute Factitious leukaemia. Miscellaneous (e.g. , thrombotic thrombocytopenic purpura/haemolytic uraemic syndrome, acute , inflamma- tory bowel disease)

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