Examination Medicine: A Guide to Physician Training, 7th Edition

CHAPTER 13. The infectious disease long case

Humanity has but three great enemies: fever, famine and war; and of these by far the greatest, by far the most terrible, is fever.

Harvey Cushing (1869–1939)

Pyrexia of unknown origin

Although not a common long case, pyrexia of unknown origin (PUO) presents both diagnostic and management problems. The term ‘pyrexia of unknown origin’ is used only for patients with a fever >38.3°C for more than 3 weeks, for whom no diagnosis has been made during a week of intensive study. The common causes of PUO are listed in Table 13.1.

Table 13.1

Important causes of pyrexia of unknown origin


The history

1. Ask about the chronological development of symptoms. Gastrointestinal tract symptoms should be sought (e.g. subphrenic abscess, diverticular abscess, cholangitis, appendiceal abscess, liver abscess, Crohn’s disease, metastatic cancer in the abdomen, Whipple’s disease). Note any preceding acute infections (e.g. diarrhoeal illness, boils).

a. Chest pain may suggest pericarditis, multiple pulmonary emboli or, rarely, intraluminal dissection of the aorta.

b. Joint pain may suggest rheumatoid arthritis, SLE, vasculitis, atrial myxoma or endocarditis.

c. Dysuria or rectal pain may indicate prostatic abscess or urinary tract infection.

d. Headache and joint or muscle pain may indicate giant cell arteritis.

e. Night sweats may indicate lymphoma, tuberculosis, brucellosis, endocarditis or an abscess.

2. Ask about place of residence and overseas travel (e.g. malaria, amoebiasis, fungal infections).

3. Ask about contact with domestic or wild animals or birds (e.g. psittacosis, brucellosis, Q fever, histoplasmosis, leptospirosis, toxoplasmosis).

4. Ask about close contact with persons who have tuberculosis.

5. Enquire about occupation and hobbies – veterinary surgeon, farming (fungal infection, raw milk ingestion, hypersensitivity pneumonitis), intravenous drug use (contaminants e.g. quinine).

6. Enquire about sexual practices (e.g. risk of HIV infection, sexually transmitted disease, pelvic inflammatory disease).

7. Ask about evidence of immunocompromised host (e.g. cytomegalovirus, Pneumocystis jirovecii).

8. Find out about medication used – drug fever (antibiotic allergy, e.g. sulfonylureas, penicillin), arsenicals, iodides, thiouracils, antihistamines, NSAIDs, antihypertensives (methyldopa, hydralazine), antiarrhythmics (procainamide, quinidine).

9. Ask about anticoagulant use (accumulation of old blood in a closed space, e.g. retroperitoneal, perisplenic).

10. Ask about iatrogenic infection (e.g. catheter, arteriovenous fistula, prosthetic heart valve).

11. Ask about factitious fever from injection of contaminated material or tampering with thermometer readings – suspect the former diagnosis if there is an excessively high temperature or the latter in the absence of tachycardia, chills or sweats; this is more common in medical or paramedical personnel.

The examination

1. Look at the temperature chart, if available, to see whether the fever pattern is characteristic. The temperature tends to fall to normal each day in pyogenic infections, tuberculosis and lymphoma, whereas in malaria the temperature can return to normal for days before rising again.

2. Inspect the patient: note whether he or she appears ill or not, whether there is cachexia (suggesting a chronic disease process) and any skin rash (e.g. erythema multiforme, erythema nodosum, adult Still’s disease (salmon-pink macular rash)).

3. Pick up the hands and look for stigmata of infective endocarditis or any vasculitic changes, and for finger clubbing.

4. Inspect the arms for injection sites (intravenous drug abuse).

5. Palpate for epitrochlear and axillary lymphadenopathy (e.g. lymphoma, solid tumour spread, focal infections).

6. Examine the eyes for iritis or conjunctivitis (e.g. connective tissue disease, sarcoidosis) or jaundice (e.g. cholangitis, liver abscess). Look in the fundi for choroidal tubercles (miliary tuberculosis), Roth’s spots (infective endocarditis), retinal haemorrhages or infiltrates (e.g. leukaemia). Note any facial rash (e.g. SLE). Feel the temporal arteries (temporal arteritis).

7. Examine the mouth for ulcers and gum disease and the teeth and tonsils for infection. Feel the parotids for parotitis and the sinuses for sinusitis.

8. Palpate the cervical lymph nodes.

9. Examine for thyroid enlargement and tenderness (subacute thyroiditis).

10. Examine the chest. Palpate for bony tenderness over the sternum and shoulders.

11. Examine the respiratory system (e.g. for signs of tuberculosis, abscess, empyema, carcinoma) and the heart for murmurs (e.g. infective endocarditis, atrial myxoma) or prosthetic heart sounds or rubs (e.g. pericarditis).

12. Examine the abdomen. Inspect for skin rash (e.g. the rose-coloured spots of typhoid (an uncommon long case)). Palpate for tenderness (e.g. abscess), hepatomegaly (e.g. granulomatous hepatitis, hepatoma, cirrhosis, metastatic deposits), splenomegaly (e.g. haemopoietic malignancy, infective endocarditis, malaria), renal enlargement (e.g. obstruction, renal cell carcinoma).

13. Feel the testes for enlargement (e.g. seminoma, tuberculosis). Feel for inguinal adenopathy. Always ask for the results of the rectal examination (e.g. prostatic abscess, rectal cancer, Crohn’s disease) and pelvic examination (pelvic pus). Look at the penis and scrotum for a discharge or rash.

14. Finally, examine the nervous system for signs of meningism (chronic meningitis) or focal neurological signs (e.g. brain abscess, mononeuritis multiplex in polyarteritis nodosa). Check the results of the urine analysis.


1. Determine how many blood cultures have been obtained and the results. Ask to review the blood count and smear (e.g. for neutropenia, eosinophilia, atypical lymphocytes), liver function tests, electrolytes and creatinine. Look at the chest X-ray. Rule out urinary tract disease if suspected.

2. Selected serological tests may be helpful depending on the clinical setting (e.g. fungal, HIV, Q fever). An autoimmune screen – ANA, ESR, CRP, an EPG and complement levels – should be assessed if a connective tissue disease is suspected. However, remember that malignancy and infection can also cause an increase in acute phase reactants and a low-titre ANA. Check the purified protein derivative (PPD) for tuberculosis exposure (see Table 13.2).

Table 13.2

Tuberculin skin testing*


If positive and no active disease on chest X-ray and by sputum for acid-fast bacteria: treat for latent TB (isoniazid for 9 months).

*Contraindicated if history of necrotic skin reaction to previous testing. Prior BCG vaccination does not invalidate the results.

False negatives occur in anergy or with recent exposure (recheck after 12 weeks) or in the elderly (recheck after 3 weeks).

3. If abdominal disease is suspected or other tests have not provided a clue, obtain a CT scan.

4. Biopsy of involved tissue (e.g. bone marrow, liver, lymph node, skin, muscle) may lead to a definitive diagnosis. The clinical setting determines what should be biopsied.

5. Exploratory laparotomy when all other tests are negative and in the absence of any evidence of abdominal disease is usually unproductive.


Therapy directed at the underlying disease should be the goal of assessment. Therapeutic trials in the absence of a diagnosis (e.g. antibiotics, antituberculosis therapy, NSAIDs, steroids) may result in resistant bacterial infection or drug toxicity and may make accurate diagnosis difficult. If the patient is thought to have a fever caused by a drug – a drug fever – it may be worth stopping the drug or using an alternative one. A possible drug fever makes trialling a change of drug worthwhile.


Patients with HIV infection or the acquired immunodeficiency syndrome (AIDS) have become increasingly available for long-case examinations. This is now often a chronic disease and patients are getting older and likely to have problems such as ischaemic heart disease. Remember that the diagnosis of AIDS can be made when someone infected with HIV has a CD4+ cell count of <200 cells/μL or an HIV-associated disease. These patients present numerous diagnostic and management problems. The candidate will be expected to display a logical approach to the case and, of course, show a sympathetic attitude to the patient with this chronic disease. There needs to be a strong emphasis in the discussion on the psychological and social effects of the illness. Public health implications may also have to be addressed. Candidates should have an approach to pretest counselling for patients being tested for HIV.

The history

1. Ask about the presenting symptoms. As usual for long cases, the candidate must find out what symptoms or complications are currently affecting the patient. These must be assessed in the context of possible longstanding disease affecting many systems of the body.

2. Enquire when the virus was acquired. This is especially important in helping predict the likely level of immunosuppression. Not all patients are prepared to discuss this. Insistent questioning by candidates is not a good idea. There have been complaints from long case patients about this being handled insensitively.

a. Find out about symptoms of a possible seroconversion illness in the past (see Table 13.3). Approximately 50% of people have a seroconversion illness. It occurs 3 to 6 weeks after infection and often resembles glandular fever. Remember that, without treatment, the development of AIDS takes roughly 7 to 10 years from the time of seroconversion. The occurrence of a seroconversion illness does not seem to be associated with a worse prognosis.

Table 13.3

Features of the seroconversion illness


b. Note from the history any of the conditions likely to occur during the period of mild-to-moderate immunosuppression that precedes the development of AIDS and those related to severe immunosuppression that define the development of AIDS (see Table 13.4).

Table 13.4

HIV-related conditions with severe immunosuppression


Note: This is a representative rather than an exhaustive list.

3. Ask about the mode of acquisition of infection. Co-morbidity differs between subgroups, so specific questions about risk factors are essential. For example, co-infections with syphilis or papilloma viruses and Kaposi’s sarcoma is often found in the homosexual male subgroup, whereas hepatitis B and C infection, endocarditis, heroin nephropathy and other disorders related to drug abuse may complicate the disease in the intravenous drug-using group. Many haemophilia A patients acquired HIV from pooled blood products.

4. Ask about sexual contacts. Contact tracing must be mentioned and the possibility of infection of sexual partners without their knowledge addressed. Ask the patient whether family and friends are aware of the diagnosis. Their attitude to this chronic illness may affect the patient’s ability to cope.

5. Ask about general constitutional symptoms. Symptoms of fever, lethargy and weight loss may indicate the AIDS-related complex or suggest an underlying opportunistic infection or malignancy.

6. Enquire about specific symptoms:

a. respiratory – cough, dyspnoea, sputum – these may result from Pneumocystis jirovecii pneumonia, lymphoid interstitial pneumonitis, tuberculosis, bacterial pneumonia or fungal pneumonia

b. gastrointestinal – diarrhoea or weight loss as a result of cryptosporidiosis, microsporidiosis, mycobacterial infection or cytomegalovirus (CMV) colitis; odynophagia as a result of oesophageal candidiasis, herpes simplex or CMV ulceration; vomiting and abdominal pain owing to biliary tract disease; drug side-effects (e.g. didanosine-induced pancreatitis) – diarrhoea is usual when patients are treated with protease inhibitors

c. neurological – meningism caused by cryptococcal meningitis, focal neurological symptoms or seizures as a result of space-occupying lesions, toxoplasmosis or non-Hodgkin’s lymphoma; cognitive decline as a result of HIV dementia or multifocal leucoencephalopathy; peripheral nervous system disease owing to peripheral neuropathy, CMV radiculopathy or myopathy

d. renal – nephrotic syndrome from HIV-associated nephropathy; renal failure owing to sepsis or drug side-effects

e. ocular – deteriorating vision, which usually suggests advanced CMV retinitis

f. dermatological – rashes may be caused by drug reactions, viral infection (e.g. herpes zoster virus (HZV) or herpes simplex virus (HSV)) or fungal infection; itch may be caused by scabies or drug reaction; and nodules can be caused by Kaposi’s sarcoma (Fig 13.1) or bacillary angiomatosis. Seborrhoeic dermatitis and psoriasis occur commonly


FIGURE 13.1 Kaposi’s sarcoma on the leg. The lesion is reddish-brown because of its vascular nature and accompanying hemosiderin deposition. J P Piccini, K R Nilsson. The Osler medical handbook, 2nd edn. Plate 19. © 2006 The Johns Hopkins University.

g. mouth – ulcers (aphthous or viral) (Figs 13.2 and 13.3), gingivitis, periodontal disease, hairy leucoplakia or candidiasis


FIGURE 13.2 Viral mouth ulcer. Immunocompromised patient with tongue ulcer and fissures secondary to herpes simplex virus. W D James, T Berger, D Elston. Andrews’ diseases of the skin: Clinical dermatology, 11th edn. Fig. 19-12. Saunders, Elsevier, 2011, with permission.


FIGURE 13.3 Recurrent intraoral herpes simplex in an adult with numerous, widely scattered vesicles and ulcers in association with pain, tenderness and fever. D W Flint, B H Haughey, V J Lund et al. Cummings otolaryngology: Head and neck surgery, 5th edn. Fig 91-32. Mosby, Elsevier, 2010, with permission.

h. cardiac – dyspnoea, chest pain or palpitations owing to myocarditis or pericarditis

i. haematological – anaemia (bone marrow suppression or infiltration, treatment with zidovudine); thrombocytopenia and neutropenia are less common.

7. Ask about previous treatment. Find out about antiretroviral drug and antibiotic treatment and about any adverse effects of these. Enquire about specific side-effects (see Table 13.5). If the disease has recently been diagnosed, ask what treatment options have been discussed with the patient.

Table 13.5

Side-effects of selected antiretroviral drugs


8. Ask about previous investigations. The patient may be able to give much helpful information on previous investigations, including viral load results, T cell CD4+ counts, MRI scans, CT scans, lumbar punctures, bone marrow biopsies and endoscopy.

9. Enquire about social, drug and alcohol history. The examiners will expect quite detailed knowledge of the patient’s social, economic and family circumstances.

10. Ask about risk factors and treatment for cardiovascular disease.

The examination

Note especially:

1. temperature

2. nutritional state (wasting is common in advanced disease); there may be fat loss on the face and fat gain over the limbs (retroviral drug effect)

3. skin (e.g. rashes – seborrhoeic dermatitis (Fig 13.4), molluscum contagiosum – pigmentation and the lesions of Kaposi’s sarcoma)


FIGURE 13.4 The hands of a patient with psoriatic arthritis and HIV infection. M C Hochberg, A J Silman, J S Smolen et al. Rheumatology, 5th edn. Fig 107.1. Mosby, Elsevier, 2010, with permission.

4. mouth (e.g. hairy leucoplakia, Kaposi’s sarcoma lesions, periodontal disease, HSV mouth ulcers)

5. eyes – acuity, visual fields and fundoscopy (e.g. CMV retinal lesions)

6. cognition, gait and coordination (e.g. AIDS dementia)

7. chest – cough, sputum, crackles (e.g. opportunistic chest infection)

8. heart – cardiac failure, pericardial disease (e.g. AIDS cardiomyopathy)

9. abdomen – rectal examination, perianal disease (especially warts and HSV)

10. haematological system – lymph nodes and spleen.


The patient is likely to have had many tests.

1. The standard screening test for HIV is an ELISA or enzyme immunoassay (EIA) test. It tests against antigens of both HIV1 and HIV2 (very rare in Australia). It has a sensitivity of more than 99%. Its specificity in low-risk populations is only about 90%. False positives can occur related to recent vaccinations, other viral infections and autoimmune diseases. The earliest detectable test is an HIV PCR DNA (within a few days of inoculation).

2. The western blot test is more specific and a negative western blot means a positive EIA test is a false positive.

3. Other tests are used to assess the severity of the illness and immunocompromisation, and to look for associated conditions (e.g. syphilis) and complications. The currently relevant tests will depend on the clinical presentation; however, certain tests are essential for all patients, either as a baseline or for monitoring (see Table 13.6).

Table 13.6

Routine initial investigations for HIV patients



1. Immune function needs to be established at this point with a full blood count, CD4+ level (levels >200 cells/μL are associated with opportunistic infections) and HIV plasma serum viral load.

2. A delayed-type hypersensitivity skin test will help define cellular immune function. The lower the CD4+ (T helper cell) level (Table 13.7) and the higher the HIV viral load, the more advanced the infection. CD4+levels may fall progressively to undetectable levels. Aggressive treatment of infections may allow continued survival of patients despite these low CD4+ levels. Antiviral treatment may slow CD4+ depletion or stabilise it for many years. About 5% of infected patients do not develop a reduction in CD4+ counts even after more than 10 years without treatment. These patients are called ‘non-progressors’.

Table 13.7

CD4+ level and common clinical features


3. It should also be established whether the patient has concurrent sexually transmitted disease (syphilis serology, hepatitis B serology) or tuberculosis (tuberculin test), and whether he or she is at risk of activation of latent infection (CMV, toxoplasma serology).

4. Renal and liver function should be checked prior to commencing antiviral drugs.


The key investigations for monitoring progress are the HIV plasma viral load and the CD4+ T cell count. Serial full blood counts and biochemistry will help assess any complications of disease or therapy.

Treatment (Table 13.8)

Table 13.8

Longer term management considerations for HIV patients


1. Candidates will be expected to know the clinical features and general treatment options for common complications of HIV infection, especially opportunistic infection and malignancy. This list would include P. jiroveci (carinii) pneumonia, Kaposi’s sarcoma, cerebral toxoplasmosis, CMV infection, Mycobacterium avium complex (MAC) infection, diarrhoeal syndromes and cryptococcal meningitis.

2. Prophylaxis for P. jirovecci with cotrimoxazole or pentamidine (if CD4+ count <200 cells/μL) and MAC with azithromycin (if CD4+ count <50 cells/μL) is an important consideration. If the CD4+ count is >200 cells/μL for three months, prophylaxis can be ceased. Pneumococcal vaccination is routine even when the CD4+ count remains >300 cells/μL.

3. Herpes simplex prophylaxis with acyclovir and Candida prophylaxis with fluconazole or ketoconazole are appropriate for prevention after one episode has occurred.

4. Multiple antiretroviral agents are now available for the treatment of HIV (see Table 13.5). Known as HAART (highly active antiretroviral therapy), these drugs in combination have dramatically improved quality of life and life expectancy in HIV disease.

5. Some doubt remains as to the optimal time to commence therapy. It is clear that symptomatic patients, or those with an increasing viral load (>20 000 copies/mL) or a falling CD4+ count (<350 cells/μL) are definite indications, but many clinicians prefer to commence treatment before this. Pregnancy, HIV-associated nephropathy and co-infection with hepatitis B are other indications. Drugs should be used only in combination to prevent emergence of resistance and most regimens contain three or more drugs. Treatment is not curative and must be continued indefinitely.

6. Regimens can be changed if there is evidence of disease progression. HAART reduces the risk of vertical transmission and probably also the risk of seroconversion following occupational exposure (e.g. needlestick injury), if given promptly.

7. Resistance testing is indicated for the treatment of the naive patient, or if treatment is failing and will be changed.

8. In pregnancy, the aim of therapy is to make the patient’s viral load undetectable. If the HIV RNA is more than 1000 copies, recommend caesarean section. Treat the mother with zidovudine as an infusion during labour, and treat the infant for 6 weeks.

9. Patients co-infected with HBV should have anti-viral treatment that is also effective for that (e.g. lamivudine, emtracitabine). Surveillance for the development of hepatic carcinoma is also indicated for these patients. For patients with HCV, wait until CD4 < 200 to avoid flares. Special care with drug monitoring is necessary if the patient has cirrhosis; zidovudine and didanosine should be avoided.

10. Patients whose disease is well controlled by antiviral agents are more likely to die of cardiovascular disease than infection. This is partly as a result of their drug treatment (e.g. with protease inhibitors). Aggresive control of cardiovascular risk factors is indicated. Hyperlipidaemia should be treated with pravastatin (which has less interaction with antiviral drugs).