8

Fever with jaundice and

a purpuric rash
A. FAIZ
Presenting problem
A 35-year-old farmer from a rural area is admitted
to the medical unit with a history of fever for 5 days and
yellowish discoloration of the eyes. He has noticed
darkening of the urine for 2 days and over the last 24h
has developed red spots over his body. The fever is
high-grade and continuous; the patient is mentally alert.
He does not take any regular medication. Prior to referral, a private practitioner carried out some routine blood
tests. The results of these tests are detailed in Box 8.1.

BOX 8.1
Initial investigations
WCC
Bilirubin
AST
Urea
Creatinine

What would your differential diagnosis include

before examining the patient?

16109/L
(103/mm3)
105mol/L
(5mg/dL)
120U/L
13.5mmol/L
(81mg/dL)
159mol/L
(1.8mg/dL)

Urine
examination
Albumin
RBC
Cast

This combination of the presenting problems: fever,

+
jaundice and rash, warrants the consideration of a wide
+
range of diseases in the differential diagnosis, depending
+
on place, period and prevalence. This is a particularly
common problem in the tropics, although it may occur
anywhere in world. The possibilities are falciparum malaria, leptospirosis,
dengue, viral hepatitis and septicaemia. Severe falciparum malaria and lepto
spirosis should always be borne in mind in endemic areas. Jaundice and renal
involvement are recognised complications in both conditions but a rash is unusual
in malaria. However, patients with falciparum malaria can develop purpuric spots
due to thrombocytopenia. A patient with acute viral hepatitis or dengue may
present with this type of picture. In acute viral hepatitis, the fever is low-grade
and usually precedes jaundice and bleeding, though this is not an absolute rule.
Similarly, in dengue haemorrhagic fever (DHF), bleeding usually occurs once
the febrile episode is over; hepatic involvement may complicate the initial febrile
phase and renal involvement is rare. Septicaemia culminating in disseminated
intravascular coagulation is also a strong possibility. Rickettsial diseases should
also be considered in areas where such infections are prevalent. Patients may
have a tell-tale eschar and brain involvement. Yellow fever should also be con
sidered in areas where the disease is endemic; it does not occur in Asia. Brady
cardia and leucopenia are observed.
The initial investigations in this patient show leucocytosis and mild renal
impairment. These two features favour the diagnosis of leptospirosis, but may
25

Figure 8.1 Bilateral conjunctival haemorrhages

and scleral jaundice in a patient with
leptospirosis.

also occur in septicaemia and severe malaria. A leucocytosis is unlikely in dengue

and viral hepatitis.
Examination
The patient is slightly pale and icteric. He has a widespread purpuric rash
with conjunctival haemorrhages (Fig. 8.1). His pulse and blood pressure are
normal. The liver is enlarged but there is no splenomegaly. The lungs are clear.
Has examination narrowed down your differential diagnosis?

Anaemia, jaundice, renal dysfunction and hepatomegaly are common in lepto

spirosis and severe malaria. A purpuric rash and conjunctival congestion are
features of both leptospirosis and DHF.
Dengue infections are a major cause of morbidity and mortality in the tropical
and subtropical regions of the world. Although sporadic cases of dengue can
occur, disease outbreaks or epidemics are much more common. The patient may
have back pain and severe myalgia (break-bone fever). The illness may be mild
and self-limiting, but severe forms of disease such as DHF or dengue shock
syndrome (DSS) can occur. The severe form is characterised by hypovolaemia,
raised haematocrit and low platelet counts. Endothelial permeability and subse
quent plasma leakage are important pathological features of DHF. Patients may
develop unilateral or bilateral pleural effusions, ascites or a perihepatic collection
of fluid. Typically, gallbladder wall thickening occurs. These findings can be
detected on ultrasonography of the abdomen and chest. The exact cause for the
drop in the platelet count is not known. Mechanisms include transient suppres
sion of haematopoiesis and immune-mediated platelet clearance. Bleeding can
occur from several sites, such as the gastrointestinal tract, lungs and nose. Intra
cranial haemorrhage can be fatal. Hypotension or shock occurs in severe cases.
Leptospirosis requires serious consideration in this patient because he has a
leucocytosis and hepatic and renal dysfunction, in addition to a purpuric rash.
Leptospirosis is common in the tropics. Recent large outbreaks have been
described in Asia, Central and South America and the USA. The disease appears
to be ubiquitous in wildlife and in many domestic animals. The most frequent
host is a rodent, especially the common rat. The organisms persist indefinitely in
the convoluted tubules of the kidney without causing apparent disease, and are
shed into the urine periodically. Leptospires can enter human hosts through intact
skin or mucous membranes, but entry is facilitated by cuts or abrasions. This
spirochaete can survive in water for months. Our patient is a farmer; certain
occupational groups are at high risk and these include agricultural workers,
26

Fever with jaundice and a purpuric rash

sewage workers, veterinarians, workers in abattoirs and those in the fishing
industry. People engaged in recreational water activities are also likely to acquire
the infection. After a brief period of bacteraemia, leptospires are distributed
throughout the body. The main organs affected in humans are the kidneys, liver,
meninges and brain. Leptospires damage the wall of small vessels, leading to
vasculitis, which is ultimately responsible for several manifestations of the
disease, including haemorrhages and hypovolaemia. In some patients, a nonoliguric hypokalaemic renal failure can occur at an early stage of leptospirosis.
Moderate to severe hypokalaemia, if present, is a useful laboratory parameter to
differentiate leptospirosis from other infectious causes of acute renal failure. Our
patient has a purpuric rash and hepatic and renal dysfunction. Leptospirosis does
not usually cause marked hepatocellular necrosis. However, it can produce severe
disease, known as Weils syndrome, characterised by hepatic and renal dysfunc
tion with bleeding manifestations. Centrilobular necrosis with Kupffer cell hyper
plasia is seen in the liver histopathology.
Hepatic involvement in leptospirosis requires differentiation from acute viral
hepatitis. In leptospirosis, fever and jaundice occur concomitantly, whereas in
acute viral hepatitis, fever is frequently low-grade and is followed by the onset
of jaundice. In contrast to acute viral hepatitis, leptospirosis produces large
increases in serum bilirubin and alkaline phosphatase, and a modest increase in
hepatic enzymes (up to 200U/L), whereas viral hepatitis causes a several-fold
increase in the hepatic enzymes (often >1000U/L) and a modest increase in
serum bilirubin. In addition, creatine phosphokinase may be elevated during the
first week in nearly half of the cases of leptospirosis. In severe cases, rhabdomy
olysis occurs and contributes to renal dysfunction. Rarely, a fatal pulmonary
syndrome may occur in severe leptospirosis due to haemorrhage in the lungs.
This syndrome may produce acute respiratory failure. Narrowing down of the
differential diagnosis requires further investigations.

Further investigations
The results of further investigation are provided in Box 8.2.
Does this narrow down your differential diagnosis?

The negative results of thick and thin films, as well as the dipstick test for
malaria, make it most unlikely that the patient is suffering from severe malaria.
Dengue and rickettsial fever have also been excluded. Leptospirosis remains a
BOX 8.2
Further investigations
Thick and thin peripheral blood film for malarial parasites
Immunochromatographic dipstick test for falciparum malaria
Bilirubin
ALT
AST
Prothrombin time
Haemoglobin
Platelets
Blood culture
Blood tests for dengue antigen and antibody
Rickettsia group-specific microscopic agglutination test

Negative
Negative
105mol/L (5mg/dL)
170U/L
240U/L
12s (control 12s)
90g/L (9g/dL)
150109/L (103/mm3)
Negative
Negative
Negative

27

strong possibility in this case, but definitive diagnostic tests are required for its
confirmation.
The definitive diagnosis of leptospirosis depends upon the isolation of the
organism, serological tests or detection of specific DNA. Blood cultures may be
positive if taken before the 10th day of the illness and leptospires appear in the
urine during the second week of illness. The serological investigation of choice
is the microscopic agglutination test (MAT). Enzyme-linked immunosorbent
assay (ELISA) and immunofluorescent assays are also available. Polymerase
chain reaction (PCR) shows great promise in detecting leptospiral DNA in blood
in early symptomatic disease; it is positive in the urine from the 8th day onward
and remains positive for many months afterwards.
Definitive investigations
Leptospires are isolated from a urine specimen and so the final diagnosis
is leptospirosis.
How will you treat this patient?

Intravenous benzylpenicillin is administered as 1.5 mega-units 6-hourly for 1

week or doxycycline in oral doses of 100mg 12-hourly for 1 week. Parenteral
ceftriaxone 1g daily or cefotaxime 1g 6-hourly is equally as effective as penicil
lin. Rarely, a Jarisch Herxheimer reaction can occur during initiation of antibiotic
treatment. The patients renal failure should be monitored closely; if deterioration
occurs, peritoneal or haemodialysis may be life-saving. The general care of the
patient is critically important. Blood should be taken early for grouping and
cross-matching. Episodes of bleeding should be treated by prompt blood transfu
sion. Higher mortality rates have been reported in elderly patients, those with
Weils syndrome and severe pulmonary haemorrhage syndrome.

More on
leptospirosis?

Key points and global issues

Dengue is endemic in South-east Asia and India, and is also seen in
Africa.

See Chapter 13 of
Davidsons Principles
& Practice of
Medicine (21st edn)

Viral haemorrhagic fever produces a non-specific syndrome and can

be caused by several different viruses. It should be included in the differential
diagnosis because of the increase in international travel.
African haemorrhagic fever due to Marburg and Ebola viruses can present
with haemorrhage and hepatitis but renal involvement is absent.
Malaria occurs throughout the tropics and subtropics at altitudes below 1500
metres.
Leptospirosis is one of the most common zoonotic diseases, favoured by a
tropical climate and flooding during monsoons.
Leptospirosis control measures should consist of avoidance of exposure to
infected urine/tissues, rodent control and vaccination of animals. Vaccination
of humans (against a specific serovar) has been successful in some Asian
and European countries.
28