The new england journal of
clinical problem-solving
From Methodist Hospital, Indianapolis
(D.R.K.); and the Department of Internal
Medicine, University of Michigan Medical
School (S.A.F., S.S.), and the Department
of Veterans Affairs Health Services Re-
search and Development Center of Excel-
lence (S.S.) — both in Ann Arbor, Mich.
Address reprint requests to Dr. Kaul at the
Division of Infectious Diseases, University
of Michigan Medical Center, Ann Arbor, MI
48109, or at kauld@umich.edu.
N Engl J Med 2005;352:1914-8.
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1914
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medicine
Clear as Mud
Daniel R. Kaul, M.D., Scott A. Flanders, M.D., and Sanjay Saint, M.D., M.P.H.
In this Journal feature, information about a real patient is presented in stages (boldface type)
to an expert clinician, who responds to the information, sharing his or her reasoning with
the reader (regular type). The authors’ commentary follows.
A 17-year-old boy presented to his primary care physician, reporting four days of low
back pain, a temperature as high as 40°C, headache, diffuse myalgias, and vomiting.
The patient had previously been healthy. He lived in the central Midwest and was
about to begin his senior year in high school. He said that he did not use drugs or al-
cohol and he was not sexually active. He played on his high-school football team.
The patient’s initial presentation is consistent with a viral syndrome, possibly gastro-
enteritis. Although low back pain is nonspecific, several serious disorders need to be
considered, since he is also febrile. Further history taking and a physical examination
should focus on ruling out pyelonephritis, epidural abscess, and vertebral osteomyeli-
tis, all of which are relatively uncommon in a 17-year-old. Headache and fever raise the
possibility of bacterial or viral meningitis.
The results of laboratory tests performed at the physician’s office revealed a creatinine
level of 7.5 mg per deciliter (663.0 µmol per liter), with a level of blood urea nitrogen of
58 mg per deciliter (20.7 mmol per liter). The serum sodium level was 133 mmol per
liter; the levels of electrolytes were otherwise normal. Urinalysis showed 20 to 50 red
cells per high-power field, 5 to 10 white cells per high-power field, and no casts. The
hemoglobin level was 12.2 g per deciliter, and the platelet count and white-cell count
were both normal, with a normal differential count. The total bilirubin level was 10
mg per deciliter (171 µmol per liter), the alkaline phosphatase level 146 U per liter
(normal range, 30 to 130), the aspartate aminotransferase level 24 U per liter (normal
range, 2 to 35), and the alanine aminotransferase level 69 U per liter (normal range,
0 to 45); the levels of serum amylase and lipase were normal.
What initially sounded like a benign viral syndrome now seems more ominous. Given
the acuity of the symptoms, I still suspect an infectious cause. The patient needs to be
hospitalized for his renal failure. Although his vomiting puts him at risk for prerenal
azotemia due to volume depletion, the ratio of blood urea nitrogen to creatinine of less
than 20 argues more for an intrinsic renal process. The absence of casts does not rule
out a glomerulonephritis, and his urine should be carefully analyzed for dysmorphic
red cells. Acute obstruction should be ruled out by renal ultrasonography. Rhabdomy-
olysis is a consideration given the patient’s diffuse myalgias. Anemia in the setting of
hyperbilirubinemia raises the concern for hemolysis, and a blood smear should be pre-
pared. However, his normal platelet count argues against a microangiopathic process,
and I would not expect the bilirubin level to be greater than 5 mg per deciliter (86 µmol
per liter) with hemolysis unless there were underlying liver disease or a conjugating de-
fect. An acute hepatitis should cause higher elevations of aminotransferase levels when
jaundice is present, and biliary obstruction should be associated with a higher eleva-
tion of the serum alkaline phosphatase level, but should be ruled out with an ultrason-
n engl j med 352;18 www.nejm.org may 5, 2005
The New England Journal of Medicine
Copyright © 2005 Massachusetts Medical Society. All rights reserved.
 clinical problem-solving

ographic evaluation. Hyperbilirubinemia of sepsis when the patient arrived at the tertiary care hospi-
or drug ingestion should be strongly considered. tal included a platelet count of 60,000 cells per cubic
millimeter, a blood smear without schistocytes, an
The patient was admitted to his local hospital for elevated fibrinogen level, at 679 mg per deciliter,
hydration. Blood cultures were obtained, and the and normal results on measures of prothrombin
patient began drug therapy with piperacillin and time, partial thromboplastin time, haptoglobin, se-
tazobactam. Abdominal ultrasonography revealed rum lactate dehydrogenase, and creatine kinase.
normal-size kidneys without any evidence of ob- The sedimentation rate was 64 mm per hour, and
struction. Hepatomegaly with increased echo- the results of both direct and indirect Coombs’ tests
genicity of the liver was noted; the gallbladder was were negative. Chest radiography showed small
small and contracted, and there was no ductal dila- lung fields with possible cardiomegaly.
tation. The following day, the patient’s creatinine
level increased to 10.4 mg per deciliter (919.4 µmol The additional history is helpful. First, the illness
per liter), and he was transferred to a tertiary care started with a rash. In the absence of travel, I am
hospital. considering Epstein–Barr virus infection, viral hep-
atitis, acute human immunodeficiency virus (HIV)
The ultrasonographic examination rules out an ob- infection, and meningococcemia. Second, the pa-
struction of urinary outflow as well as acute biliary tient’s environmental exposures put him at risk for
obstruction. A rising level of creatinine despite fluid illnesses such as Rocky Mountain spotted fever,
resuscitation could indicate the onset of acute tu- ehrlichiosis, and — given his exposure to standing
bular necrosis after prolonged renal hypoperfusion, water — leptospirosis with Weil’s syndrome.
but I continue to worry about an acute glomerular His physical examination is notable for a normal
or interstitial process. Hepatomegaly with increased blood pressure and only mild tachycardia. If he were
echogenicity on ultrasonography is most often seen in septic shock, I would have expected more se-
with fatty liver, an infiltrating process, or early cir- vere hemodynamic instability. His back and mus-
rhosis, but this finding is not specific for any single cle pain seem greater than would be expected with
entity. viral myalgias. Patients with rickettsial diseases
as well as leptospirosis can have such severe myal-
On arrival at the referral hospital, the patient was gias. A localized infection, such as an epidural ab-
in moderate distress and said that he had back and scess, should be ruled out with further imaging.
muscle pain. He was oriented to name only. His The change in mental status is a cause for concern.
temperature was 37.4°C, his pulse 98 beats per This change may be due to worsening uremia, but
minute, and his blood pressure 131/72 mm Hg. in the setting of thrombocytopenia, hemorrhage in
His conjunctivae were injected. His lungs were the central nervous system should be ruled out by
clear to auscultation, and he had no murmurs or ad- computed tomography (CT) of the patient’s head,
ditional heart sounds. His abdomen was not tender. and a lumbar puncture should be performed to rule
Linear excoriations were visible on his feet and ab- out meningitis. Conjunctival injection is nonspecif-
domen, but no other skin lesions were seen. Fur- ic and accompanies many viral infections, but it is a
ther history obtained from his parents revealed prominent finding with leptospirosis.
that the patient had had a faint erythematous rash The patient is now thrombocytopenic, which
on his torso along with his initial symptoms, and could be explained by disseminated intravascu-
his parents had observed him scratching it; the lar coagulation, but this usually also leads to a low
rash resolved within two days. The patient had no fibrinogen level and elevated coagulation values;
known exposure to animals or toxins and no con- thrombotic thrombocytopenic purpura, in turn,
tact with sick people, recent travel, or family history should result in the presence of schistocytes and a
of any rheumatic disease. In mid-July, two weeks markedly elevated serum lactate dehydrogenase lev-
before his illness, he and a friend rode all-terrain el. It is also important to note that several of the in-
vehicles through a state recreation area that in- fections already considered, such as Rocky Moun-
cluded a lake and wetlands, and his mother noted tain spotted fever, ehrlichiosis, and leptospirosis,
that the patient was covered in mud when he re- can cause isolated thrombocytopenia. Vasculitis is
turned home. still a possibility, but my leading consideration re-
The results of laboratory studies performed mains an acute infectious process. In order to treat

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 The new england journal of medicine

rickettsial diseases and leptospirosis, I would add leptospira antibodies are common in the acute
doxycycline to his regimen. phase of leptospirosis, which is why convalescent
titers are needed to make the diagnosis. I remain
Doxycycline was added to piperacillin and tazo- concerned about this possibility. Samples of serum
bactam, and hemodialysis was initiated. CT scan- and urine can be cultured, but the organism often
ning performed without the administration of takes weeks to grow. In any case, the patient is re-
intravenous contrast material revealed small bilat- ceiving appropriate therapy for leptospirosis. He
eral pleural effusions with bibasilar infiltrates and does not appear to have a systemic autoimmune
a small amount of free pelvic fluid. Echocardiogra- disease that warrants immunosuppressive therapy
phy revealed a slight increase in the size of the left and he has no apparent neoplasm. Given the
ventricle, without valvular abnormalities, pericar- thrombocytopenia, a bone marrow biopsy may be
dial thickening, or effusion. Repeated abdominal required if his condition does not improve and if a
ultrasonographic imaging showed normal kid- cause is not found soon.
neys and hepatomegaly with hepatic parenchymal
inhomogeneity consistent with edema. The patient was started on prednisone at 1 mg per
kilogram of body weight per day, and his treatment
Most of the findings on diagnostic testing are non- with piperacillin and tazobactam was changed to
specific and do not dramatically narrow the differ- aqueous penicillin G. Doxycycline therapy and he-
ential diagnosis. The pulmonary infiltrates and modialysis were continued. Within 48 hours, the
pleural effusions are probably due to the diffuse in- patient’s mental status returned to normal, his ap-
flammatory process rather than to pneumonia or a petite improved, and his fever resolved. One week
pulmonary–renal syndrome. The abdominal CT is later, his bilirubin level was down to 1.4 mg per
of limited value in the absence of contrast material, deciliter (23.9 µmol per liter), and his platelet count
but did not reveal any masses or evidence of an ab- increased to 276,000 cells per cubic millimeter.
dominal catastrophe. I continue to be concerned After 10 days of treatment, doxycycline was discon-
about ruling out a process of the central nervous tinued and the intravenous penicillin was changed
system. to oral penicillin. His urine output increased, and
dialysis was discontinued after 16 days. Blood and
A renal biopsy revealed a marked infiltrate that in- urine cultures for leptospira remained negative,
cluded lymphocytes, neutrophils, and eosinophils and serologic tests for Rocky Mountain spotted
in the interstitium. Immunofluorescence and elec- fever and ehrlichia were negative.
tron microscopical studies of multiple glomeruli
revealed no abnormalities. The results of addition- Systemic corticosteroids may be helpful in some
al tests were negative, including viral hepatitis se- cases of interstitial nephritis, usually in conjunc-
rologic studies and tests for antinuclear antibody, tion with the removal of an offending drug or with
glomerular basement membrane antibody IgG, treatment of the underlying infectious cause. The
rheumatoid factor, HIV antibody, and indirect hem- rapid resolution in this case adds to my suspicion
agglutinin antibody for leptospira. The results of that the patient has leptospirosis with Weil’s syn-
complement studies were within normal limits. A drome. Either penicillin or doxycycline is most
24-hour urinary protein measurement was 678 mg. commonly used to treat leptospirosis. The diagno-
sis is often confirmed on the basis of positive cul-
The renal-biopsy findings and laboratory results tures after four to six weeks of growth or a rise in
argue against an acute glomerular process or a pul- antibody titers during the convalescent phase of
monary–renal syndrome. The negative test for an- the illness.
tinuclear antibody and the normal complement lev-
els reduce the likelihood of a diagnosis of lupus Tapering of prednisone was begun; all antibiotics
erythematosus or an infection-related (e.g., post- were discontinued when a three-week course with
streptococcal) glomerulonephritis. The marked cel- oral penicillin was completed. Just before dis-
lular infiltrate in the biopsy specimen is consistent charge, a repeated leptospira test — on a blood
with a tubulointerstitial process. This finding is sample sent to the laboratory 10 days after admis-
nonspecific and can be caused by infection, drugs, sion — was positive at a titer of 1:1600. The health
or immune-mediated diseases. Negative tests for department in the county in which the patient had

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 clinical problem-solving
ridden his all-terrain vehicle was contacted, as was
the family of the boy who rode with him. No addi-
tional cases were reported. The patient was seen at
a follow-up visit three weeks later. His serum cre-
atinine level was 1.1 mg per deciliter (97.2 µmol
per liter) and, except for mild hypertension requir-
ing medical treatment, he had returned to his pre-
vious state of health.
commentary
A hallmark of a skilled clinician is the ability to
identify quickly a pattern suggesting a given diag-
nosis when presented with clinical information.
Although learning how to recognize patterns is a
skill that is emphasized during medical training,1
substantial clinical experience is required before
this skill is mastered. In the present case, conjunc-
tival injection, isolated hyperbilirubinemia, and re-
nal failure followed a febrile illness in an otherwise
healthy young man. The discussant recognized this
pattern as characteristic of leptospirosis. Crucial to
the discussant’s ability to limit the differential di-
agnosis was his recognition of the importance of the
patient’s exposure history. Because there was no
known drug use or toxic ingestion (such as mush-
room poisoning), it was unlikely that either of these
caused the patient’s renal and hepatic failure. In
contrast, his history of exposure to standing water
was a sentinel clue to the correct diagnosis. Expo-
sure to the rural wetlands of the central United
States could have put the patient at risk for lepto-
spirosis, rickettsial disease, tularemia, ehrlichiosis,
hantavirus infection, histoplasmosis, or babesiosis.
The diagnosis of an uncommon disease usually
hinges on recognizing an unusual combination of
clinical findings (pattern recognition), as occurred
in the case under discussion, or on obtaining the
result of a highly specific diagnostic test after nu-
merous laboratory studies have been performed
(sometimes referred to as a “gropagram” evalua-
tion). The diagnosis of leptospirosis generally re-
lies on serologic testing, although urine, blood, or
spinal fluid may be cultured soon after infection.
Culture requires special media and meticulous han-
dling, and as long as four months may be required
to isolate the organism.2 Antibiotic therapy reduc-
es the yield, and thus it is not surprising that cul-
tures were negative in the present case.
Polymerase-chain-reaction testing may allow an
earlier diagnosis, but it is not yet widely available.3
n engl j med 352;18 www.nejm.org
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The microscopic agglutination assay, the gold-stan-
dard serologic test, requires specialized facilities
and is time-consuming. An indirect hemagglutinin
assay, used in this case, relies on the agglutination
of human red cells coated with leptospira antigens
when antibody-containing serum from the patient
is added. The assay does not distinguish between
IgM or IgG, and the sensitivity varies according to
the serogroup of leptospira present in a particular
geographic area.4 In comparison with other tests,
the newer IgM enzyme-linked immunosorbent as-
says detect antibodies sooner after infection, but
they have a sensitivity of 70 percent or less in acute
disease.5 Seroconversion may occur late; in as many
as 1 in 10 patients, seroconversion does not occur
within 30 days.2 Thus, the early negative serologic
results seen in this case are not unusual.
Leptospirosis is a spirochetal disease that is
found throughout the world. Leptospires infect a
broad array of wild and domestic mammals, which
then excrete leptospires in their urine and contam-
inate lakes or standing water. Human infection
usually occurs through contact with this water6
and has an average incubation period of 5 to 14
days.2 Although most cases are mild and self-limit-
ed, leptospirosis characterized by renal and hepat-
ic dysfunction (accounting for 10 percent of cases)
is associated with a mortality as high as 40 per-
cent.2 In addition, pulmonary hemorrhage may oc-
cur, in which case the disorder may be difficult to
distinguish from other causes of a pulmonary–renal
syndrome.7 Patients who survive severe leptospi-
rosis generally recover completely, but mild renal
failure may persist in a minority of cases.8
Oral doxycycline, ampicillin, or penicillin is the
recommended treatment for mild leptospirosis, and
intravenous penicillin G or ampicillin is recom-
mended for more severe disease.2 A meta-analysis
of three randomized, controlled trials comparing
either penicillin or doxycycline with placebo showed
no significant effect on mortality, but revealed a re-
duction in the hospital stay, the duration of fever,
and the number of spirochetes in urine.9-12 In ad-
dition, prophylactic doxycycline has been shown
to prevent illness in soldiers training in an area
where the disease is endemic.13 As is the case with
other diseases caused by spirochetes, such as sec-
ondary syphilis or relapsing fever, antibiotic treat-
ment may result in a Jarisch–Herxheimer reaction
characterized by fever, rigors, and hypotension.2
Correctly diagnosing a particular infectious dis-
may 5, 2005 1917
 clinical problem-solving

ease, especially one that is caused by an organism
that is difficult to culture, often requires a detailed
history designed to elicit potential exposures to any
of a variety of agents. Occasionally, it is only after
we ask about the “mud” that the picture becomes
clear.
Supported by a Career Development Award from the Health Ser-
vices Research and Development Program of the Department of Vet-
erans Affairs and a Patient Safety Developmental Center Grant from
the Agency for Healthcare Research and Quality (P20-HS11540)
(both to Dr. Saint).
We are indebted to Barbara Haehner-Daniels, M.D., for her clini-
cal care of the patient.

refer enc es
1. Dunn MM, Woolliscroft JO. Assessment
of a pattern-recognition examination in a
clinical clerkship. Acad Med 1994;69:683-4.
2. Tappero JW, Ashford DA, Perkins BA.
Leptospira species: leptospirosis. In: Mandell
GL, Bennett JE, Dolin R, eds. Mandell, Doug-
las, and Bennett’s principles and practice
of infectious disease. 5th ed. Philadelphia:
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3. Smythe LD, Smith IL, Smith GA, et al.
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4. Effler PV, Domen HY, Bragg SL, Aye T,
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5. Vinetz JM. Leptospirosis. Curr Opin
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Leptospirosis: a zoonotic disease of global
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7. Luks AM, Lakshminarayanan S, Hirsch-
mann JV. Leptospirosis presenting as dif-
fuse alveolar hemorrhage: case report and
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8. Covic A, Goldsmith DJ, Gusbeth-
Tatomir P, Seica A, Covic M. A retrospective
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review of the literature. Nephrol Dial Trans-
plant 2003;18:1128-34.
9. Edwards CN, Nicholson GD, Hassel TA,
Everard CO, Callander J. Penicillin therapy
in icteric leptospirosis. Am J Trop Med Hyg
1988;39:388-90.
10. Guidugli F, Castro AA, Atallah AN. Anti-
biotics for treating leptospirosis. Cochrane
Database Syst Rev 2000;2:CD001306.
11. McClain JB, Ballou WR, Harrison SM,
Steinweg DL. Doxycycline therapy for lep-
tospirosis. Ann Intern Med 1984;100:696-
8.
12. Watt G, Padre LP, Tuazon ML, et al. Pla-
cebo-controlled trial of intravenous penicil-
lin for severe and late leptospirosis. Lancet
1988;1:433-5.
13. Guidugli F, Castro AA, Atallah AN. Anti-
biotics for preventing leptospirosis. Cochrane
Database Syst Rev 2000;4:CD001305.
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