Nej m Cps 042340

8/8/2019 Nej m Cps 042340

http://slidepdf.com/reader/full/nej-m-cps-042340 1/5

clinical problem-solving

The new england journal of medicine

n engl j med 352;18

www.nejm.org may 5, 2005

1914

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.

Clear as Mud

Daniel R. Kaul, M.D., Scott A. Flanders, M.D., and Sanjay Saint, M.D., M.P.H.

From Methodist Hospital, Indianapolis(D.R.K.); and the Department of InternalMedicine, University of Michigan MedicalSchool (S.A.F., S.S.), and the Departmentof 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 theDivision of Infectious Diseases, Universityof Michigan Medical Center, Ann Arbor, MI48109, or at [email protected].

N Engl J Med 2005;352:1914-8.

Copyright © 2005 Massachusetts Medical Society.

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 beconsidered, 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-

The New England Journal of Medicine

Downloaded from www.nejm.org on October 1, 2010. For personal use only. No other uses without permission.

Copyright © 2005 Massachusetts Medical Society. All rights reserved.

8/8/2019 Nej m Cps 042340


n engl j med 352;18



1915

ographic evaluation. Hyperbilirubinemia of sepsis

or drug ingestion should be strongly considered.

The patient was admitted to his local hospital for

hydration. Blood cultures were obtained, and the

patient began drug therapy with piperacillin and

tazobactam. Abdominal ultrasonography revealednormal-size kidneys without any evidence of ob-

struction. Hepatomegaly with increased echo-

genicity of the liver was noted; the gallbladder was

small and contracted, and there was no ductal dila-

tation. The following day, the patient’s creatinine

level increased to 10.4 mg per deciliter (919.4 µmol

per liter), and he was transferred to a tertiary care

hospital.

The ultrasonographic examination rules out an ob-

struction of urinary outflow as well as acute biliary

obstruction. A rising level of creatinine despite fluid

resuscitation could indicate the onset of acute tu-bular necrosis after prolonged renal hypoperfusion,

but I continue to worry about an acute glomerular

or interstitial process. Hepatomegaly with increased

echogenicity on ultrasonography is most often seen

with fatty liver, an infiltrating process, or early cir-

rhosis, but this finding is not specific for any single

entity.

On arrival at the referral hospital, the patient was

in moderate distress and said that he had back and

muscle pain. He was oriented to name only. His

temperature was 37.4°C, his pulse 98 beats per

minute, and his blood pressure 131/72 mm Hg.His conjunctivae were injected. His lungs were

clear to auscultation, and he had no murmurs or ad-

ditional heart sounds. His abdomen was not tender.

Linear excoriations were visible on his feet and ab-

domen, but no other skin lesions were seen. Fur-

ther history obtained from his parents revealed

that the patient had had a faint erythematous rash

on his torso along with his initial symptoms, and

his parents had observed him scratching it; the

rash resolved within two days. The patient had no

known exposure to animals or toxins and no con-

tact with sick people, recent travel, or family history

of any rheumatic disease. In mid-July, two weeks

before his illness, he and a friend rode all-terrain

vehicles through a state recreation area that in-

cluded a lake and wetlands, and his mother noted

that the patient was covered in mud when he re-

turned home.

The results of laboratory studies performed

when the patient arrived at the tertiary care hospi-

tal included a platelet count of 60,000 cells per cubic

millimeter, a blood smear without schistocytes, an

elevated fibrinogen level, at 679 mg per deciliter,

and normal results on measures of prothrombin

time, partial thromboplastin time, haptoglobin, se-

rum lactate dehydrogenase, and creatine kinase.The sedimentation rate was 64 mm per hour, and

the results of both direct and indirect Coombs’ tests

were negative. Chest radiography showed small

lung fields with possible cardiomegaly.

The additional history is helpful. First, the illness

started with a rash. In the absence of travel, I am

considering Epstein–Barr virus infection, viral hep-

atitis, acute human immunodeficiency virus (HIV)

infection, and meningococcemia. Second, the pa-

tient’s environmental exposures put him at risk for

illnesses such as Rocky Mountain spotted fever,

ehrlichiosis, and — given his exposure to standing water — leptospirosis with Weil’s syndrome.

His physical examination is notable for a normal

blood pressure and only mild tachycardia. If he were

in septic shock, I would have expected more se-

vere hemodynamic instability. His back and mus-

cle pain seem greater than would be expected with

viral myalgias. Patients with rickettsial diseases

as well as leptospirosis can have such severe myal-

gias. A localized infection, such as an epidural ab-

scess, should be ruled out with further imaging.

The change in mental status is a cause for concern.

This change may be due to worsening uremia, but

in the setting of thrombocytopenia, hemorrhage inthe central nervous system should be ruled out by

computed tomography (CT) of the patient’s head,

and a lumbar puncture should be performed to rule

out meningitis. Conjunctival injection is nonspecif-

ic and accompanies many viral infections, but it is a

prominent finding with leptospirosis.

The patient is now thrombocytopenic, which

could be explained by disseminated intravascu-

lar coagulation, but this usually also leads to a low

fibrinogen level and elevated coagulation values;

thrombotic thrombocytopenic purpura, in turn,

should result in the presence of schistocytes and a

markedly elevated serum lactate dehydrogenase lev-

el. It is also important to note that several of the in-

fections already considered, such as Rocky Moun-

tain spotted fever, ehrlichiosis, and leptospirosis,

can cause isolated thrombocytopenia. Vasculitis is

still a possibility, but my leading consideration re-

mains an acute infectious process. In order to treat




8/8/2019 Nej m Cps 042340


n engl j med 352;18

www.nejm.org may 5

, 2005

The

new england journal of

medicine

1916

rickettsial diseases and leptospirosis, I would add

doxycycline to his regimen.

Doxycycline was added to piperacillin and tazo-

bactam, and hemodialysis was initiated. CT scan-

ning performed without the administration of

intravenous contrast material revealed small bilat-eral pleural effusions with bibasilar infiltrates and

a small amount of free pelvic fluid. Echocardiogra-

phy revealed a slight increase in the size of the left

ventricle, without valvular abnormalities, pericar-

dial thickening, or effusion. Repeated abdominal

ultrasonographic imaging showed normal kid-

neys and hepatomegaly with hepatic parenchymal

inhomogeneity consistent with edema.

Most of the findings on diagnostic testing are non-

specific and do not dramatically narrow the differ-

ential diagnosis. The pulmonary infiltrates and

pleural effusions are probably due to the diffuse in-flammatory process rather than to pneumonia or a

pulmonary–renal syndrome. The abdominal CT is

of limited value in the absence of contrast material,

but did not reveal any masses or evidence of an ab-

dominal catastrophe. I continue to be concerned

about ruling out a process of the central nervous

system.

A renal biopsy revealed a marked infiltrate that in-

cluded lymphocytes, neutrophils, and eosinophils

in the interstitium. Immunofluorescence and elec-

tron microscopical studies of multiple glomeruli

revealed no abnormalities. The results of addition-al tests were negative, including viral hepatitis se-

rologic studies and tests for antinuclear antibody,

glomerular basement membrane antibody IgG,

rheumatoid factor, HIV antibody, and indirect hem-

agglutinin antibody for leptospira. The results of

complement studies were within normal limits. A

24-hour urinary protein measurement was 678 mg.

The renal-biopsy findings and laboratory results

argue against an acute glomerular process or a pul-

monary–renal syndrome. The negative test for an-

tinuclear antibody and the normal complement lev-

els reduce the likelihood of a diagnosis of lupus

erythematosus or an infection-related (e.g., post-

streptococcal) glomerulonephritis. The marked cel-

lular infiltrate in the biopsy specimen is consistent

with a tubulointerstitial process. This finding is

nonspecific and can be caused by infection, drugs,

or immune-mediated diseases. Negative tests for

leptospira antibodies are common in the acute

phase of leptospirosis, which is why convalescent

titers are needed to make the diagnosis. I remain

concerned about this possibility. Samples of serum

and urine can be cultured, but the organism often

takes weeks to grow. In any case, the patient is re-

ceiving appropriate therapy for leptospirosis. Hedoes not appear to have a systemic autoimmune

disease that warrants immunosuppressive therapy

and he has no apparent neoplasm. Given the

thrombocytopenia, a bone marrow biopsy may be

required if his condition does not improve and if a

cause is not found soon.

The patient was started on prednisone at 1 mg per

kilogram of body weight per day, and his treatment

with piperacillin and tazobactam was changed to

aqueous penicillin G. Doxycycline therapy and he-

modialysis were continued. Within 48 hours, the

patient’s mental status returned to normal, his ap-petite improved, and his fever resolved. One week

later, his bilirubin level was down to 1.4 mg per

deciliter (23.9 µmol per liter), and his platelet count

increased to 276,000 cells per cubic millimeter.

After 10 days of treatment, doxycycline was discon-

tinued and the intravenous penicillin was changed

to oral penicillin. His urine output increased, and

dialysis was discontinued after 16 days. Blood and

urine cultures for leptospira remained negative,

and serologic tests for Rocky Mountain spotted

fever and ehrlichia were negative.

Systemic corticosteroids may be helpful in somecases of interstitial nephritis, usually in conjunc-

tion with the removal of an offending drug or with

treatment of the underlying infectious cause. The

rapid resolution in this case adds to my suspicion

that the patient has leptospirosis with Weil’s syn-

drome. Either penicillin or doxycycline is most

commonly used to treat leptospirosis. The diagno-

sis is often confirmed on the basis of positive cul-

tures after four to six weeks of growth or a rise in

antibody titers during the convalescent phase of

the illness.

Tapering of prednisone was begun; all antibiotics

were discontinued when a three-week course with

oral penicillin was completed. Just before dis-

charge, a repeated leptospira test — on a blood

sample sent to the laboratory 10 days after admis-

sion — was positive at a titer of 1:1600. The health

department in the county in which the patient had




8/8/2019 Nej m Cps 042340


n engl j med 352;18



1917

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.

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 otherwisehealthy 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

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 betweenIgM 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, whichthen excrete leptospires in their urine and contam-

inate lakes or standing water. Human infection

usually occurs through contact with this water

6

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 renalfailure 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-

com m en t ary




8/8/2019 Nej m Cps 042340


n engl j med 352;18

www.nejm.org may 5

, 2005

1918


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.

references

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:

Churchill Livingstone, 2000:2495-501.

3.

Smythe LD, Smith IL, Smith GA, et al.

A quantitative PCR (TaqMan) assay for patho-

genic Leptospira spp. BMC Infect Dis 2002;

2:13.

4.

Effler PV, Domen HY, Bragg SL, Aye T,

Sasaki DM. Evaluation of the indirect hem-

agglutination assay for diagnosis of acute

leptospirosis in Hawaii. J Clin Microbiol

2000;38:1081-4.

5.

Vinetz JM. Leptospirosis. Curr Opin

Infect Dis 2001;14:527-38.

6.

Bharti AR, Nally JE, Ricaldi JN, et al.

Leptospirosis: a zoonotic disease of global

importance. Lancet Infect Dis 2003;3:757-

71.

7.

Luks AM, Lakshminarayanan S, Hirsch-

mann JV. Leptospirosis presenting as dif-

fuse alveolar hemorrhage: case report and

literature review. Chest 2003;123:639-43.

8.

Covic A, Goldsmith DJ, Gusbeth-

Tatomir P, Seica A, Covic M. A retrospective

5-year study in Moldova of acute renal fail-

ure due to leptospirosis: 58 cases and a

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.

Copyright © 2005 Massachusetts Medical Society.

view current job postings at the nejm careercenter

Visit our online CareerCenter for physicians at www.nejmjobs.org

to see the ex-

panded features and services available. Physicians can conduct a quick search of the

public data base by specialty and view hundreds of current openings that are updated

daily online at the CareerCenter.




Documents

Nej m Cps 042340