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The n e w e ng l a n d j o u r na l of m e dic i n e

Clinical Problem-Solving

Caren G. Solomon, M.D., M.P.H., Editor

The Devil Is in the Details


Eli Ben‑Chetrit, M.D., Linda Shavit, M.D., Ariella Tvito, M.D., Maya Korem, M.D.,
and Alon Bnaya, M.D.​​

In this Journal feature, information about a real patient is presented in stages (boldface type) to an expert
clinician, who responds to the information by sharing relevant background and reasoning with the reader
(regular type). The authors’ commentary follows.

A 75-year-old woman was admitted to the hospital with a 4-month history of weight From the Infectious Diseases Unit (E.B.-C.),
loss (total weight loss, 8 kg) and night sweats. She reported no fever, arthralgias, the Adult Nephrology Unit (L.S., A.B.), and
the Department of Hematology (A.T.),
cough, abdominal pain, or diarrhea. Shaare Zedek Medical Center, Hebrew
University–Hadassah School of Medi-
The patient presents with nonspecific yet alarming symptoms. The differential cine, and the Department of Clinical
Microbiology and Infectious Diseases,
­
diagnosis is broad. Weight loss and nights sweats may be associated with a ma- Hadassah–Hebrew University Medical
lignant disorder such as lymphoma, inflammatory conditions such as vasculitis, Center (M.K.) — both in Jerusalem. Ad-
or infections. dress reprint requests to Dr. Ben-Chetrit
at the Infectious Diseases Unit, Shaare
Zedek Medical Center, P.O. Box 3235, Jeru-
The patient was born in Morocco. She was a retired cook and lived alone. She had a salem, Israel, or at ­elibc@​­szmc​.­org​.­il.
4-year history of diabetes mellitus that was complicated by microalbuminuria; N Engl J Med 2019;380:581-6.
glucose levels were well controlled with metformin. She reported that she did not DOI: 10.1056/NEJMcps1808400
smoke, consume alcohol, or use illicit drugs. She had no sick contacts or exposure Copyright © 2019 Massachusetts Medical Society.

to animals. Six years earlier, she had visited Morocco, but she had not traveled
since then.
On physical examination, she appeared well. Her temperature was 36.6°C (97.9°F),
blood pressure 150/74 mm Hg, heart rate 88 beats per minute, and respiratory rate
16 breaths per minute. The oxygen saturation was 98% while she was breathing
ambient air. Funduscopic examination did not reveal signs of retinopathy. There
was no thyromegaly. The heart sounds were normal, apart from a systolic murmur
(grade 2/6) over the apex, and the lungs were clear. The abdomen was soft, with no
organomegaly. There was no lymphadenopathy.

Because the patient was originally from Morocco and had visited that country
6 years earlier, tuberculosis should be considered, even in the absence of respiratory
symptoms. The murmur may suggest infective endocarditis, although no fever was
noted. A malignant disorder or an underlying vasculitis still should be considered.

The hematocrit was 27.8%, the mean corpuscular volume 85 fl, and the red-cell dis-
tribution width 13.5%. The white-cell count was 5700 per cubic millimeter, with
79% segmented neutrophils, 6% monocytes, 11% lymphocytes, and 4% eosinophils.
The platelet count was 180,000 per cubic millimeter. The blood smear was normal.
The blood urea nitrogen level was 27 mg per deciliter (9.6 mmol per liter), and the
creatinine level 1.45 mg per deciliter (130 μmol per liter). Four months earlier, the
blood urea nitrogen level had been 19.6 mg per deciliter (7.0 mmol per liter), and
the creatinine level 0.82 mg per deciliter (70 μmol per liter). The glucose level was

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The n e w e ng l a n d j o u r na l of m e dic i n e

160 mg per deciliter (8.9 mmol per liter), sodium cells in the urine may suggest a nephritic com-
134 mmol per liter, potassium 4.9 mmol per liter, ponent, but this finding is nonspecific, and there
calcium 9 mg per deciliter (2.25 mmol per liter), are no casts. Connective-tissue diseases such as
albumin 3.7 g per deciliter, and total protein vasculitis associated with antineutrophil cyto-
8.3 mg per deciliter. Levels of alanine aminotrans- plasmic antibodies (ANCA) and systemic lupus
ferase, aspartate aminotransferase, γ-glutamyl­ erythematosus (SLE) should also be considered.
transferase, alkaline phosphatase, and bilirubin The normal chest radiograph makes tuberculo-
were all normal. The glycated hemoglobin level sis less likely, and the absence of fever and
was 6.9%. The erythrocyte sedimentation rate positive blood cultures argues against infective
was 60 mm per hour. Iron, transferrin, ferritin, endocarditis, although culture-negative endocar-
folic acid, and vitamin B12 levels were within the ditis cannot be ruled out.
normal range. Dipstick urinalysis showed +1
blood and +3 protein. Examination of the urine CT of the chest, abdomen, and pelvis was per-
sediment showed a few red cells but no casts. The formed without the use of contrast material and
ratio of protein to creatinine in the urine was showed no masses, lymphadenopathy, or organo-
6682 mg of protein per gram of creatinine (nor- megaly. A test for antinuclear antibodies was
mal value, <200), and the ratio of albumin to cre- positive at a titer of 1:200, with a homogeneous
atinine in the urine was 2652 mg of albumin per pattern; testing for anti–double-stranded DNA
gram of creatinine (normal range, 0 to 30). Two (dsDNA), anti-Ro, anti-La, anti-Smith, anti-RNP,
sets of blood cultures were sterile. A chest radio- and ANCA was negative. Complement levels (C3
graph was normal. Abdominal ultrasonography and C4) were normal. Tests for cryoglobulins,
showed normal-size kidneys and no hydrone- rheumatoid factor, and hepatitis B and C viruses
phrosis. The liver and spleen were not enlarged. were negative. The IgG level was 2453 mg per
deciliter (normal range, 650 to 1600), IgM 101 mg
The patient has normocytic anemia, worsening per deciliter (normal range, 50 to 300), and IgA
renal function, and nephrotic-range proteinuria. 419 mg per deciliter (normal range, 70 to 400).
Diabetic nephropathy is a leading cause of pro- Serum and urine immunofixation showed a poly-
teinuria in the elderly, but the relatively acute on- clonal pattern. The free kappa:lambda ratio was
set of substantial proteinuria, renal insufficiency, normal.
and systemic symptoms in a patient with well-
controlled diabetes suggests a different glomeru- The CT does not show evidence of cancer or a
lar disease. Membranous nephropathy, minimal focal infection; however, the fact that contrast
change disease, focal segmental glomeruloscle- material was not used limits the interpretation.
rosis, and other glomerulonephritides may be The low titer of antinuclear antibodies and the
primary or secondary causes of nephrotic-range negative test for anti-dsDNA antibodies with
proteinuria in adults. The patient’s weight loss normal complement levels do not support the
and night sweats arouse concern for glomerular diagnosis of SLE, and the negative test for ANCA
disease as a paraneoplastic syndrome. For exam- does not support a diagnosis of ANCA-associated
ple, membranous nephropathy, a common cause vasculitis. The polyclonal gammopathy is incon-
of nephrotic syndrome in elderly persons, may sistent with multiple myeloma and is nonspecific
be associated with solid tumors, and minimal in lymphoproliferative or infectious conditions.
change disease may be associated with Hodgkin’s
lymphoma. Computed tomography (CT) of the A renal biopsy was performed, and the patient
chest, abdomen, and pelvis is warranted to de- was discharged for further follow-up at the ne-
termine whether cancer is present. The marked phrology clinic. Three glomeruli were seen on
discrepancy between the urinary protein-to-creat- light microscopy. Proliferation of mesangial cells
inine ratio and albumin-to-creatinine ratio may — without endocapillary proliferation, crescents,
indicate the presence of a paraprotein and mono- or fibrinoid necrosis — was noted. An interstitial
clonal gammopathy–related renal disease such infiltrate of lymphocytes, plasma cells, and small
as multiple myeloma. Tubular proteinuria should numbers of eosinophils was seen. Immunofluo-
also be considered but is unlikely to explain rescence staining was positive for mesangial IgG
nephrotic-range proteinuria. The finding of red (+2 staining), IgM (+2 staining), and C3 (+1 stain-

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Clinical Problem-Solving

ing), as well as lambda and some kappa light blood urea nitrogen level was 67 mg per deciliter
chains. Immunostaining showed no IgA or C1q. (24 mmol per liter), and the creatinine level was
Electron microscopy showed expansion of mesan- 2.1 mg per deciliter (190 μmol per liter). Salmonella
gial regions and mesangial, paramesangial, and enteritidis was isolated from urine and blood cul-
subendothelial electron-dense deposits (Fig. 1). tures. The patient noted that she had had two epi-
Podocyte morphologic features were preserved. sodes of diarrhea a week earlier. On questioning,
Congo red staining identified no amyloid. she reported that she had consumed undercooked
eggs bought directly from a farmer near her
In general, evaluation of at least 8 to 10 glomer­ home. Intravenous ceftriaxone was administered
uli is recommended for diagnosis. Given that only and resulted in rapid clinical improvement. The
3 glomeruli were sampled, the interpretation of prednisone dose was reduced. The fever resolved,
the kidney biopsy sample is limited. The mesan- and repeat urine and blood cultures were sterile.
gial deposition of IgM, IgG, and C3 suggests an A CT scan obtained without contrast material
immune-complex process. The proliferation of showed mild perinephric stranding of the left
mesangial cells, along with immune deposition kidney and atherosclerotic changes along the aor-
of IgM and complement, raises the possibility of tic arch and descending aorta. After receiving in-
IgM nephropathy, but subendothelial electron- travenous ceftriaxone for 2 weeks, the patient was
dense deposits are not found in this disorder. discharged with instructions to take oral amoxi-
The predominance of lambda free light-chain cillin for 4 weeks.
deposition might suggest monoclonal gammop-
athy–related renal disease, but monoclonal gam- Consumption of undercooked eggs may pose a
mopathy was not detected in blood or urine risk for salmonella infection, and treatment with
samples. The findings on electron microscopy of high-dose glucocorticoids may increase the risk
mesangial and subendothelial electron-dense de- of invasive disease. The most likely source of
posits are consistent with, but not diagnostic of, bacteremia is the gastrointestinal tract. The pres-
membranoproliferative glomerulonephritis, which ence of urinary symptoms, a positive urine cul-
may be mediated by the immune complex (as ture for S. enteritidis, and perinephric stranding of
can be seen in chronic infections, monoclonal the left kidney may suggest an ascending uri-
gammopathy, and autoimmune diseases) or, less nary tract infection, although this route of infec-
commonly, by complement (such as in C3 glo- tion is rare. Nontyphoidal salmonella bacteremia
merulopathy). The findings on light microscopy in an elderly patient should prompt further im-
that are typically seen with membranoprolifera-
tive glomerulonephritis — including cellular
proliferation and characteristic changes of the
glomerular basement membrane, such as “split-
ting” or “tram-tracking” — are not reported, but
it is possible that these findings were missed in
the scant biopsy specimen.
*
At a follow-up appointment 1 month after hospi-
tal discharge, the blood urea nitrogen level had
increased to 50 mg per deciliter (18 mmol per
liter), and the creatinine level had increased to
2.2 mg per deciliter (190 μmol per liter). A 24-
hour urine collection showed 7 g of protein. The
hematocrit was 27.8%, and the white-cell count
was 5300 per cubic millimeter, with 74.5% seg-
mental neutrophils, 7% monocytes, and 15% lym- Figure 1. Renal-Biopsy Specimen.
phocytes. A regimen of prednisone (60 mg daily) Electron microscopy shows subendothelial electron-
was started. dense deposits (asterisk). The morphologic features
Two weeks later, the patient was admitted to of podocyte foot processes are preserved (arrows).
the hospital with fever, chills, and dysuria. The

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The n e w e ng l a n d j o u r na l of m e dic i n e

aging studies to rule out endovascular infection;


noncontrast CT is insensitive for this diagnosis.

Two weeks after discharge, the patient was seen


in the outpatient clinic. She reported that a pru-
ritic rash had developed over the previous 2 weeks.
A diffuse erythematous and violaceous rash with
small plaques, scaling, and desquamation was
seen predominantly on the back, arms, and feet
(Fig. 2). There was no eosinophilia.

Beta-lactam antibiotic agents may cause a rash,


but the rash is usually a maculopapular exan-
them; plaques, scaling, and desquamation are
not typical of an adverse skin reaction to a drug.
In the context of night sweats and weight loss,
vasculitis and cutaneous T-cell lymphoma are
major concerns. Vasculitis is more likely to be
associated with renal insufficiency.

A skin biopsy was performed. Microscopy re-


vealed a mild mononuclear perivascular infiltrate
with clusters of lymphocytes in the upper dermis
(Fig. 3). Polymerase-chain-reaction analysis to de- Figure 2. Photograph of Rash.
tect T-cell receptor gene rearrangement revealed a An erythematous and violaceous rash with small plaques,
monoclonal T-cell peak possibly consistent with scaling, and desquamation developed in the patient,
predominantly on the back (shown), arms, and feet.
cutaneous T-cell lymphoma. A peripheral-blood
smear was normal. A bone marrow biopsy was
performed, and the results showed hypercellular
marrow (40 to 50% cellularity). Reticulin staining Although the hypercellular bone marrow, nor-
showed focal paratrabecular fibrotic aggregates. mocytic anemia, and relative leukopenia may
No atypical or dysplastic cells were seen. Immu- suggest myelodysplastic syndrome, the absence
nohistochemical analysis did not show cutaneous of red-cell and white-cell dysplasia in the periph-
T-cell lymphoma. Immunohistochemical staining eral-blood smear and the absence of increased
blasts, ring sideroblasts, and dysplastic cytologic
of light chains revealed polyclonality. The propor-
tion of cells that stained positive for CD138 (a features on bone marrow biopsy argue against
universal plasma cell marker) was 5%. Congo red this diagnosis. Furthermore, myelodysplastic syn-
staining showed no amyloid. The patient was re- drome would not account for renal dysfunction
ferred to the hematology clinic. or rash. The low percentage of plasma cells and
polyclonality of light chains are inconsistent with
The diagnosis of cutaneous T-cell lymphoma is myeloma. The Congo red staining showing no
challenging because many of its clinical and amyloid argues against amyloidosis.
pathologic features are nonspecific. The discrete
perivascular lymphocytic infiltrate in the upper The patient had recurrent fever and chills and was
dermis (along with clusters of lymphocytes) and readmitted to the hospital before her planned
the monoclonal T-cell peak may suggest mycosis visit to the hematology clinic. Urine and blood
fungoides. However, clonal T-cell receptor gene cultures obtained on admission yielded S. enteriti-
rearrangements may be detected in healthy elderly dis. The patient reported that she had not taken
patients and in patients with benign dermato- oral amoxicillin as recommended and that she
ses. No abnormal cells were seen in a peripher- had continued to eat eggs from the nearby farm.
al-blood smear or in the bone marrow biopsy A transesophageal echocardiogram did not show
specimen. valve vegetations. A positron-emission tomograph-

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Clinical Problem-Solving

ic scan showed no signs of endovascular or other


infection. Abdominal ultrasonography showed no
gallstones.

The patient’s recurrent salmonella infection may


be explained by her nonadherence to antibiotic
therapy, by repeated exposure to potentially con-
taminated eggs, or by gallbladder colonization
or an endovascular focus of infection. Her older
age and the prolonged glucocorticoid therapy
may also have contributed. Imaging revealed no
gallstones and no endovascular focus of infec-
tion. Recurrent nontyphoidal salmonella bactere-
mia is an acquired immunodeficiency syndrome
(AIDS)–defining condition, and — especially
given the unexplained kidney disease and rash,
which are suggestive of cutaneous T-cell lym-
phoma — human immunodeficiency virus (HIV) Figure 3. Skin-Biopsy Specimen.
infection should be ruled out. Hematoxylin and eosin staining shows acanthosis and hyperkeratosis in
the epidermis, with foci of basal-cell vacuolization, and a mild mononuclear
The white-cell count was 6000 per cubic millime- perivascular infiltrate with exocytosis of scattered lymphocytes in the upper
dermis. At higher magnification (inset), clusters of lymphocytes (arrow)
ter, with an absolute lymphocyte count of 972 per
can be seen.
cubic millimeter (normal range, 1200 to 3400).
The CD4 count was 110 per cubic millimeter. HIV
type 1 serologic testing was positive, with a viral C om men ta r y
load of 156,000 copies per milliliter. Serologic
testing for adult human T-cell leukemia–lym- The primary concern in this 75-year-old woman
phoma virus types 1 and 2 was negative. Antiret- who presented with weight loss, night sweats,
roviral therapy (ART) with abacavir, lamivudine, and anemia was a malignant disorder, and test-
and dolutegravir was started. Sexual history and ing was focused on this suspected diagnosis.
risk factors for HIV were addressed in the HIV This case illustrates a cognitive bias based on
clinic after the patient’s discharge from the hospi- pattern recognition.1,2 Presumably owing to her
tal. The patient’s husband had died suddenly 10 older age, the possibility of AIDS, which may
years earlier; she did not have information on his well have explained all her clinical manifesta-
medical history. The patient reported that she had tions, was considered only late in the course of
not had sex with other partners and did not recall illness.
ever having received blood products. Six months In retrospect, there were many clues to the
after the initiation of ART, the viral load was un- diagnosis of HIV infection. The patient’s white-
detectable, the patient felt well, the rash had re- cell counts showed relative lymphocytopenia,
solved, and renal function had improved (blood although treatment with glucocorticoids could
urea nitrogen level, 25 mg per deciliter [8.9 mmol have explained this finding. The nephropathy
per liter], and creatinine, 1.6 mg per deciliter was another clue. HIV-associated nephropathy
[140 μmol per liter]). with nephrotic-range proteinuria is usually a late
manifestation of HIV infection.3 The classic histo-
The documentation of HIV infection along with morphologic finding is collapsing glomerulopa-
a low CD4 count and recurrent salmonella infec- thy, a distinctive variant of focal segmental glo-
tions is consistent with the diagnosis of AIDS. merulosclerosis with tubulointerstitial disease.4
Seroconversion had probably occurred several HIV-associated immune-complex kidney diseases
years before the first admission, as reflected by have been increasingly reported as well.5 Insuf-
the low CD4 count and the presence of compli- ficient glomeruli were sampled in the renal bi-
cations that typically manifest late in the course opsy to determine the cause of renal failure and
of HIV infection. proteinuria.

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Clinical Problem-Solving

Moreover, pruritic rashes are common in pa- factors until after the diagnosis was made. Fre-
tients with HIV. Paradoxically, cutaneous T-cell quently, a sexual history is not obtained from
lymphoma, a CD4-positive neoplasm, has been elderly patients; some physicians feel uncom-
reported in association with HIV infection.6,7 An fortable addressing this subject.11,12 Among a
atypical cutaneous lymphoproliferative disorder national probability sample of 3005 older adults
— a mainly reactive inflammatory condition that in the United States, more than half the respon-
mimics cutaneous T-cell lymphoma — has also dents 65 to 74 years of age and 26% of respon-
been described in HIV-infected patients and rarely dents 75 to 85 years of age reported that they
progresses to malignant lymphoma.6,8 Distin- were sexually active, yet only 38% of men and
guishing between the two entities may be diffi- 22% of women reported that they had had a
cult. Several weeks after administration of gluco- discussion with a physician about sexual activity
corticoids and initiation of ART, the cutaneous since the age of 50.11 However, history may not
findings resolved. This supports the diagnosis of be revealing; many patients (including elderly
an atypical cutaneous lymphoproliferative disor- patients) may be reluctant to disclose that they
der.6,8 Hypercellularity and reticulin fibrosis, as have risk factors for HIV, and some may be un-
seen in this patient, are nonspecific but are well aware of what the risk factors are. The U.S.
described in bone marrow biopsy specimens from Preventive Services Task Force currently recom-
persons with HIV infection.9 Finally, although re- mends routine annual HIV screening in persons
currence of nontyphoidal salmonella bacteremia 15 to 65 years of age.13
may have been related to the patient’s nonadher- In 2016, almost 5% of the 39,782 patients
ence to antibiotics and possible repeated expo- who received a new diagnosis of HIV infection
sures to a source of salmonella infection, it is an in the United States were 60 years of age or
AIDS-defining condition,10 and in this case it older.14 This case underscores the need to rou-
pointed the physicians to the correct diagnosis. tinely consider the possibility of HIV infection,
AIDS was considered in our patient only late regardless of the age of the patient.
in the course of her illness. The delay in diagno-
No potential conflict of interest relevant to this article was
sis in this case is probably related, in part, to the reported.
fact that different physicians managed different Disclosure forms provided by the authors are available with
problems without considering the whole picture. the full text of this article at NEJM.org.
We thank Prof. Vera Leibovic and Dr. Alexander Maly for their
Of note was the failure of the treating physicians interpretation of the skin biopsies and Dr. Ana Tobar for her
to obtain a sexual history or ask about HIV risk interpretation of the kidney biopsy.

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