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Indian Pediatr 2011;48:
867-872 |
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Rickettsial Diseases in Central India:
Proposed Clinical Scoring System for Early Detection of Spotted
Fever |
Narendra B Rathi, *Akanksha N Rathi,
#Michael H Goodman, and
#Zubair H Aghai
From Rathi Children’s Hospital and Maternity Home, Akola,
MS, India; * Seth G S Medical College and KEM Hospital, Parel, Mumbai,
India; and #Department of Pediatrics, Cooper University Hospital, UMDNJ-Robert
Wood Johnson Medical School,
One Cooper Plaza, Camden, NJ, 08103, USA.
Correspondence to: Dr Narendra Rathi, Rathi Children’s
Hospital & Maternity Home, Civil Lines, Akola 444001, MS, India. [email protected]
Initial received: July 6, 2010;
Review: August 10, 2010;
Accepted: October 28, 2010.
Published online:
2011 March 15.
PII: S0974755910INPE00083-1
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Objectives: To report a series of cases of rickettsial infections from
central India and to develop a clinical scoring system for its early
detection.
Design: Retrospective review of children
hospitalized during one year period with fever without a source, and
presence of one or more of the clinical features suggestive of rickettsial
infection. Diagnosis of rickettsial disease was made by classical clinical
features and detection of IgM antibody by ELISA. A clinical scoring system
was developed to diagnose spotted fever group by using classical clinical
and laboratory findings.
Results: 161 patients were admitted and met the
inclusion criteria, 75 (45.6%) were diagnosed with rickettsial diseases.
52 (69.3%) had spotted fever group and 23 (30.7%) scrub typhus. The
mortality rate with rickettsial diseases was 9%. By using proposed
clinical scoring system, a score of 14 has sensitivity and specificity of
96.15% and 98.84%, respectively in making a diagnosis of spotted fever
group.
Conclusion: Rickettsial diseases are common in the
central part of India and should be included in the differential diagnosis
of patients with fever of undetermined source. The proposed scoring system
can be used for early detection, treatment and prevention of mortality and
morbidity from spotted fever group.
Key words: Clinical scoring system, Diagnosis, India,
Rickettsiae, Spotted fever, Scrub typhus.
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R ickettsial diseases have been
reported
from various parts of India [1-5].
However, no study has been done in
central India to investigate the existence of rickettsial disease in this
region. Physicians, including pediatricians, usually do not include
rickettsial infection in their differential diagnosis. Factors
predisposing to rickettsial infections are prevalent in this part of the
country.
The greatest challenge to the clinician is the
diagnostic dilemma posed by these infections early in their clinical
course when antibiotic therapy is most effective [6,7]. Only the
Weil-Felix test is easily available for diagnosis in India but most of the
western literature has advised against performing this test for diagnosis
of rickettsial infections [7,8]. Other serological tests are based on
detecting antibodies, and aid in diagnosis only 5-7 days after the onset
of the disease and are not helpful in the early initiation of therapy in a
suspected case. Immunofluorescence assay (IFA), the gold standard
diagnostic test for rickettsial infections, is not available in India, is
expensive, and can take more than a week to get the results. As no single
laboratory finding is specific for early diagnosis, treatment needs to be
started on clinical suspicion. We are reporting a series of cases of
rickettsial infections, recently diagnosed in our practice with a dramatic
response to appropriate antibiotics. Given the urgent need for a clinical
diagnostic tool, we herein propose a clinical scoring system for early
detection of spotted fever group.
Methods
We conducted a retrospective review of children
admitted at our center in Central India between January 2009 and December
2009.
Inclusion criteria: Age <20 years; hospitalized
with fever without a source; presence of one or more of the following
clinical features: rash, edema, hepatospenomegaly, lymphadenopathy, eschar,
and tick bite or tick exposure.
Exclusion criteria: The cause of fever known at the
time of admission; and patients treated on an outpatient basis.
The Institutional Review Committee at Cooper University
Hospital, Camden, USA, approved the study. One hundred and sixty one
patients qualified for the review. The clinical and laboratory data were
collected from the patient’s medical records. The ELISA for spotted fever
IgM antibody (Panbio, Brisbane, Australia) and scrub typhus IgM antibody (InBios
International, Seattle, USA) were performed on 146 patients. Weil-Felix
test (Tulip Diagnostics Pvt Ltd. Goa, India) was done in 157 cases and a
titer of 1:80 or more was considered as a positive test. IFA IgM for
spotted fever group (Focus Tech Inc, Cypress, CA), was performed on 10
patients diagnosed with rickettsial disease by clinical features and
positive ELISA for IgM antibody and a titer of 1:64 or more was considered
as a positive test. The serological tests were performed more than 7 days
after the onset of the disease. The suspected cases were treated with
doxycycline (dose 5 mg/kg/day for 7-10 days) and response to treatment and
days to defervescence were recorded. In seriously ill patients,
doxycycline was given via Ryle’s tube. The diagnosis of rickettsial
disease was made by the detection of IgM antibody by ELISA, exclusion of
other diseases, and prompt response to the treatment. Rural area was
defined as a village with a population of less than 10,000. Tick exposure
was said to occur when ticks were seen on the clothes of the child or
inside the house, or history of playing in an area where ticks are seen.
The patients were categorized into rickettsial
infection group and no rickettsial infection group. The baseline
demographics, risk factors, clinical and laboratory characteristics were
compared between the two groups.
Clinical scoring system: A clinical scoring system
viz. Rathi Goodman Aghai (RGA) Clinical scoring system was developed using
classical clinical and laboratory findings seen in spotted fever group (SFG).
A score of 0-3 was given for each clinical or laboratory finding based on
their association with SFG. This scoring system was applied on each
patient in SFG and no rickettsial infection group. The total scores were
compared between the two groups. Receiver operating characteristics (ROC)
curve analysis was performed to determine the cut off level of total score
for the diagnosis of SFG. The sensitivity, specificity, positive
predictive value (PPV) and negative predictive value (NPV), likelihood
ratio of positive test (LR+) and likelihood ratio of negative test (LR-)
were calculated using the total score from each patient.
Statistical analyses were performed using Sigma Stat
3.1 for Windows statistical package (Systat Software, Inc; Point Richmond,
CA). ROC curve analysis was performed using MedCalc (Broekstraat, Belgium)
statistical software The comparisons between groups were performed using
Student’s t-test and Mann-Whitney Rank Sum test for continuous data
and c2
or Fisher’s exact test for categorical data. The difference
was considered significant for P<0.05.
Results
A total of 161 admitted patients met the inclusion
criteria. Seventy five patients (45.6%) were diagnosed with rickettsial
diseases while 86 patients had other diagnoses. Of the 75 patients with
rickettsial infections, 52 (69.3%) had spotted fever group (SFG) and 23
(30.7%) scrub typhus (ST). No case of typhus fever was seen in our series.
ELISA for IgM antibody against spotted fever was positive in 47 out of 52
patients (90%) with SFG. Five patients who were included in the SFG group
with negative IgM antibody for spotted fever had strong clinical features
of rickettsial infection, other diagnoses were excluded and responded
promptly to doxycycline. IFA was performed in 10 patients with SFG who
were positive for IgM antibody against spotted fever by ELISA. Each of
them had positive IgM by IFA. ELISA for IgM antibody against scrub typhus
was positive in 21 out of 23 patients (91%) with ST. Two patients included
in the ST group with negative IgM antibody had strong clinical features of
scrub typhus (one was positive for Weil-Felix), other diagnoses were
excluded and responded promptly to doxycycline.
Clinical features in the two groups are described in
Table I. Anorexia, irritability, myalgia and headache were
present in the majority of patients with rickettsial diseases. There was
no significant difference in the number of cases with rash in the two
groups. However, the rash was more purpuric, palpable purpuric, ecchymotic
or necrotic in patients with rickettsial diseases. The laboratory findings
between the two groups are compared in Table II. The
Weil-Felix test was positive only in 49% of the patients with rickettsial
diseases (sensitivity 49%, specificity 96%). ELISA for IgM antibody had a
sensitivity and specificity of 91% and 100%, respectively for making a
diagnosis of rickettsial infection.
TABLE I Demographics and Baseline Clinical Characteristics of Patients With and Without Rickettsial Infections
|
Rickettsiae |
No Rickettsiae |
P |
|
(n=75) |
(n=86) |
value |
Age (y)* |
5 (2m-20y) |
4 (7m-15y) |
0.3 |
Sex (M:F) |
52:23 |
51:35 |
0.3 |
Rural (%) |
60 (80) |
26 (30) |
<0.001 |
Pets (%) |
29 (39) |
16 (19) |
0.008 |
Tick
exposure (%) |
60 (80) |
17 (20) |
<0.001 |
Tick bite
(%) |
21 (28) |
0 (0) |
<0.001 |
Duration
of fever (d)* |
10 (5-22) |
7 (3-25) |
<0.001 |
Rash (%) |
62 (83) |
72 (84) |
0.97 |
Duration
of rash (d)* |
7 (2-20) |
2 (1-11) |
<0.001 |
Onset of
rash after fever (d)* |
3 (2-6) |
4 (1-14) |
<0.001 |
Purpura,
or rash (%) |
53 (62) |
3 (4) |
<0.001 |
#Conjunctival
congestion (%) |
39 (52) |
11 (13) |
<0.001 |
Pedal
edema (%) |
69 (92) |
18 (21) |
<0.001 |
Anasarca
(%) |
21 (28) |
9 (10) |
0.008 |
Eschar
(%) |
5 (7) |
0 (0) |
0.048 |
Rash on
palms and soles (%) |
44 (59) |
15 (17) |
<0.001 |
Hepatomegaly (%) |
74 (99) |
40 (46) |
<0.001 |
Lymphadenopathy(%) |
31 (41) |
17 (20) |
0.005 |
Died (%) |
7 (9) |
7 (8) |
1.0 |
*median (range), #Non
exudative. |
TABLE II Laboratory Findings in Children With and Without Rickettsial Infections
|
Rickettssial Infection |
P value |
|
Present
(n=75)
No (%) |
Absent
(n=86)
No (%) |
|
TLC (X103/cumm)* |
9.8 (1.8-38.0) |
4.3 (2.1-43.6) |
0.007 |
Hemoglobin (g/dL)* |
8.8 (4.2-12.2) |
11.1 (2.3-14.8) |
<0.001 |
Hemoglobin ≤9 g/dL (%) |
53 (71) |
19 (22) |
<0.001 |
Platelets (X 103/cumm)* |
103 (12-599) |
141(12-754) |
0.01 |
Platelets ≤150,000/cumm |
51 (68) |
42 (49) |
0.02 |
CRP (mg/L)* |
55 (6-169) |
10 (3-138) |
<0.001 |
CRP ≥50 mg/L |
42 (56) |
17 (20) |
<0.001 |
Serum albumin g/dL* |
3 (1.8-4.4) |
3.9 (2-5) |
<0.001 |
Albumin <3 g/dL |
38 (51) |
21 (24) |
0.001 |
Urine albumin ≤2+ |
30 (40) |
3 (3) |
<0.001 |
SGPT ≥100 (U/L) |
49 (65) |
21 (24) |
<0.001 |
Na ≤130 (meq/L) |
48 (64) |
14 (16) |
<0.001 |
Positive Weil Felix test |
37 (49) |
3 (3.4) |
<0.001 |
Positive ELISA IgM antibody |
68 (91) |
0* (0) |
<0.001 |
* Median (range); Performed on 71 patients;
CRP- C reactive protein; TLC- Total leucocyte count; SGPT- Serum
glutamic pyruvic transaminase |
The clinical and laboratory characteristics were also
compared between the patients with SFG and ST. The patients with SFG were
younger, more likely to have rash but the duration of the fever and rash
was shorter (Table III). Anasarca, eschar and
lymphadenopathy were more common in patients with ST. There was no
significant difference in the laboratory findings in the two groups.
TABLE III Demographic and Baseline Clinical Characteristics of Children with
Spotted Fever Group (SFG) and Scrub Typhus (ST)
|
SFG (n=52) |
ST (n=23) |
P value |
|
No. (%) |
No. (%) |
|
Age *
|
4 (2m-16y) |
8 (8 m-20y) |
0.009 |
Sex (M:F) |
33:19 |
19:4 |
0.2 |
Rural (%) |
43 (81) |
17 (74) |
0.5 |
Pets (%) |
19 (36) |
10 (43) |
0.8 |
Tick
exposure (%) |
43 (81) |
17 (74) |
0.5 |
Tick bite
(%) |
14 (27) |
7 (30) |
0.9 |
Duration
of fever (d)* |
9 (5-20) |
13 (7-22) |
<0.001 |
Rash(%) |
51 (98) |
10 (43) |
<0.001 |
Duration
of rash (d)* |
7 (2-17) |
16 (6-20) |
<0.001 |
Onset of
rash after fever (d)* |
3 (2-6) |
3 (2-3) |
0.6 |
#Conjunctival
congestion (%) |
27 (52) |
12 (52) |
0.9 |
Pedal
edema (%) |
49 (94) |
20 (87) |
0.8 |
Anasarca
(%) |
4 (8) |
17 (74) |
<0.001 |
Eschar
(%) |
0 (0) |
5 (22) |
0.002 |
Hepatomegaly (%) |
52 (100) |
22 (97) |
1.0 |
Lymphadenopathy (%) |
13 (25) |
18 (78) |
<0.001 |
Died (%) |
4 (8) |
3 (13) |
0.7 |
#Non exudative; *Median
(range). |
Abnormal neurological finding (28%) was the most common
complication of rickettsial diseases (encephalopathy 15%, meningitis 5%,
meningo-encephalitis 5%, encephalitis 3%). Pnuemonia (21%), gangrene
(11%), renal failure (7%) and shock, myocarditis, gastrointestinal
hemorrhage, DIC, ARDS (5% each) were other complications reported in our
patients. Two patients (3%) had hemophagocytic syndrome. The median age of
defervescence was 2 days (range 1-5 days). The mortality rate with
rickettsial diseases was 9%. All 4 patients who developed ARDS and two
patients who had hemophagocytic syndrome died. One more patient who died
of rickettsial disease had encephalitis.
A clinical scoring system utilizing clinical and
laboratory characteristics seen more frequently with SFG was developed and
tested. As described in Table IV, a score of 0-3 was given
for each clinical or laboratory finding. The RGA scoring system has a
total score of 35 (25 clinical and 10 laboratory findings). The median
score in the SFG was 22 (range, 10-30), compared to 6.5 (range, 1-16) in
the no rickettsial group (P<0.001). On ROC curve analysis the
cut-off score with the highest accuracy was found to be 14, with a
sensitivity and specificity of 96.15% and 98.84%, and a PPV and NPV of
98.0% and 97.7%, respectively. With a cut-off score of 14, the likelihood
ratio of positive test (LR+) and likelihood ratio of negative test (LR-)
were 82.7 and 0.04, respectively. Fifty out of 52 patients (96%) in
spotted fever group had a score of 14 or more compared to only 1 out of 86
(1%) with no rickettsial infection (P<0.001). A score of 17 had
100% specificity (sensitivity 86.5%) and a score of 9 had 100% sensitivity
(specificity 81.4%).
TABLE IV Scoring System to Diagnose Spotted Fever Group (Total Score = 35)
Clinical features |
Score |
Laboratory |
Score |
Rural |
1 |
Hemoglobin ≤9 g/dL(%) |
1 |
Pets |
1 |
Platelets <150,000 (cells/L) |
1 |
Tick exposure |
2 |
CRP ≥50 (mg/dL) |
2 |
Tick bite |
3 |
Serum albumin <3 g/dL |
1 |
Conjunctival |
2 |
Urine albumin ≥2+ |
1 |
congestion (Non |
|
SGPT ≥100 (U/L) |
2 |
exudative) |
|
Na ≤130 (mEg/L) |
2 |
Maculopapular rash |
1 |
|
|
Purpura |
2 |
|
|
Palpable purpura/ ecchymosis/ necrotic rash |
3 |
|
|
Rash appearing 48-96 h after fever |
2 |
|
|
Pedal edema |
2 |
|
|
Rash on palms and soles |
3 |
|
|
Hepatomegaly |
2 |
|
|
Lymphadenopathy |
1 |
|
|
Total |
25 |
|
10 |
Discussion
While rickettsial diseases are reported from various
parts of India [1-5], this is the first study showing its existence in
central India.
However, the reported cases underestimate the burden of
rickettsial diseases in India due to the lack of both community based
studies and availability of specific laboratory tests [9]. We are
reporting a large series of cases that were diagnosed during a short
period of time from Akola and adjoining districts from Maharashtra in
Central India. We found that 45.6% of children hospitalized with fever of
undetermined sources had rickettsial diseases. Rickettsial infection in
our series is prevalent across all age groups and the youngest child was
only 2 months old. Majority of our cases were seen during the months of
June to October. SFG was more common than ST and no case of typhus fever
was identified. Kamasaru, et al. [10] reported higher incidence of
ST in Tamil Nadu, whereas SFG was more common in a case series reported by
Kulkarni, et al. [4] from the Western part of India [5,14]. More
recently, a single case of scrub typhus was reported from Mumbai [5].
The common clinical features of rickettsial infections
in this series were similar to those reported earlier [1-5]. We, however,
could identify specific clinical and laboratory characteristics to develop
a scoring system to differentiate SFG from non-rickettsial infections in
patients presenting with fever of undetermined source. The clinical
scoring system was tested on each patient from both the groups. When
applied to the patients presenting with fever of unknown source, a
clinical score of 14 or more on proposed RGA scoring system has
sensitivity and specificity similar to the detection of specific IgM
antibody by ELISA. The clinical scoring system may help physicians in
early diagnosis, prompt treatment and prevention of complications and
death from this dreaded disease. Another important clinical tool in
differentiating rickettsial infections from non rickettsial infections is
the response to treatment with doxycycline. 73 out of 75 patients with
rickettsial infections in our series had prompt defervescence with
doxycycline in a median time of 2 days.
Several investigators have expressed that rickettsial
infections are under-reported in India [4, 10]. Although, no case has been
reported from the Central India (Vidharba, Madhya Pradesh and Chattisgarh),
factors predisposing to rickettsial infections are prevalent in this part
of the country. Since no case has been documented, pediatricians usually
do not include rickettsial infections in their differential diagnosis. It
is not obvious whether rickettsial infections were endemic or re-emerging
in Central India. Awareness of the existence of rickettsial infection will
also prevent excessive investigations in patients with fevers of unknown
sources and lower the economic burden to families and society.
We recognize several limitations of the current report.
This is a retrospective review from a single center reporting data from
patients who were hospitalized with fever of undetermined source and other
clinical features commonly seen with rickettsial infections. The sample
size for developing the scoring system is also small. A larger study, at
multiple centers, involving hospitalized as well as patients in an
ambulatory set up is required to find true prevalence of rickettsial
infection in Central India. The proposed clinical scoring system needs to
be validated using a larger sample size at multiple sites.
Despite these limitations, we conclude that rickettsial
diseases are common in the Central India and should be included in the
differential diagnosis of patients with fever of undetermined source. The
RGA scoring system can be used for early detection, treatment and
prevention of mortality and morbidity from SFG.
Contributors: NR: concept, design, analysis and
acquisition of data, drafting; AR: review of literature, drafting and
acquisition of data; MG: concept, design, drafting, critical review; ZA:
concept, design, analysis of data, drafting. The final manuscript was
approved by all authors.
Funding: None.
Competing interests: None stated.
What is Already Known?
• Rickettsial diseases are reported from
various parts of India. Definitive treatment should be instituted
on the basis of clinical and epidemiological clues as early as
possible.
What This Study Adds?
• Rickettsial diseases are common in the
Central India.
• When applied to the patients presenting with fever of unknown
source, a clinical score of 14 or more on the proposed scoring
system has very high sensitivity and specificity for the diagnosis
of spotted fever group of rickettsial diseases.
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