DR. HANIF AHMADDR. HANIF AHMAD

TMO Medical B UnitTMO Medical B Unit

LRHLRH

Case HistoryCase History

18 yrs old un-married,male patient18 yrs old un-married,male patient

sanitory workersanitory worker

from Lahori gate Peshawar ,from Lahori gate Peshawar ,

Admitted to Dermatology unit LRH through Admitted to Dermatology unit LRH through casualty on 31casualty on 31stst January 2008 January 2008

Shifted to Medical B on 2Shifted to Medical B on 2ndnd Feb. Feb.

Presenting complaintsPresenting complaints

High grade fever & headache 10 -12 days High grade fever & headache 10 -12 days

Nausea,vomiting & diarrheaNausea,vomiting & diarrhea

Generalised body aches and pains with Generalised body aches and pains with burning and pricking sensation of burning and pricking sensation of extremitiesextremities

Rash on the trunk & extremities Rash on the trunk & extremities

Difficulty in walkingDifficulty in walking

HOPIHOPI

He developed abrupt onset high grade He developed abrupt onset high grade intermittent fever with sweating,dry intermittent fever with sweating,dry cough,nausea,vomiting & watery diarrhea.cough,nausea,vomiting & watery diarrhea.Headache, chest and abdominal pain, Headache, chest and abdominal pain, arthralgias, myalgias,easy fatiguability. arthralgias, myalgias,easy fatiguability. Restricted ADLRestricted ADLDiffuse rash initially on the trunk,then spreading Diffuse rash initially on the trunk,then spreading to etremitiesto etremitiesPainful extremities with burning and pricking Painful extremities with burning and pricking sensation with color changes (blackening) after sensation with color changes (blackening) after a week .a week .Conjunctival injectionConjunctival injectionOn/off history of oral ulcers, dysphagia.On/off history of oral ulcers, dysphagia.

No history ofNo history of

Neurological symptomsNeurological symptoms

Urinary symptomsUrinary symptoms

Alopecia, photosensitivity, dry itchy Alopecia, photosensitivity, dry itchy eyes,pruritis,or joint swellingeyes,pruritis,or joint swelling

Bleeding stigmataBleeding stigmata

Palpitations,dizziness,syncopy,or vertigoPalpitations,dizziness,syncopy,or vertigo

Weight lossWeight loss

Past Hx:Past Hx: Appendicectomy 03 months ago Appendicectomy 03 months ago No other premorbidities No other premorbidities

DRUG HxDRUG Hx:: Not significant (no hx of using complementary Not significant (no hx of using complementary or alternative medicine)or alternative medicine)

FAMILY HISTORY:FAMILY HISTORY:Father is sanitory worker by professionFather is sanitory worker by professionThey Live in a rented house of three rooms in crowded,unsanitory They Live in a rented house of three rooms in crowded,unsanitory conditions.conditions.Has one married elder brother living in the same house.Has one married elder brother living in the same house.sister died at the age of 12yrs because of pulm TB.sister died at the age of 12yrs because of pulm TB.No significant illness in the family.No significant illness in the family.

SOCIO-ECONOMIC Hx:SOCIO-ECONOMIC Hx: Not satisfactory Not satisfactory

PERSONAL Hx:PERSONAL Hx:Student of 8Student of 8thth class class Disturbed sleep and appetite during the Disturbed sleep and appetite during the illness,otherwise was normalillness,otherwise was normalNo hx of any substance abuse.No hx of any substance abuse.No hx of sexual,or animal contact.No hx of sexual,or animal contact.

Clinical ExaminationClinical ExaminationFebrile,normotensive,conscious & well Febrile,normotensive,conscious & well oriented;pulse=90/min(regular,non-collapsing); oriented;pulse=90/min(regular,non-collapsing); R.R=20/min with no cyanosis or resp distress.R.R=20/min with no cyanosis or resp distress.Mildly pale,but not icteric.Mildly pale,but not icteric.Conjunctival injection was presentConjunctival injection was presentENT examination was unremarkable except congested ENT examination was unremarkable except congested throat.throat.Diffuse Diffuse red maculopappular rashred maculopappular rash with rain drops like with rain drops like hypopigmentation & scarring involving the trunk & hypopigmentation & scarring involving the trunk & extremitiesextremitiesGangrenous changes in left toes & bilateral finger tips Gangrenous changes in left toes & bilateral finger tips with intact peripheral pulses.with intact peripheral pulses.No nail changes or lymphadenopathy;no edema.No nail changes or lymphadenopathy;no edema.

CNS,CVS,RESP, & GIT examination was CNS,CVS,RESP, & GIT examination was unremarkableunremarkable

No joint deformities or swellingNo joint deformities or swelling

No evidence of proximal muscle weaknessNo evidence of proximal muscle weakness

No gait disorder or spine deformityNo gait disorder or spine deformity

No genital ulcers,but poor personal No genital ulcers,but poor personal hygiene.hygiene.

On the basis of:On the basis of:RashRash and and digital gngrenesdigital gngrenes, the possibility of , the possibility of VASCULITISVASCULITIS,possibly due to ,possibly due to MCTD MCTD was raised. was raised.

However a possibility ofHowever a possibility of Idiopathic Vasculitis OR Idiopathic Vasculitis OR CryoglobulinemiaCryoglobulinemia was kept in mind. was kept in mind.

Was put on Steroids & Nifedipine emperically in Was put on Steroids & Nifedipine emperically in dermatology unit.dermatology unit.

However he failed to show any improvement. Rather his However he failed to show any improvement. Rather his digital gangrene started to aggravate. A call was sent to digital gangrene started to aggravate. A call was sent to us and we, in consultation with dermatology VP, us and we, in consultation with dermatology VP, transferred him to MMB.transferred him to MMB.

LAB STUDIESLAB STUDIES

Hb=8.9Hb=8.9,with otherwise normal CBC,with otherwise normal CBC

ESR=30 mm in 1ESR=30 mm in 1stst hr. hr.

Normal LFTs,RFTs,S/E,RBS,Urine Normal LFTs,RFTs,S/E,RBS,Urine R/ER/E,CXR,USG abdomen & ,CXR,USG abdomen & pelvis,ECG,ECHO,PT,APTT & INR,pelvis,ECG,ECHO,PT,APTT & INR,

Normal Doppler U/S of upper & lower Normal Doppler U/S of upper & lower limbslimbs

ANA: ANA: NegativeNegative RA-factor: RA-factor: NegativeNegative

TREATMENTTREATMENT

Steroid therapySteroid therapy was stepped up ( was stepped up (Methylprednisolone pulse therapyMethylprednisolone pulse therapy was considered) and full supportive therapy was also instituted.was considered) and full supportive therapy was also instituted.

HeparinHeparin was started in full therapeutic doses, but his condition kept was started in full therapeutic doses, but his condition kept on deteriorating.on deteriorating.

Methotrexate, cyclophosphamide,azathioprine, & prednisone Methotrexate, cyclophosphamide,azathioprine, & prednisone are the are the recommended treatment options for vasculitis.recommended treatment options for vasculitis.

Cyclophosphamide Cyclophosphamide is the drug of choice in this setting. However as is the drug of choice in this setting. However as oral form is not available and IV access was a problem with failed oral form is not available and IV access was a problem with failed canulae sites so oral canulae sites so oral Azathioprine Azathioprine was started but to no avail.was started but to no avail.

At this time At this time iv cyclophosphamideiv cyclophosphamide was considered to be the only and was considered to be the only and most potent option left with us. A CV-line was passed and was given most potent option left with us. A CV-line was passed and was given two pulses of intravenous cyclophosphamide,but again we were two pulses of intravenous cyclophosphamide,but again we were disappointed as we saw this young boy slipping away from our disappointed as we saw this young boy slipping away from our hands day by day.hands day by day.

SerendipitySerendipity

At this time one of our colleagues Dr S.Iqbal shah, while At this time one of our colleagues Dr S.Iqbal shah, while going through a color atlas of medicine came across this going through a color atlas of medicine came across this picture:picture:

The picture belonged to a patient suffering from Typhus. The picture belonged to a patient suffering from Typhus.

This clicked his mind because that picture had a lot of This clicked his mind because that picture had a lot of resemblance to our patient’s lesions;resemblance to our patient’s lesions;

The Real DiagnosisThe Real Diagnosis

After that the possibility of vasculitis secondary After that the possibility of vasculitis secondary to to TYPHUSTYPHUS rather than idiopathic vasculitis was rather than idiopathic vasculitis was strongly considered in our patient.strongly considered in our patient.

We went back to patient’s history and we could We went back to patient’s history and we could extract quite a few relevant points e.g:extract quite a few relevant points e.g:patient’s personal hygiene has been poor.patient’s personal hygiene has been poor.

some relatives had visited them from Lahore who, some relatives had visited them from Lahore who, reportedly, were lice-infested.reportedly, were lice-infested.

Sigh of reliefSigh of relief

We sent his blood sample immediately to AKUH We sent his blood sample immediately to AKUH lab for Typhus serology and put him on anti-lab for Typhus serology and put him on anti-typhustyphus tretment i.e: Doxycycline. tretment i.e: Doxycycline.

To our surprise and satisfaction he showed To our surprise and satisfaction he showed dramatic response within 48hrs, with marked dramatic response within 48hrs, with marked symptomatic improvement and mobilisation symptomatic improvement and mobilisation within a couple of days.within a couple of days.

Cytotoxic drugs were stopped & steroids are Cytotoxic drugs were stopped & steroids are being tapered off and the patient is in full spirits.being tapered off and the patient is in full spirits.

Final diagnosisFinal diagnosis

LOUSE BORNE TYPHUS LOUSE BORNE TYPHUS CAUSED BYCAUSED BY

Rickettsiae ProwazekiiRickettsiae Prowazekii

Epidemic (louse-borne Typhus)Epidemic (louse-borne Typhus)Epidemiology, Etiology and PathogenesisEpidemiology, Etiology and PathogenesisLouse-borne or epidemic typhus caused by R.prowazekii killed millions of people in Louse-borne or epidemic typhus caused by R.prowazekii killed millions of people in eastern eureope and Russia during the periodic wars during the past two centuries.eastern eureope and Russia during the periodic wars during the past two centuries.Fortunately, epidemic typhus is now a rare disease however sporadic outbreaks still Fortunately, epidemic typhus is now a rare disease however sporadic outbreaks still occure in parts of asia, russia, algeria and burndi and in the andes mountians of occure in parts of asia, russia, algeria and burndi and in the andes mountians of south america.south america.War, famine and human cruelty crowded un sanitory living conditions can result in War, famine and human cruelty crowded un sanitory living conditions can result in epidemics.epidemics.Until 25 years ago, typhus was thought to involve in exculsive cycle b/w the body Until 25 years ago, typhus was thought to involve in exculsive cycle b/w the body louse and infected humans.louse and infected humans.However, a sylvatic cycle of infection with R prowazekii is now known to be endemic However, a sylvatic cycle of infection with R prowazekii is now known to be endemic in the eastern united states.in the eastern united states.This sylvatic cycle involves flying squirals and their ecto parasites.This sylvatic cycle involves flying squirals and their ecto parasites.A case report of epidemic typhus in a patient from the south western united states A case report of epidemic typhus in a patient from the south western united states ( an area outside the known geographic range of the flying squiral) suggests the ( an area outside the known geographic range of the flying squiral) suggests the existance of aditional vectors or wild animals reserviors for R prowazekii.existance of aditional vectors or wild animals reserviors for R prowazekii.The prinicipal vector for epidemic typhus is the human body louse (padiculus The prinicipal vector for epidemic typhus is the human body louse (padiculus humanus corporis) althought occassinally the head louse (p humanis capitis) can also humanus corporis) althought occassinally the head louse (p humanis capitis) can also transmit infection. Both squiral flea and squira louse can also act as vectors for R-p in transmit infection. Both squiral flea and squira louse can also act as vectors for R-p in the sylvatic cycle of infection. the sylvatic cycle of infection.

While taking a blood meal from humans, body lice defecate and regurgitate While taking a blood meal from humans, body lice defecate and regurgitate infective GI contents.infective GI contents.These highly infective substances are then inocculated into the skin where These highly infective substances are then inocculated into the skin where the person scratches the pruritic feeding site. the person scratches the pruritic feeding site. Lice feces remain infectious for as long as 100 days. Lice feces remain infectious for as long as 100 days. Dry infectious louse feaces may also enter the respiratory tract. Dry infectious louse feaces may also enter the respiratory tract. Thus human to human transmission of R-P can occur via the sharing of Thus human to human transmission of R-P can occur via the sharing of clothings or via transfer of infected lice feces from one human to another. clothings or via transfer of infected lice feces from one human to another. Transimissin of sylvatic form of epidemic typhus to humans occurs only Transimissin of sylvatic form of epidemic typhus to humans occurs only when humans have direct contact with infected squirals or when squirals when humans have direct contact with infected squirals or when squirals nesting in the attics of homes or removed or killed, leaving the lice that nesting in the attics of homes or removed or killed, leaving the lice that infested their nets to seek an alternative (human host).infested their nets to seek an alternative (human host).Patients are infectious for the lice during the febrile period and perhaps two Patients are infectious for the lice during the febrile period and perhaps two to three days after the fever returns to normal.to three days after the fever returns to normal.Infected lice pass R-P in their feces within 2 to 6 days of their blood meal Infected lice pass R-P in their feces within 2 to 6 days of their blood meal can be infectious earlier if crushed. can be infectious earlier if crushed.

PathophysiologyPathophysiology

After entering the human body R-P spreads via the blood After entering the human body R-P spreads via the blood stream and lymphatics to produce a generalized stream and lymphatics to produce a generalized vasculitis.vasculitis.The precise mechanism by which R-P produces cellular The precise mechanism by which R-P produces cellular injury is poorly understood. injury is poorly understood. But the net effect of this infection is wide spread But the net effect of this infection is wide spread endothelial injury along with activation of humoral endothelial injury along with activation of humoral immune response, inflammation and coagulation.immune response, inflammation and coagulation.This vasculitis may produce diffuse myocarditis, along This vasculitis may produce diffuse myocarditis, along with macroscopic and microscopic damage to msls and with macroscopic and microscopic damage to msls and neural tissue, the spleen, kidneys and other internal neural tissue, the spleen, kidneys and other internal organs (like interstitial pneumonia).organs (like interstitial pneumonia).

CNS involvement may result in so called CNS involvement may result in so called typhus nodules, which comprise peri typhus nodules, which comprise peri vascular infiltrates consisting of vascular infiltrates consisting of lymphocytes, macrophages and plasma lymphocytes, macrophages and plasma cells.cells.

DiagnosisDiagnosis

Clinical menifestations: Clinical menifestations: R-P infection produces two distinct clinical syndromes. R-P infection produces two distinct clinical syndromes. The most common is an acute severe infection that occurs 7-10 The most common is an acute severe infection that occurs 7-10 days after exposur to infected lice and may result in death.days after exposur to infected lice and may result in death.A second, recrudescent form called Brill-zinsser disease may occur A second, recrudescent form called Brill-zinsser disease may occur from 1-5 decades after a primary infection (R-P servives in lymphoid from 1-5 decades after a primary infection (R-P servives in lymphoid tissue)tissue)Patients with acute epidemic typhus infection typically become Patients with acute epidemic typhus infection typically become abruptly ill with fever, headache and myalgias.abruptly ill with fever, headache and myalgias.Other no specific symptoms such as cough abd.pain, nausea and Other no specific symptoms such as cough abd.pain, nausea and diarrhea are common. diarrhea are common. Skin rash in patients with epidemic typhus classically beghins Skin rash in patients with epidemic typhus classically beghins several days after the onset of symptoms as a red macular or several days after the onset of symptoms as a red macular or macculpapular erruption on the trunk that then spreads to the macculpapular erruption on the trunk that then spreads to the extrimities.extrimities.

Although the skin rash is classically described as sparing the palms and Although the skin rash is classically described as sparing the palms and soles and face, exceptions to this rule occure.soles and face, exceptions to this rule occure.In sever cases of epi typhus skin rash may become petechial. Rarely In sever cases of epi typhus skin rash may become petechial. Rarely gangrene of the extrimities has been described.gangrene of the extrimities has been described.Conjunctivitis, hearing loss (8Conjunctivitis, hearing loss (8thth CN neuropathy), flushed face, rales at lung CN neuropathy), flushed face, rales at lung bases, often splenomegaly can occur.bases, often splenomegaly can occur.In spontaneous recover improvemnet begins 13-16 days after onset with a In spontaneous recover improvemnet begins 13-16 days after onset with a rapid drop of fever. rapid drop of fever. In humans, the clinacal featurs of sylvatic form of typhus are similar to those In humans, the clinacal featurs of sylvatic form of typhus are similar to those of the epi Form. of the epi Form. In one series, however only half of the pts. With the sylvatic form of R-P had In one series, however only half of the pts. With the sylvatic form of R-P had a skin rash.a skin rash.Pts. With epi typhus often have neurologic symptoms that may range from Pts. With epi typhus often have neurologic symptoms that may range from mild confussion and drowsiness to coma, siezures and focal neurologic mild confussion and drowsiness to coma, siezures and focal neurologic findings.findings.As in other rickettsial diseases, jaundice and myocarditis may occur in sever As in other rickettsial diseases, jaundice and myocarditis may occur in sever cases.cases.

Recrudescent RP infection (brill-zinsser disease) is Recrudescent RP infection (brill-zinsser disease) is generaly a much milder illness than acute epi Typhus.generaly a much milder illness than acute epi Typhus.The onset of BZ disease is often abrupt with chills fever The onset of BZ disease is often abrupt with chills fever and headache. and headache. Skin rash typically begins 4-6 days after the onset of Skin rash typically begins 4-6 days after the onset of symptoms and it is often scant or evanescent.symptoms and it is often scant or evanescent.Because pts. With BZ disease are often elderly or have Because pts. With BZ disease are often elderly or have other chronic medical conditions, their symptoms (EG, other chronic medical conditions, their symptoms (EG, confusion, dyspnoea and lethargy) may be in correctly confusion, dyspnoea and lethargy) may be in correctly attributed to pre existing or co existing cardiac, CVS or attributed to pre existing or co existing cardiac, CVS or pulmonary disease. pulmonary disease.

Lab studiesLab studies

Both forms of RP infections are best diagnosed by Both forms of RP infections are best diagnosed by serologic testing. serologic testing. The indirect immunoflourescent antibody (IFA) test and The indirect immunoflourescent antibody (IFA) test and an immunoblot technique are reliable serologic methods. an immunoblot technique are reliable serologic methods. A 4 fold rise in antibody titres 10-21 days after onset of A 4 fold rise in antibody titres 10-21 days after onset of symptoms is considered diagnostic in both forms of RP symptoms is considered diagnostic in both forms of RP infection, although only an IgG antibody response is infection, although only an IgG antibody response is illicited in BZ disease.illicited in BZ disease.Common accompanying lab findings in acute epidemic Common accompanying lab findings in acute epidemic typhus include increase plasma transferase level and typhus include increase plasma transferase level and thrombocytopenia, protienuria and hematuria. thrombocytopenia, protienuria and hematuria. Pts. With sever involvement may have pulmonary Pts. With sever involvement may have pulmonary infiltrates on CXR and other lab evidance of myocarditis.infiltrates on CXR and other lab evidance of myocarditis.

TreatmentTreatment

Tetracyclines and chloremphenicol are effective Tetracyclines and chloremphenicol are effective treatments for both actue and recrudescent RP treatments for both actue and recrudescent RP infections but the drug of choice is Doxycycline. infections but the drug of choice is Doxycycline. In one study, 35 of 37 pts. With epi Typhus were cured In one study, 35 of 37 pts. With epi Typhus were cured with a single 200mg dose of Doxycycline however the 2 with a single 200mg dose of Doxycycline however the 2 remaining pts. Had relapse 6 and 7 days after the initial remaining pts. Had relapse 6 and 7 days after the initial response.response.Patients with RP infection, charicteristically imporve Patients with RP infection, charicteristically imporve within 48 hrs of anti-RK therapy. within 48 hrs of anti-RK therapy. Doxcycline 200mg/d for 4-10days and Chloremphenicol Doxcycline 200mg/d for 4-10days and Chloremphenicol 50-100mg/kg/d in 4 divided doses for 4-10 days. 50-100mg/kg/d in 4 divided doses for 4-10 days. In severe cases, supportive care with vasopressors, IV In severe cases, supportive care with vasopressors, IV fluids, Oxygen and even dialysis may be necessary. fluids, Oxygen and even dialysis may be necessary.

PreventionPreventionBecause humans who have contacted with other lice infested humans can Because humans who have contacted with other lice infested humans can secondarily acquire lice even if they have good hygiene, all louse infested secondarily acquire lice even if they have good hygiene, all louse infested persons and workers in closed contact with such persons should use long persons and workers in closed contact with such persons should use long acting topical insecticides such as melathione, lindane or permithrine.acting topical insecticides such as melathione, lindane or permithrine.Fabrics and clothing treated with permethrine remained toxic to lice even Fabrics and clothing treated with permethrine remained toxic to lice even after 20 washings. after 20 washings. In epidemic settings the use of chloremphenicol or tetracycline for In epidemic settings the use of chloremphenicol or tetracycline for prophylaxis of RP infection is highly effective. prophylaxis of RP infection is highly effective. Even a single 200mg dose of doxycycline takes once weekly by travellers or Even a single 200mg dose of doxycycline takes once weekly by travellers or health care workers in areas where epi typhus is present has been shown to health care workers in areas where epi typhus is present has been shown to protect against infectionprotect against infectionProphylaxis should be continued for one week after leaving epidemic areaProphylaxis should be continued for one week after leaving epidemic areaIn activated vaccines have been shown to confere protection against In activated vaccines have been shown to confere protection against experimental RP infectionsexperimental RP infectionsSuch vaccines are not currently commersially available nor are they likely to Such vaccines are not currently commersially available nor are they likely to become avialable inveiw of the affectiveness of both prophylactic antibiotics become avialable inveiw of the affectiveness of both prophylactic antibiotics and other preventive mesures.and other preventive mesures.

PrognosisPrognosis

In the pre antibiotic era higher mortality In the pre antibiotic era higher mortality from epi Typhus was associated with old from epi Typhus was associated with old age and male gender age and male gender

With prompt institution of anti biotic With prompt institution of anti biotic therapy however mortality is now raretherapy however mortality is now rare