When to investigate for secondary hyperhidrosis: data from a retrospective cohort of all causes of recurrent sweating

Figures & data

Figure 1. Flow chart.

Table 1. Main aetiologies of recurrent sweating.

Aetiologies		N	N (%)
Cancer (non-haematologic)	Lung carcinoma	13	60 (14.3)
	Renal carcinoma	6
	Breast carcinoma	5
	Cholangiocarcinoma	5
	Pancreatic adenocarcinoma	5
	Colorectal adenocarcinoma	4
	Prostate adenocarcinoma	3
	Hepatocellular carcinoma	2
	Kaposi’s sarcoma	2
	Leiomyosarcoma	2
	Melanoma	2
	Non-seminomatous mediastinal germ cell tumour	2
	Metastasis (undetermined)	2
Cardiovascular	High blood pressure	4	9 (2.1)
	Vasovagal syncope	2
Digestive	Crohn’s disease	5	10 (2.4)
	Ulcerative colitis	2
	Chronic inflammatory bowel disease (unspecified)	2
Endocrine	Dysthyroidism	8	22 (5.2)
	Pituitary adenoma	5
	Adrenal insufficiency	2
	Diabetes	2
	Ovarian insufficiency	2
Haematologic
Oncologic	Lymphoma	47	59 (14)
	Non-Hodgkin’s lymphoma	35
	Hodgkin’s lymphoma	11
	Chronic lymphocytic leukaemia	8
	Multiple myeloma	3
Non-Oncologic	Myelofibrosis	3	12 (2.9)
	Histiocytosis	2
Infectious diseases	Mycobacterium tuberculosis	13	44 (10.5)
	Non-tuberculous mycobacteria	2
	HIV	3
	Cytomegalovirus	3
	Helicobacter pylori gastritis	2
	Chronic osteoarticular infection	3
	Male urinary tract infection	2
	Malaria	2
	Pneumonia	2
	Post-viral syndrome	2
Medications	(see Table 2)		33 (7.9)
Neurologic	Peripheral neuropathy	4	13 (3.1)
	Neuropathic pain	3
	Dysautonomia	2
Physiologic	Menopause/perimenopause	5	6 (1.4)
Psychiatric	Depressive and/or anxiety disorder	12	17 (4)
	Withdrawal syndrome	3
Respiratory	Obstructive sleep apnoea	5	12 (2.9)
Rheumatologic	Peripheral spondyloarthropathy	3	19 (4.5)
	Fibromyalgia	2
	Rheumatoid arthritis	2
	RS3PE	2
	Arthritis (unspecified)	2
Systemic	Vasculitis	6	24 (5.7)
(General,	Lupus	3
Autoimmune or	Sarcoidosis	3
Autoinflammatory)	Autoinflammatory disease (unspecified)	3
	Still’s disease	2
Primary hyperhidrosis / No aetiology		70	(16.7)
Others*		10	(2.3)

N = 420 patients (aetiologies with a frequency of 1 in 420 are not shown and are presented in Appendix 2).

*Including allergies, dermatologic, and gynaecologic diseases, ENT-related diseases, environmental and nutritional diseases, and surgical complications.

Table 2. Drug-induced recurrent sweating.

Pharmacological class	N	Main reported drugs	Pathophysiology
Corticosteroids	3	^b	Increased sympathetic activity through glucocorticoid receptors
Immunosuppressive therapy	3	Tacrolimus^a, Mycophenolate mofetil^b, Leflunomide^c
Anti-PD-1 Ab	2	Pembrolizumab
TNFα inhibitors	2	Adalimumab^a, Infliximab^a	Imbalance in cytokines network
Anti-IL-17 Ab	1	Ixekizumab
Tyrosine kinase inhibitors	1	Sunitinib
Chemotherapy (unspecified)	1	^b
Anti-androgen/GnRH agonists	3	Cyproterone acetate, Leuprorelinea + Abiraterone, Triptorelin^a	Anti-estrogenic action
Aromatase inhibitor	2	Letrozole^a, Exemestane^c	Anti-estrogenic action
Estrogen receptor modulators	1	Tamoxifen^b	Anti-estrogenic action
Hormonal contraception	1	Ethinylestradiol + Levonorgestrel^c
Antiretroviral	1	Emtricitabine + Rilpivirine + Tenofovir alafenamide
Morphine	2	Fentanyl^a	Histamine release
Cholinesterase inhibitors	1	Pyridostigmine^a	Cholinesterase inhibition
SNRI	3	Venlafaxine^a	Serotonergic effect on hypothalamus or spinal cord
SSRI	3	Paroxetine^a, Fluoxetine^a	Serotonergic effect on hypothalamus or spinal cord
GABA-R modulators	1	Etifoxine
Antipsychotic	1	Paliperidone
Antiepileptic	1	Lamotrigine^c, Lacosamide

Ab: antibodies; SNRI: Serotonin-Noradrenaline Reuptake Inhibitors; SSRI: Selective Serotonin Reuptake Inhibitors. For precise database results, see Appendix 3.

^aMedications with a mention of sweat-inducing potential in their summary of product characteristics.

^bMedications with no mention of sweat-inducing potential in their summary of product characteristics but with a previously reported association with sweating in scientific literature^{[12,13,20–24]}.

^cMedications with no mention of sweat-inducing potential in their summary of product characteristics nor in scientific literature but with reported cases in pharmacovigilance databases.

Table 3. Patients’ characteristics by group of pathologies.

	Total	Malignancy	Infection	Other inflammatory	Other non- inflammatory	No diagnosis
N	420 (100)	119 (28.3)	44 (10.5)	71 (16.9)	116 (27.6)	70 (16.7)
Sex (F/M) (N)	213/207	48/71	13/31	40/31	69/47	43/27
Age (median)	53 (39–67)	64 (51.5–73)	43 (28.5–53)	49 (33.5–66)	53 (39–64)	47 (39.5–61)
BMI (median)	24 (21–27.4)	24.3 (21.4–27.1)	22.9 (19.2–25)	23.6 (21.3–28)	25 (22.5–30.8)	23.6 (20.5–27.3)
Menopause^a (N)	111 (52.4)	36 (75)	3 (23.1)	17 (42.5)	41 (59.4)	14 (33.3)
Medical history (N)
ID^b	76 (18.1)	17 (14.3)	8 (18.2)	17 (23.9)	20 (17.2)	14 (20)
HIV	17 (4)	5 (4.2)	4 (9.1)	1 (1.4)	4 (3.4)	3 (4.3)
SOT^c	15 (3.6)	4 (3.4)	2 (4.5)	1 (1.4)	4 (3.4)	4 (5.7)
Sleep apnoea	23 (5.5)	4 (3.4)	1 (2.3)	1 (1.4)	11 (9.5)	6 (8.6)
Smokers	119 (28.3)	28 (23.5)	13 (29.5)	17 (23.9)	36 (31)	25 (35.7)
Hospitalized	226 (53.8)	80 (67.2)	31 (70.5)	45 (63.4)	46 (39.7)	24 (34.3)
Duration (N)
15 to 21 days	19 (4.5)	2 (1.7)	10 (22.7)	3 (4.2)	3 (2.6)	1 (1.4)
≥ 21 days to 3 months	192 (45.7)	69 (58)	21 (47.7)	30 (42.3)	47 (40.5)	25 (35.7)
≥ 3 months to 12 months	124 (29.5)	39 (32.8)	12 (27.3)	21 (29.6)	32 (27.6)	20 (28.6)
≥ 1 year	85 (20.2)	9 (7.6)	1 (2.3)	17 (23.9)	34 (29.3)	24 (34.3)
Fever (N)	87 (20.9)	26 (24.8)	22 (51.2)	28 (39.4)	7 (6)	4 (5.7)
General state impairment (N)	248 (59)	98 (82.4)	33 (75)	51 (71.8)	39 (33.6)	27 (38.6)
Symptoms’ occurrence (N)
Night only	375 (89.3)	106 (89.1)	40 (90.1)	70 (98.6)	97 (83.6)	62 (88.6)
Night and day	42 (10)	12 (10.1)	4 (9.1)	19 (26.8)	1 (0.9)	6 (8.6)
Day only	3 (0.7)	1 (0.8)	0	0	0	2 (2.9)
Laboratory characteristics
CRP (mg/l)	8.2 (1.3–55.6)	26 (4.9–85.2)	44.1 (6.1–86.3)	14.9 (1.3–72.4)	2.2 (0.7–8.2)	1.2 (0.7–2.2)
LDH (UI/l)	235 (187–313)	261 (206–354)	235 (170–247)	235 (191–266)	223 (180–260)	183 (159–240)
WBC^d (10^9 cells/l)	8 (6–10.8)	9.1 (7–13.6)	7.9 (5.8–10.5)	8.2 (5.9–11.1)	7.4 (6–8.8)	6.6 (4.8–8.4)
Lymphocytes (10^9 cells/l)	1.7 (1.2–2.3)	1.5 (0.9–2.2)	1.6 (1.1–2.2)	1.8 (1.2–2.3)	2 (1.5–2.4)	1.9 (1.4–2.6)
Neutrophils (10^9 cells/l)	5 (3.3–7.2)	5.7 (3.7–8.2)	5.3 (3.3–7.1)	5.2 (3.1–8)	4.5 (3.3–6)	3.9 (2.8–5.2)
Haemoglobin (g/dl)	12.9 (11.4–13.9)	11.8 (10.7–13.2)	12.8 (11.8–13.5)	12.4 (11.3–13.9)	13.6 (12.6–14.4)	13.7 (12.3–15.1)

Data are N (%) or median (± IQR).

^aAmong the female population. ^bImmunodeficiency. ^cSolid organ transplant. ^dWhite blood cells.

Table 4. Diagnostic performance of clinical and biological parameters.

Parameter	Cut-point	PPV	NPV	Sensitivity (95% CI)	Specificity (95% CI)	AUC (95% CI)	Accuracy
In favour of malignancy, infection, and other inflammatory aetiologies (vs others)
Fever		0.87	0.53	33	94	–	0.6
Imp. Gen. condition		0.73	0.7	78	65	–	0.72
CRP	5.6 mg/l	0.86	0.57	71.1 (65–77.2)	76.5 (68.4–85)	79.2 (74.1–84.4)	0.73
LDH	226.5 UI/l	0.8	0.39	59.8 (51.2–68.5)	63.5 (50–75.1)	65.2 (56.5–73.8)	0.61
Neutrophils	5.3 × 10^9/l	0.77	0.43	51.2 (44.5–57.9)	70.4 (62–78.7)	61.1 (54.9–67.3)	0.58
In favour of other aetiologies and primary hyperhidrosis (vs malignancy and infection)
≥ 1 year duration		0.88	0.46	29	94	–	0.54

For continuous variables, optimal cut-points were established using a ROC curve. Sensitivity and specificity were assessed for different cut-points and the optimal cut-point was defined as the maximisation of Youden’s index. Accuracy is defined as: (True positive + True negative)/total of patients. PPV: Positive predictive value; NPV: Negative predictive value; AUC: Area under the curve; Imp. Gen. condition: Impaired general condition.

Figure 2. Diagnostic approach for recurrent sweating. CBC: Blood cell count; ANCA: antineutrophil cytoplasmic antibodies; TSH: thyroid-stimulating hormone: GH: growth hormone; IGF-1: Insulin-like growth factor 1; LH: Luteinizing hormone; FSH: follicle-stimulating hormone.

Table

Department	Total N (%)	Hospitalization N	Consultation N
Internal Medicine	82 (20)	48	34
Haematology	60 (14)	31	29
Pneumology	47 (11)	31	16
Infectious Diseases	46 (11)	32	14
Emergency	29 (7)	14	15
Rheumatology	25 (6)	21	4
Hepato-Gastro-Enterology	21 (5)	17	4
Nephrology & Transplantation	20 (5)	9	11
Endocrinology	19 (4)	7	12
Oncology	17 (4)	7	10
Neurology	16 (4)	8	8
Dermatology	16 (4)	8	8
Psychiatry	11 (2)	3	8
Gynaecology & Obstetrics	8 (2)	3	5
Digestive Surgery	7 (2)	4	3
Others*	36 (9)	–	–

*1%: Intensive Care, Cardiology, Neurosurgery, Orthopaedic surgery, Geriatrics, Nutrition; < 1%: ENT, Palliative care, Thoracic surgery, Nuclear Medicine, Physiatry.

Table

Aetiologies		N	N total (%)
Allergy	Grass pollen allergy	1	(0.2)
Cancer (non-haematologic)	Lung carcinoma	13	60 (14.3)
	Metastatic	7
	Renal carcinoma	6
	Metastatic	4
	Breast carcinoma	5
	Metastatic	3
	Cholangiocarcinoma	5
	Metastatic	5
	Pancreatic adenocarcinoma	5
	Metastatic	3
	Colorectal adenocarcinoma	4
	Metastatic	3
	Prostate adenocarcinoma	3
	Metastatic	1
	Hepatocellular carcinoma	2
	Kaposi’s sarcoma	2
	Leiomyosarcoma	2
	Melanoma	2
	Metastatic	2
	Non-seminomatous mediastinal germ cell tumour	2
	Adrenocortical carcinoma	1
	Cutaneous squamous-cell carcinoma	1
	Endometrial adenocarcinoma	1
	Larynx carcinoma	1
	Metastatic	1
	Oropharyngeal carcinoma	1
	Osteosarcoma	1
	Pheochromocytoma	1
	Metastasis (undetermined)	2
Cardiovascular	High blood pressure	4	9 (2.1)
	Vasovagal syncope	2
	Heart failure	1
	Leriche syndrome	1
	Orthostatic hypotension	1
Dermatologic	Bullous pemphigoid	1	2 (0.5)
	Chronic wound	1
Digestive	Crohn’s disease	5	10 (2.4)
	Ulcerative colitis	2
	Chronic inflammatory bowel disease (unspecified)	2
	Auto-immune hepatitis	1
Endocrine	Dysthyroidism	8	22 (5.2)
	Graves’ orbitopathy	1
	Pituitary adenoma	5
	Growth hormone	3
	IGF-1 + prolactin	1
	Prolactin	1
	Adrenal insufficiency	2
	Diabetes	2
	Ovarian insufficiency	2
	Adrenal adenoma	1
	Hypercalcemia	1
	Thymoma	1
ENT	Meniere’s disease	1	(0.2)
Environmental	Synthetic duvet	1	(0.2)
Gynaecologic	Endometriosis	1	2 (0.5)
	Uterine fibroid necrosis	1
Haematologic
Oncologic	Lymphoma	47	59 (14)
	Non-Hodgkin’s lymphoma	35
	Diffuse large B-cell lymphoma	16
	T-cell lymphoma	5
	Follicular lymphoma	4
	Mantle cell lymphoma	4
	Waldenström’s macroglobulinemia	3
	Marginal zone lymphoma	1
	Hodgkin’s lymphoma	11
	Chronic lymphocytic leukaemia	8
	Multiple myeloma	3
	Acute lymphoblastic leukaemia	1
Non-Oncologic	Myelofibrosis	3	12 (2.9)
	Histiocytosis	2
	AL Amyloidosis	1
	Essential thrombocythemia	1
	Hemophagocytic lymphohistiocytosis (no primary aetiological finding)	1
	Lymphoid hyperplasia	1
	Lymphangiomatosis	1
	Mastocytosis	1
	Myelodysplastic syndrome	1
Infectious diseases	Mycobacterium tuberculosis	13	44 (10.5)
	Pulmonary	10
	Lymphadenitis	5
	Pericarditis	1
	Spinal/bone	1
	Erythema nodosum	1
	Non-tuberculous mycobacteria	2
	HIV	3
	Pneumocystis jirovecii	1
	Mycobacterium intermediae	1
	Cytomegalovirus colitis	1
	Non-compliance with treatment	1
	Cytomegalovirus (acute infection)	2
	Cytomegalovirus (reactivation)	1
	Parvovirus B19 (acute infection)	1
	Helicobacter pylori gastritis	2
	Chronic osteoarticular infection	3
	Cutibacterium acnes	1
	Staphylococcus epidermidis	1
	Streptococcus mitis	1
	Male urinary tract infection	2
	Endocarditis	1
	Staphylococcus aureus	1
	Bartonella henselae (meningitis and hepatitis)	1
	Coxiella urnetiid / Q fever (acute infection)	1
	Plasmodium ovale	1
	Plasmodium vivax	1
	Post-streptococcal erythema nodosum	1
	Pneumonia	2
	Pulmonary abscess	1
	Cutaneous abscess	1
	Ovarian abscess (with peritonitis)	1
	Viral infection (undetermined)	1
	Post-viral syndrome	2
	Non documented infection	1
Medications	Corticosteroids	3	33 (7.9)
	Tacrolimus	1
	Mycophenolate mofetil	1
	Leflunomide	1
	Pembrolizumab	2
	Infliximab	1
	Adalimumab	1
	Ixekizumab	1
	Sunitinib	1
	Chemotherapy (unspecified)	1
	Cyproterone acetate	1
	Ethinylestradiol + Levonorgestrel	1
	Enantone + Abiraterone	1
	Exemestane	1
	Tamoxifen	1
	Letrozole	1
	Triptorelin	1
	Emtricitabine + Rilpivirine + Tenofovir alafenamide	1
	Morphine	2
	Pyridostigmine	1
	Venlafaxine	3
	Paroxetine	2
	Fluoxetine	1
	Etifoxine	1
	Paliperidone	1
	Lamotrigine + Lacosamide	1
Nutrition	Obesity	1	(0.2)
Neurologic	Peripheral neuropathy	4	13 (3.1)
	Neuropathic pain	3
	Dysautonomia	2
	Chronic polyradiculoneuritis	1
	Occipital neuralgia	1
	Small fibre neuropathy	1
	Tolosa-Hunt syndrome	1
Physiologic	Menopause/perimenopause	5	6 (1.4)
	Pregnancy	1
Psychiatric	Depressive and/or anxiety disorder	12	17 (4)
	Depressive disorder	4
	Anxiety disorder	10
	Withdrawal syndrome	3
	Burn-out	1
	Psychogenic non-epileptic seizure	1
Respiratory	Obstructive sleep apnoea	5	12 (2.9)
	Asthma	1
	Chronic obstructive pulmonary disease	1
	Cystic fibrosis	1
	Lymphocytic interstitial pneumonia	1
	Post-infectious bronchiolitis	1
	Post-radiotherapy pneumonia	1
	Pulmonary arterial hypertension	1
Rheumatologic	Peripheral spondyloarthropathy	3	19 (4.5)
	Fibromyalgia	2
	Rheumatoid arthritis	2
	RS3PE	2
	Arthritis (unspecified)	2
	Ankylosing spondylitis	1
	Avascular necrosis of the talus	1
	Chondrocalcinosis	1
	Complex regional pain syndrome	1
	Polymyalgia rheumatica	1
	Sciatica	1
	Seronegative arthritis	1
	Inflammatory arthromyalgia (unspecified)	1
Surgical complication	Post-operative pain	1	2 (0.5)
	Inflammatory periprosthetic lymphocele (breast)	1
Systemic	Vasculitis	6	24 (5.7)
(General,	Giant cell arteritis	1
Autoimmune or	Granulomatosis with polyangiitis	2
Autoinflammatory)	Microscopic polyangiitis	1
	Polyarteritis nodosa	1
	Not specified	1
	Lupus	3
	Sarcoidosis	3
	Autoinflammatory disease (unspecified)	3
	Still’s disease	2
	Familial Mediterranean fever	1
	Erythema nodosum	1
	IgA deficiency	1
	Non-allergic histaminic angioedema	1
	Polyserositis (unspecified)	1
	Polyadenitis (unspecified)	1
	Relapsing polychondritis	1
Primary hyperhidrosis / No aetiology		70	(16.7)

Table

Pharmacological class	Main reported drugs	Summary of product characteristics	French National PV database	Worldwide PV database (= Vigilyze)
Corticosteroids		No
Immunosuppressive therapy	Tacrolimus Mycophenolate mofetil Leflunomide	Yes (hyperhidrosis, common) No No	1 1 5	80 77 105
Anti-PD-1 Ab	Pembrolizumab	No	0	85
TNFα inhibitors	Adalimumab Infliximab	Yes (night sweats, uncommon) Yes (hyperhidrosis, common)	21 64	4012 1483
Anti-IL-17 Ab	Ixekizumab	No	1	113
Tyrosine kinase inhibitors	Sunitinib	No	0	181
Chemotherapy (unspecified)
Anti-androgen / GnRH agonists	Cyproterone acetate Leuproreline Triptorelin	No Yes (sweats, very common) Yes (hyperhidrosis, very common)	3 3 0	24 1283 105
Aromatase inhibitor	Letrozole Exemestane	Yes (very common) No	5 6	267 133
Estrogen receptor modulators	Tamoxifen	No	4	249
Hormonal contraception	Ethinylestradiol + Levonorgestrel	No	7	128
Antiretroviral	Emtricitabine + Rilpivirine + Ténofovir alafenamide	No	2	24
Morphine	Fentanyl	Yes (hyperhidrosis, common)	22	3166
Cholinesterase inhibitors	Pyridostigmine	Yes (not known)	6	41
SNRI	Venlafaxine	Yes (hyperhidrosis, including night sweats, very common)	78	2549
SSRI	Paroxetine Fluoxetine	Yes (hyperhidrosis, very rare) Yes (hyperhidrosis, common)	91 27	2958 1073
GABA-R modulators	Etifoxine	No	1	2
Antipsychotic	Paliperidone	No	4	126
Antiepileptic	Lamotrigine Lacosamide	No No	12 1	295 39

Values in bold represent drugs that were considered sufficiently reported in their respective database (N ≥ 5 for FPVD and N ≥ 100 for Vigilyze).

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Data availability statement

The data that support the findings of this study are available from Nived Collercandy, upon reasonable request. All authors had access to the data and a role in writing the manuscript.